RBCC

Full text data of LMNA

LMNA (LMN1) [Confidence: low (only semi-automatic identification from reviews)]
Prelamin-A/C; Lamin-A/C (70 kDa lamin; Renal carcinoma antigen NY-REN-32; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02545
ID LMNA_HUMAN Reviewed; 664 AA.
AC P02545; B4DI32; D3DVB0; D6RAQ3; E7EUI9; P02546; Q5I6Y4; Q5I6Y6;
read moreAC Q5TCJ2; Q5TCJ3; Q6UYC3; Q969I8; Q96JA2;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 20-MAR-1987, sequence version 1.
DT 22-JAN-2014, entry version 191.
DE RecName: Full=Prelamin-A/C;
DE Contains:
DE RecName: Full=Lamin-A/C;
DE AltName: Full=70 kDa lamin;
DE AltName: Full=Renal carcinoma antigen NY-REN-32;
DE Flags: Precursor;
GN Name=LMNA; Synonyms=LMN1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND C).
RX PubMed=3453101; DOI=10.1038/319463a0;
RA McKeon F.D., Kirschner M.W., Caput D.;
RT "Homologies in both primary and secondary structure between nuclear
RT envelope and intermediate filament proteins.";
RL Nature 319:463-468(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND C), AND PROTEIN SEQUENCE OF
RP 583-644.
RX PubMed=3462705; DOI=10.1073/pnas.83.17.6450;
RA Fisher D.Z., Chaudhary N., Blobel G.;
RT "cDNA sequencing of nuclear lamins A and C reveals primary and
RT secondary structural homology to intermediate filament proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:6450-6454(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), SUBCELLULAR LOCATION (ISOFORM
RP C), VARIANTS CMD1A TRP-190; GLY-192 AND SER-541, AND CHARACTERIZATION
RP OF VARIANTS CMD1A GLY-192 AND SER-541.
RX PubMed=16061563; DOI=10.1136/jmg.2004.023283;
RA Sylvius N., Bilinska Z.T., Veinot J.P., Fidzianska A., Bolongo P.M.,
RA Poon S., McKeown P., Davies R.A., Chan K.-L., Tang A.S.L., Dyack S.,
RA Grzybowski J., Ruzyllo W., McBride H., Tesson F.;
RT "In vivo and in vitro examination of the functional significances of
RT novel lamin gene mutations in heart failure patients.";
RL J. Med. Genet. 42:639-647(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6).
RA Csoka A.B.;
RT "The progerin allele of lamin A disrupts chromatin organization.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Corpus callosum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND C).
RC TISSUE=Kidney, Lung, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 12-25; 29-90; 102-117; 120-166; 172-189; 197-216;
RP 226-233; 241-260; 281-316; 320-329; 352-386; 440-453; 456-482;
RP 472-482; 516-542; 585-624 AND 628-644, PHOSPHORYLATION AT SER-22, AND
RP MASS SPECTROMETRY.
RC TISSUE=Ovarian carcinoma;
RA Bienvenut W.V., Lilla S., von Kriegsheim A., Lempens A., Kolch W.,
RA Norman J.C.;
RL Submitted (OCT-2009) to UniProtKB.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 375-664 (ISOFORM ADELTA10).
RC TISSUE=Colon;
RX PubMed=8621584; DOI=10.1074/jbc.271.16.9249;
RA Machiels B.M., Zorenc A.H., Endert J.M., Kuijpers H.J., van Eys G.J.,
RA Ramaekers F.C., Broers J.L.;
RT "An alternative splicing product of the lamin A/C gene lacks exon
RT 10.";
RL J. Biol. Chem. 271:9249-9253(1996).
RN [11]
RP PROTEOLYTIC CLEAVAGE, ISOPRENYLATION AT CYS-661, AND METHYLATION AT
RP CYS-661.
RX PubMed=8175923;
RA Sinensky M., Fantle K., Trujillo M., McLain T., Kupfer A., Dalton M.;
RT "The processing pathway of prelamin A.";
RL J. Cell Sci. 107:61-67(1994).
RN [12]
RP PROTEOLYTIC CLEAVAGE, ISOPRENYLATION AT CYS-661, AND METHYLATION AT
RP CYS-661.
RX PubMed=9030603; DOI=10.1074/jbc.272.8.5298;
RA Kilic F., Dalton M.B., Burrell S.K., Mayer J.P., Patterson S.D.,
RA Sinensky M.;
RT "In vitro assay and characterization of the farnesylation-dependent
RT prelamin A endoprotease.";
RL J. Biol. Chem. 272:5298-5304(1997).
RN [13]
RP IDENTIFICATION AS A RENAL CANCER ANTIGEN.
RC TISSUE=Renal cell carcinoma;
RX PubMed=10508479;
RX DOI=10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5;
RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H.,
RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T.,
RA Old L.J.;
RT "Antigens recognized by autologous antibody in patients with renal-
RT cell carcinoma.";
RL Int. J. Cancer 83:456-464(1999).
RN [14]
RP INTERACTION WITH NARF, AND MUTAGENESIS OF CYS-661.
RX PubMed=10514485; DOI=10.1074/jbc.274.42.30008;
RA Barton R.M., Worman H.J.;
RT "Prenylated prelamin A interacts with Narf, a novel nuclear protein.";
RL J. Biol. Chem. 274:30008-30018(1999).
RN [15]
RP INTERACTION WITH TMPO-ALPHA AND RB1.
RX PubMed=12475961; DOI=10.1091/mbc.E02-07-0450;
RA Markiewicz E., Dechat T., Foisner R., Quinlan R.A., Hutchison C.J.;
RT "Lamin A/C binding protein LAP2alpha is required for nuclear anchorage
RT of retinoblastoma protein.";
RL Mol. Biol. Cell 13:4401-4413(2002).
RN [16]
RP ALTERNATIVE SPLICING, INVOLVEMENT IN HGPS (ISOFORM 6), AND VARIANTS
RP HGPS LYS-145 AND SER-608.
RX PubMed=12714972; DOI=10.1038/nature01629;
RA Eriksson M., Brown W.T., Gordon L.B., Glynn M.W., Singer J., Scott L.,
RA Erdos M.R., Robbins C.M., Moses T.Y., Berglund P., Dutra A., Pak E.,
RA Durkin S., Csoka A.B., Boehnke M., Glover T.W., Collins F.S.;
RT "Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford
RT progeria syndrome.";
RL Nature 423:293-298(2003).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-277, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-19; SER-22; SER-390;
RP SER-392; SER-395; SER-628; SER-632 AND SER-636, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-628, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [20]
RP SUBCELLULAR LOCATION, SUMOYLATION AT LYS-201, MUTAGENESIS OF LYS-201,
RP AND CHARACTERIZATION OF VARIANTS CMD1A GLY-203 AND LYS-203.
RX PubMed=18606848; DOI=10.1083/jcb.200712124;
RA Zhang Y.Q., Sarge K.D.;
RT "Sumoylation regulates lamin A function and is lost in lamin A mutants
RT associated with familial cardiomyopathies.";
RL J. Cell Biol. 182:35-39(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-628, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-632, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-12; SER-18; THR-19;
RP SER-22; SER-301; SER-390; SER-392; SER-395; SER-458; SER-628; SER-632;
RP SER-636 AND SER-652, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [25]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH EMD.
RX PubMed=19323649; DOI=10.1042/BC20080175;
RA Capanni C., Del Coco R., Mattioli E., Camozzi D., Columbaro M.,
RA Schena E., Merlini L., Squarzoni S., Maraldi N.M., Lattanzi G.;
RT "Emerin-prelamin A interplay in human fibroblasts.";
RL Biol. Cell 101:541-554(2009).
RN [26]
RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS FPLD2 CYS-439
RP AND TRP-482.
RX PubMed=19220582; DOI=10.1111/j.1582-4934.2009.00690.x;
RA Verstraeten V.L., Caputo S., van Steensel M.A., Duband-Goulet I.,
RA Zinn-Justin S., Kamps M., Kuijpers H.J., Ostlund C., Worman H.J.,
RA Briede J.J., Le Dour C., Marcelis C.L., van Geel M., Steijlen P.M.,
RA van den Wijngaard A., Ramaekers F.C., Broers J.L.;
RT "The R439C mutation in LMNA causes lamin oligomerization and
RT susceptibility to oxidative stress.";
RL J. Cell. Mol. Med. 13:959-971(2009).
RN [27]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-108; LYS-270; LYS-311 AND
RP LYS-450, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [28]
RP FUNCTION.
RX PubMed=20079404; DOI=10.1016/j.bbagen.2010.01.002;
RA De Vos W.H., Houben F., Hoebe R.A., Hennekam R., van Engelen B.,
RA Manders E.M., Ramaekers F.C., Broers J.L., Van Oostveldt P.;
RT "Increased plasticity of the nuclear envelope and hypermobility of
RT telomeres due to the loss of A-type lamins.";
RL Biochim. Biophys. Acta 1800:448-458(2010).
RN [29]
RP SUBCELLULAR LOCATION, AND VARIANTS CMD1A LEU-89; PRO-101; PRO-166;
RP GLN-190; LYS-203; SER-210; PRO-215; THR-318; HIS-388; CYS-399 AND
RP HIS-471.
RX PubMed=20160190; DOI=10.1161/CIRCGENETICS.109.905422;
RA Cowan J., Li D., Gonzalez-Quintana J., Morales A., Hershberger R.E.;
RT "Morphological analysis of 13 LMNA variants identified in a cohort of
RT 324 unrelated patients with idiopathic or familial dilated
RT cardiomyopathy.";
RL Circ. Cardiovasc. Genet. 3:6-14(2010).
RN [30]
RP FUNCTION, PROTEOLYTIC PROCESSING, AND TISSUE SPECIFICITY.
RX PubMed=20458013; DOI=10.1161/CIRCULATIONAHA.109.902056;
RA Ragnauth C.D., Warren D.T., Liu Y., McNair R., Tajsic T., Figg N.,
RA Shroff R., Skepper J., Shanahan C.M.;
RT "Prelamin A acts to accelerate smooth muscle cell senescence and is a
RT novel biomarker of human vascular aging.";
RL Circulation 121:2200-2210(2010).
RN [31]
RP INTERACTION WITH SUN1, CHARACTERIZATION OF VARIANTS EDMD2 PRO-527 AND
RP PRO-530, AND CHARACTERIZATION OF VARIANT HGPS SER-608.
RX PubMed=19933576; DOI=10.1074/jbc.M109.071910;
RA Haque F., Mazzeo D., Patel J.T., Smallwood D.T., Ellis J.A.,
RA Shanahan C.M., Shackleton S.;
RT "Mammalian SUN protein interaction networks at the inner nuclear
RT membrane and their role in laminopathy disease processes.";
RL J. Biol. Chem. 285:3487-3498(2010).
RN [32]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT THR-3; SER-12; THR-19; SER-22; SER-212; SER-277;
RP SER-301; SER-390; SER-392; SER-395; SER-404; SER-414; SER-431;
RP SER-458; SER-463; THR-505; SER-628; SER-632; SER-636 AND SER-652, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [33]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [34]
RP INTERACTION WITH MLIP.
RX PubMed=21498514; DOI=10.1074/jbc.M110.165548;
RA Ahmady E., Deeke S.A., Rabaa S., Kouri L., Kenney L., Stewart A.F.,
RA Burgon P.G.;
RT "Identification of a novel muscle enriched A-type Lamin interacting
RT protein (MLIP).";
RL J. Biol. Chem. 286:19702-19713(2011).
RN [35]
RP MUTAGENESIS OF ARG-644; LEU-647; LEU-648; ASN-650 AND CYS-661, AND
RP CHARACTERIZATION OF VARIANT HGPS CYS-644.
RX PubMed=22355414; DOI=10.1371/journal.pone.0032120;
RA Barrowman J., Hamblet C., Kane M.S., Michaelis S.;
RT "Requirements for efficient proteolytic cleavage of prelamin A by
RT ZMPSTE24.";
RL PLoS ONE 7:E32120-E32120(2012).
RN [36]
RP SUBCELLULAR LOCATION, DISEASE, AND VARIANT GLY-300.
RX PubMed=23666920; DOI=10.1002/ajmg.a.35971;
RA Kane M.S., Lindsay M.E., Judge D.P., Barrowman J., Ap Rhys C.,
RA Simonson L., Dietz H.C., Michaelis S.;
RT "LMNA-associated cardiocutaneous progeria: An inherited autosomal
RT dominant premature aging syndrome with late onset.";
RL Am. J. Med. Genet. A 161:1599-1611(2013).
RN [37]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH SUV39H1.
RX PubMed=23695662; DOI=10.1038/ncomms2885;
RA Liu B., Wang Z., Zhang L., Ghosh S., Zheng H., Zhou Z.;
RT "Depleting the methyltransferase Suv39h1 improves DNA repair and
RT extends lifespan in a progeria mouse model.";
RL Nat. Commun. 4:1868-1868(2013).
RN [38]
RP INTERACTION WITH DMPK.
RX PubMed=21949239; DOI=10.1074/jbc.M111.241455;
RA Harmon E.B., Harmon M.L., Larsen T.D., Yang J., Glasford J.W.,
RA Perryman M.B.;
RT "Myotonic dystrophy protein kinase is critical for nuclear envelope
RT integrity.";
RL J. Biol. Chem. 286:40296-40306(2011).
RN [39]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-390; SER-392; SER-404;
RP SER-414; SER-458 AND SER-636, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 435-552.
RX PubMed=11901143; DOI=10.1074/jbc.C200038200;
RA Dhe-Paganon S., Werner E.D., Chi Y.I., Shoelson S.E.;
RT "Structure of the globular tail of nuclear lamin.";
RL J. Biol. Chem. 277:17381-17384(2002).
RN [41]
RP STRUCTURE BY NMR OF 428-549.
RX PubMed=12057196; DOI=10.1016/S0969-2126(02)00777-3;
RA Krimm I., Ostlund C., Gilquin B., Couprie J., Hossenlopp P.,
RA Mornon J.-P., Bonne G., Courvalin J.-C., Worman H.J., Zinn-Justin S.;
RT "The Ig-like structure of the C-terminal domain of lamin A/C, mutated
RT in muscular dystrophies, cardiomyopathy, and partial lipodystrophy.";
RL Structure 10:811-823(2002).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 305-387.
RX PubMed=15476822; DOI=10.1016/j.jmb.2004.08.093;
RA Strelkov S.V., Schumacher J., Burkhard P., Aebi U., Herrmann H.;
RT "Crystal structure of the human lamin A coil 2B dimer: implications
RT for the head-to-tail association of nuclear lamins.";
RL J. Mol. Biol. 343:1067-1080(2004).
RN [43]
RP VARIANTS EDMD2 TRP-453; PRO-527 AND PRO-530.
RX PubMed=10080180; DOI=10.1038/6799;
RA Bonne G., Di Barletta M.R., Varnous S., Becane H.-M., Hammouda E.-H.,
RA Merlini L., Muntoni F., Greenberg C.R., Gary F., Urtizberea J.-A.,
RA Duboc D., Fardeau M., Toniolo D., Schwartz K.;
RT "Mutations in the gene encoding lamin A/C cause autosomal dominant
RT Emery-Dreifuss muscular dystrophy.";
RL Nat. Genet. 21:285-288(1999).
RN [44]
RP VARIANTS CMD1A GLY-60; ARG-85; LYS-195 AND GLY-203.
RX PubMed=10580070; DOI=10.1056/NEJM199912023412302;
RA Fatkin D., MacRae C., Sasaki T., Wolff M.R., Porcu M., Frenneaux M.,
RA Atherton J., Vidaillet H.J. Jr., Spudich S., De Girolami U.,
RA Seidman J.G., Seidman C.E.;
RT "Missense mutations in the rod domain of the lamin A/C gene as causes
RT of dilated cardiomyopathy and conduction-system disease.";
RL N. Engl. J. Med. 341:1715-1724(1999).
RN [45]
RP VARIANTS FPLD2 ASP-465; GLN-482; TRP-482 AND HIS-582.
RX PubMed=10739751; DOI=10.1086/302836;
RA Speckman R.A., Garg A., Du F., Bennett L., Veile R., Arioglu E.,
RA Taylor S.I., Lovett M., Bowcock A.M.;
RT "Mutational and haplotype analyses of families with familial partial
RT lipodystrophy (Dunnigan variety) reveal recurrent missense mutations
RT in the globular C-terminal domain of lamin A/C.";
RL Am. J. Hum. Genet. 66:1192-1198(2000).
RN [46]
RP ERRATUM.
RA Speckman R.A., Garg A., Du F., Bennett L., Veile R., Arioglu E.,
RA Taylor S.I., Lovett M., Bowcock A.M.;
RL Am. J. Hum. Genet. 67:775-775(2000).
RN [47]
RP VARIANTS EDMD2 TYR-222; GLN-249; GLN-336; TRP-453; THR-469; PRO-527
RP AND LYS-528.
RX PubMed=10739764; DOI=10.1086/302869;
RA Raffaele di Barletta M., Ricci E., Galluzzi G., Tonali P., Mora M.,
RA Morandi L., Romorini A., Voit T., Orstavik K.H., Merlini L.,
RA Trevisan C., Biancalana V., Housmanowa-Petrusewicz I., Bione S.,
RA Ricotti R., Schwartz K., Bonne G., Toniolo D.;
RT "Different mutations in the LMNA gene cause autosomal dominant and
RT autosomal recessive Emery-Dreifuss muscular dystrophy.";
RL Am. J. Hum. Genet. 66:1407-1412(2000).
RN [48]
RP VARIANTS EDMD2 CYS-45; PRO-50; SER-63; GLU-112 DEL; PRO-222; GLU-232;
RP GLN-249; LYS-261 DEL; PRO-294; LYS-358; LYS-371; LYS-386; TRP-453;
RP LYS-456; SER-520; PRO-527 AND LYS-528.
RX PubMed=10939567;
RX DOI=10.1002/1531-8249(200008)48:2<170::AID-ANA6>3.3.CO;2-A;
RA Bonne G., Mercuri E., Muchir A., Urtizberea A., Becane H.M., Recan D.,
RA Merlini L., Wehnert M., Boor R., Reuner U., Vorgerd M., Wicklein E.M.,
RA Eymard B., Duboc D., Penisson-Besnier I., Cuisset J.M., Ferrer X.,
RA Desguerre I., Lacombe D., Bushby K., Pollitt C., Toniolo D.,
RA Fardeau M., Schwartz K., Muntoni F.;
RT "Clinical and molecular genetic spectrum of autosomal dominant Emery-
RT Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.";
RL Ann. Neurol. 48:170-180(2000).
RN [49]
RP VARIANT FPLD2 GLN-482.
RX PubMed=10587585; DOI=10.1093/hmg/9.1.109;
RA Cao H., Hegele R.A.;
RT "Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-
RT type familial partial lipodystrophy.";
RL Hum. Mol. Genet. 9:109-112(2000).
RN [50]
RP VARIANTS LGMD1B LYS-208 DEL AND HIS-377.
RX PubMed=10814726; DOI=10.1093/hmg/9.9.1453;
RA Muchir A., Bonne G., van der Kooi A.J., van Meegen M., Baas F.,
RA Bolhuis P.A., de Visser M., Schwartz K.;
RT "Identification of mutations in the gene encoding lamins A/C in
RT autosomal dominant limb girdle muscular dystrophy with
RT atrioventricular conduction disturbances (LGMD1B).";
RL Hum. Mol. Genet. 9:1453-1459(2000).
RN [51]
RP VARIANTS FPLD2 LEU-482 AND TRP-482.
RX PubMed=10655060; DOI=10.1038/72807;
RA Shackleton S., Lloyd D.J., Jackson S.N.J., Evans R., Niermeijer M.F.,
RA Singh B.M., Schmidt H., Brabant G., Kumar S., Durrington P.N.,
RA Gregory S., O'Rahilly S., Trembath R.C.;
RT "LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.";
RL Nat. Genet. 24:153-156(2000).
RN [52]
RP VARIANTS EDMD2 PRO-150 AND LYS-261 DEL.
RX PubMed=10908904;
RA Felice K.J., Schwartz R.C., Brown C.A., Leicher C.R., Grunnet M.L.;
RT "Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod
RT domain of the lamin A/C gene.";
RL Neurology 55:275-280(2000).
RN [53]
RP VARIANTS EDMD2 PRO-25; THR-43; SER-50; PRO-133; 196-ARG--THR-199
RP DELINS SER; GLN-249; LYS-261 DEL; LYS-358; TRP-453; ILE-456; PRO-527
RP AND HIS-624.
RX PubMed=11503164; DOI=10.1002/ajmg.1463;
RA Brown C.A., Lanning R.W., McKinney K.Q., Salvino A.R., Cherniske E.,
RA Crowe C.A., Darras B.T., Gominak S., Greenberg C.R., Grosmann C.,
RA Heydemann P., Mendell J.R., Pober B.R., Sasaki T., Shapiro F.,
RA Simpson D.A., Suchowersky O., Spence J.E.;
RT "Novel and recurrent mutations in lamin A/C in patients with Emery-
RT Dreifuss muscular dystrophy.";
RL Am. J. Med. Genet. 102:359-367(2001).
RN [54]
RP VARIANT CMD1A LYS-203.
RX PubMed=11561226; DOI=10.1054/jcaf.2001.26339;
RA Jakobs P.M., Hanson E.L., Crispell K.A., Toy W., Keegan H.,
RA Schilling K., Icenogle T.B., Litt M., Hershberger R.E.;
RT "Novel lamin A/C mutations in two families with dilated cardiomyopathy
RT and conduction system disease.";
RL J. Card. Fail. 7:249-256(2001).
RN [55]
RP CHARACTERIZATION OF VARIANTS CMD1A GLY-60; ARG-85; LYS-195 AND
RP GLY-203, CHARACTERIZATION OF VARIANTS EDMD2 LYS-358; LYS-371; LYS-386;
RP TRP-453; SER-520; PRO-527; LYS-528 AND PRO-530, AND CHARACTERIZATION
RP OF VARIANTS FPLD2 GLN-482; TRP-482 AND ASN-486.
RX PubMed=11792809;
RA Oestlund C., Bonne G., Schwartz K., Worman H.J.;
RT "Properties of lamin A mutants found in Emery-Dreifuss muscular
RT dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy.";
RL J. Cell Sci. 114:4435-4445(2001).
RN [56]
RP VARIANT LGMD1B HIS-481.
RX PubMed=11525883; DOI=10.1016/S0960-8966(01)00207-3;
RA Kitaguchi T., Matsubara S., Sato M., Miyamoto K., Hirai S.,
RA Schwartz K., Bonne G.;
RT "A missense mutation in the exon 8 of lamin A/C gene in a Japanese
RT case of autosomal dominant limb-girdle muscular dystrophy and cardiac
RT conduction block.";
RL Neuromuscul. Disord. 11:542-546(2001).
RN [57]
RP VARIANT CMD1A PRO-215.
RX PubMed=12486434; DOI=10.1067/mhj.2002.126737;
RA Hershberger R.E., Hanson E.L., Jakobs P.M., Keegan H., Coates K.,
RA Bousman S., Litt M.;
RT "A novel lamin A/C mutation in a family with dilated cardiomyopathy,
RT prominent conduction system disease, and need for permanent pacemaker
RT implantation.";
RL Am. Heart J. 144:1081-1086(2002).
RN [58]
RP VARIANT CMT2B1 CYS-298.
RX PubMed=11799477; DOI=10.1086/339274;
RA De Sandre-Giovannoli A., Chaouch M., Kozlov S., Vallat J.-M.,
RA Tazir M., Kassouri N., Szepetowski P., Hammadouche T.,
RA Vandenberghe A., Stewart C.L., Grid D., Levy N.;
RT "Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope
RT proteins, cause autosomal recessive axonal neuropathy in human
RT (Charcot-Marie-Tooth disorder type 2) and mouse.";
RL Am. J. Hum. Genet. 70:726-736(2002).
RN [59]
RP ERRATUM.
RA De Sandre-Giovannoli A., Chaouch M., Kozlov S., Vallat J.-M.,
RA Tazir M., Kassouri N., Szepetowski P., Hammadouche T.,
RA Vandenberghe A., Stewart C.L., Grid D., Levy N.;
RL Am. J. Hum. Genet. 70:1075-1075(2002).
RN [60]
RP VARIANT MADA HIS-527.
RX PubMed=12075506; DOI=10.1086/341908;
RA Novelli G., Muchir A., Sangiuolo F., Helbling-Leclerc A.,
RA D'Apice M.R., Massart C., Capon F., Sbraccia P., Federici M.,
RA Lauro R., Tudisco C., Pallotta R., Scarano G., Dallapiccola B.,
RA Merlini L., Bonne G.;
RT "Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding
RT lamin A/C.";
RL Am. J. Hum. Genet. 71:426-431(2002).
RN [61]
RP VARIANTS FPLD2 TRP-28 AND GLY-62.
RX PubMed=12015247; DOI=10.1016/S0002-9343(02)01070-7;
RA Garg A., Speckman R.A., Bowcock A.M.;
RT "Multisystem dystrophy syndrome due to novel missense mutations in the
RT amino-terminal head and alpha-helical rod domains of the lamin A/C
RT gene.";
RL Am. J. Med. 112:549-555(2002).
RN [62]
RP VARIANTS CMD1A GLU-97; TRP-190 AND LYS-317.
RX PubMed=11897440; DOI=10.1016/S0735-1097(02)01724-2;
RA Arbustini E., Pilotto A., Repetto A., Grasso M., Negri A., Diegoli M.,
RA Campana C., Scelsi L., Baldini E., Gavazzi A., Tavazzi L.;
RT "Autosomal dominant dilated cardiomyopathy with atrioventricular
RT block: a lamin A/C defect-related disease.";
RL J. Am. Coll. Cardiol. 39:981-990(2002).
RN [63]
RP VARIANT EDMD2 GLN-249, AND VARIANT LGMD1B LEU-377.
RX PubMed=12032588; DOI=10.1007/s100380200029;
RA Ki C.-S., Hong J.S., Jeong G.-Y., Ahn K.J., Choi K.-M., Kim D.-K.,
RA Kim J.-W.;
RT "Identification of lamin A/C (LMNA) gene mutations in Korean patients
RT with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-
RT girdle muscular dystrophy 1B.";
RL J. Hum. Genet. 47:225-228(2002).
RN [64]
RP VARIANTS FPLD2 GLY-60 AND PRO-527.
RX PubMed=12196663;
RA van der Kooi A.J., Bonne G., Eymard B., Duboc D., Talim B.,
RA Van der Valk M., Reiss P., Richard P., Demay L., Merlini L.,
RA Schwartz K., Busch H.F.M., de Visser M.;
RT "Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and
RT muscular dystrophy.";
RL Neurology 59:620-623(2002).
RN [65]
RP VARIANT APICAL LEFT VENTRICULAR ANEURYSM CYS-541.
RX PubMed=14675861; DOI=10.1016/S1388-9842(03)00149-1;
RA Forissier J.-F., Bonne G., Bouchier C., Duboscq-Bidot L., Richard P.,
RA Wisnewski C., Briault S., Moraine C., Dubourg O., Schwartz K.,
RA Komajda M.;
RT "Apical left ventricular aneurysm without atrio-ventricular block due
RT to a lamin A/C gene mutation.";
RL Eur. J. Heart Fail. 5:821-825(2003).
RN [66]
RP VARIANT LGMD1B HIS-377.
RX PubMed=12673789; DOI=10.1002/humu.10170;
RA Charniot J.-C., Pascal C., Bouchier C., Sebillon P., Salama J.,
RA Duboscq-Bidot L., Peuchmaurd M., Desnos M., Artigou J.-Y., Komajda M.;
RT "Functional consequences of an LMNA mutation associated with a new
RT cardiac and non-cardiac phenotype.";
RL Hum. Mutat. 21:473-481(2003).
RN [67]
RP VARIANTS CMD1A LEU-89; HIS-377 AND LEU-573.
RX PubMed=12628721; DOI=10.1016/S0735-1097(02)02954-6;
RG Familial dilated cardiomyopathy registry research group;
RA Taylor M.R.G., Fain P.R., Sinagra G., Robinson M.L., Robertson A.D.,
RA Carniel E., Di Lenarda A., Bohlmeyer T.J., Ferguson D.A.,
RA Brodsky G.L., Boucek M.M., Lascor J., Moss A.C., Li W.-L.P.,
RA Stetler G.L., Muntoni F., Bristow M.R., Mestroni L.;
RT "Natural history of dilated cardiomyopathy due to lamin A/C gene
RT mutations.";
RL J. Am. Coll. Cardiol. 41:771-780(2003).
RN [68]
RP ERRATUM.
RG Familial dilated cardiomyopathy registry research group;
RA Taylor M.R.G., Fain P.R., Sinagra G., Robinson M.L., Robertson A.D.,
RA Carniel E., Di Lenarda A., Bohlmeyer T.J., Ferguson D.A.,
RA Brodsky G.L., Boucek M.M., Lascor J., Moss A.C., Li W.-L.P.,
RA Stetler G.L., Muntoni F., Bristow M.R., Mestroni L.;
RL J. Am. Coll. Cardiol. 42:590-590(2003).
RN [69]
RP VARIANT FPLD2 LEU-133.
RX PubMed=12629077; DOI=10.1210/jc.2002-021506;
RA Caux F., Dubosclard E., Lascols O., Buendia B., Chazouilleres O.,
RA Cohen A., Courvalin J.-C., Laroche L., Capeau J., Vigouroux C.,
RA Christin-Maitre S.;
RT "A new clinical condition linked to a novel mutation in lamins A and C
RT with generalized lipoatrophy, insulin-resistant diabetes, disseminated
RT leukomelanodermic papules, liver steatosis, and cardiomyopathy.";
RL J. Clin. Endocrinol. Metab. 88:1006-1013(2003).
RN [70]
RP VARIANTS HGPS CYS-471; CYS-527 AND SER-608.
RX PubMed=12768443; DOI=10.1007/s10038-003-0025-3;
RA Cao H., Hegele R.A.;
RT "LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not
RT in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090).";
RL J. Hum. Genet. 48:271-274(2003).
RN [71]
RP VARIANT CMD1A LYS-161.
RX PubMed=12920062; DOI=10.1136/jmg.40.8.560;
RA Sebillon P., Bouchier C., Bidot L.D., Bonne G., Ahamed K., Charron P.,
RA Drouin-Garraud V., Millaire A., Desrumeaux G., Benaiche A.,
RA Charniot J.-C., Schwartz K., Villard E., Komajda M.;
RT "Expanding the phenotype of LMNA mutations in dilated cardiomyopathy
RT and functional consequences of these mutations.";
RL J. Med. Genet. 40:560-567(2003).
RN [72]
RP VARIANTS EDMD2 GLY-25; LYS-32 DEL; VAL-35; GLY-65; GLU-112 DEL;
RP PRO-248; GLN-249; CYS-267; VAL-446; TRP-453; ARG-528 AND HIS-541, AND
RP VARIANT CMD1A CYS-435.
RX PubMed=14684700; DOI=10.1136/jmg.40.12.e132;
RA Vytopil M., Benedetti S., Ricci E., Galluzzi G., Dello Russo A.,
RA Merlini L., Boriani G., Gallina M., Morandi L., Politano L.,
RA Moggio M., Chiveri L., Hausmanova-Petrusewicz I., Ricotti R.,
RA Vohanka S., Toman J., Toniolo D.;
RT "Mutation analysis of the lamin A/C gene (LMNA) among patients with
RT different cardiomuscular phenotypes.";
RL J. Med. Genet. 40:E132-E132(2003).
RN [73]
RP VARIANT CMDHH PRO-57, AND VARIANT HGPS ARG-140.
RX PubMed=12927431; DOI=10.1016/S0140-6736(03)14069-X;
RA Chen L., Lee L., Kudlow B.A., Dos Santos H.G., Sletvold O.,
RA Shafeghati Y., Botha E.G., Garg A., Hanson N.B., Martin G.M.,
RA Mian I.S., Kennedy B.K., Oshima J.;
RT "LMNA mutations in atypical Werner's syndrome.";
RL Lancet 362:440-445(2003).
RN [74]
RP VARIANTS EDMD2 ASN-63; PRO-140; GLN-249; LEU-377; LYS-386 AND PRO-527.
RX PubMed=12649505; DOI=10.1161/01.STR.0000064322.47667.49;
RA Boriani G., Gallina M., Merlini L., Bonne G., Toniolo D., Amati S.,
RA Biffi M., Martignani C., Frabetti L., Bonvicini M., Rapezzi C.,
RA Branzi A.;
RT "Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker
RT implant, and heart failure in Emery-Dreifuss muscular dystrophy: a
RT long-term longitudinal study.";
RL Stroke 34:901-908(2003).
RN [75]
RP VARIANTS CMD1A TRP-190 AND LEU-349.
RX PubMed=15219508; DOI=10.1016/j.amjcard.2004.03.029;
RA Hermida-Prieto M., Monserrat L., Castro-Beiras A., Laredo R.,
RA Soler R., Peteiro J., Rodriguez E., Bouzas B., Alvarez N., Muniz J.,
RA Crespo-Leiro M.;
RT "Familial dilated cardiomyopathy and isolated left ventricular
RT noncompaction associated with lamin A/C gene mutations.";
RL Am. J. Cardiol. 94:50-54(2004).
RN [76]
RP VARIANT CMD1A PRO-143.
RX PubMed=15140538; DOI=10.1016/j.ehj.2004.01.020;
RA Kaerkkaeinen S., Helioe T., Miettinen R., Tuomainen P., Peltola P.,
RA Rummukainen J., Ylitalo K., Kaartinen M., Kuusisto J., Toivonen L.,
RA Nieminen M.S., Laakso M., Peuhkurinen K.;
RT "A novel mutation, Ser143Pro, in the lamin A/C gene is common in
RT Finnish patients with familial dilated cardiomyopathy.";
RL Eur. Heart J. 25:885-893(2004).
RN [77]
RP INVOLVEMENT IN LTSCS.
RX PubMed=15317753; DOI=10.1093/hmg/ddh265;
RA Navarro C.L., De Sandre-Giovannoli A., Bernard R., Boccaccio I.,
RA Boyer A., Genevieve D., Hadj-Rabia S., Gaudy-Marqueste C., Smitt H.S.,
RA Vabres P., Faivre L., Verloes A., Van Essen T., Flori E., Hennekam R.,
RA Beemer F.A., Laurent N., Le Merrer M., Cau P., Levy N.;
RT "Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization
RT and identify restrictive dermopathy as a lethal neonatal
RT laminopathy.";
RL Hum. Mol. Genet. 13:2493-2503(2004).
RN [78]
RP VARIANTS ILE-10; VAL-578 AND CYS-644.
RX PubMed=15060110; DOI=10.1136/jmg.2003.015651;
RA Csoka A.B., Cao H., Sammak P.J., Constantinescu D., Schatten G.P.,
RA Hegele R.A.;
RT "Novel lamin A/C gene (LMNA) mutations in atypical progeroid
RT syndromes.";
RL J. Med. Genet. 41:304-308(2004).
RN [79]
RP VARIANT HGPS ASN-542.
RX PubMed=15286156; DOI=10.1136/jmg.2004.019661;
RA Plasilova M., Chattopadhyay C., Pal P., Schaub N.A., Buechner S.A.,
RA Mueller H., Miny P., Ghosh A., Heinimann K.;
RT "Homozygous missense mutation in the lamin A/C gene causes autosomal
RT recessive Hutchinson-Gilford progeria syndrome.";
RL J. Med. Genet. 41:609-614(2004).
RN [80]
RP VARIANT CMT2 ASP-33, AND VARIANT EDMD2 GLY-33.
RX PubMed=14985400; DOI=10.1136/jmg.2003.013383;
RA Goizet C., Yaou R.B., Demay L., Richard P., Bouillot S., Rouanet M.,
RA Hermosilla E., Le Masson G., Lagueny A., Bonne G., Ferrer X.;
RT "A new mutation of the lamin A/C gene leading to autosomal dominant
RT axonal neuropathy, muscular dystrophy, cardiac disease, and
RT leuconychia.";
RL J. Med. Genet. 41:E29-E29(2004).
RN [81]
RP VARIANT HGPS PHE-143.
RX PubMed=15622532; DOI=10.1002/ana.20359;
RA Kirschner J., Brune T., Wehnert M., Denecke J., Wasner C., Feuer A.,
RA Marquardt T., Ketelsen U.-P., Wieacker P., Boennemann C.G.,
RA Korinthenberg R.;
RT "p.S143F mutation in lamin A/C: a new phenotype combining myopathy and
RT progeria.";
RL Ann. Neurol. 57:148-151(2005).
RN [82]
RP VARIANT CMDA1 ASN-260.
RX PubMed=16156025;
RA Arbustini Eloisa A.E., Pilotto A., Pasotti M., Grasso M., Diegoli M.,
RA Campana C., Gavazzi A., Alessandra R., Tavazzi L.;
RT "Gene symbol: LMNA. Disease: cardiomyopathy, dilated, with conduction
RT defect 1.";
RL Hum. Genet. 117:298-298(2005).
RN [83]
RP VARIANT MADA VAL-529.
RX PubMed=15998779; DOI=10.1210/jc.2004-2560;
RA Garg A., Cogulu O., Ozkinay F., Onay H., Agarwal A.K.;
RT "A novel homozygous Ala529Val LMNA mutation in Turkish patients with
RT mandibuloacral dysplasia.";
RL J. Clin. Endocrinol. Metab. 90:5259-5264(2005).
RN [84]
RP VARIANT LGMD1B HIS-377, AND VARIANTS EDMD2 ASN-63; PRO-140; GLN-190;
RP GLN-249 AND PRO-527.
RX PubMed=15744034; DOI=10.1136/jmg.2004.026112;
RA Cenni V., Sabatelli P., Mattioli E., Marmiroli S., Capanni C.,
RA Ognibene A., Squarzoni S., Maraldi N.M., Bonne G., Columbaro M.,
RA Merlini L., Lattanzi G.;
RT "Lamin A N-terminal phosphorylation is associated with myoblast
RT activation: impairment in Emery-Dreifuss muscular dystrophy.";
RL J. Med. Genet. 42:214-220(2005).
RN [85]
RP VARIANT MADA LEU-573.
RX PubMed=16278265; DOI=10.1210/jc.2005-1297;
RA Van Esch H., Agarwal A.K., Debeer P., Fryns J.-P., Garg A.;
RT "A homozygous mutation in the lamin A/C gene associated with a novel
RT syndrome of arthropathy, tendinous calcinosis, and progeroid
RT features.";
RL J. Clin. Endocrinol. Metab. 91:517-521(2006).
RN [86]
RP VARIANT CMDHH ARG-59.
RX PubMed=17150192; DOI=10.1016/j.bbrc.2006.11.070;
RA Nguyen D., Leistritz D.F., Turner L., MacGregor D., Ohson K.,
RA Dancey P., Martin G.M., Oshima J.;
RT "Collagen expression in fibroblasts with a novel LMNA mutation.";
RL Biochem. Biophys. Res. Commun. 352:603-608(2007).
RN [87]
RP VARIANTS FPLD2 ASN-230; CYS-399 AND LEU-573.
RX PubMed=17250669; DOI=10.1111/j.1399-0004.2007.00740.x;
RA Lanktree M., Cao H., Rabkin S.W., Hanna A., Hegele R.A.;
RT "Novel LMNA mutations seen in patients with familial partial
RT lipodystrophy subtype 2 (FPLD2; MIM 151660).";
RL Clin. Genet. 71:183-186(2007).
RN [88]
RP VARIANT LGMD1B HIS-377.
RX PubMed=17136397; DOI=10.1007/s10048-006-0070-0;
RA Rudnik-Schoeneborn S., Botzenhart E., Eggermann T., Senderek J.,
RA Schoser B.G.H., Schroeder R., Wehnert M., Wirth B., Zerres K.;
RT "Mutations of the LMNA gene can mimic autosomal dominant proximal
RT spinal muscular atrophy.";
RL Neurogenetics 8:137-142(2007).
RN [89]
RP VARIANTS MDCL SER-39; PRO-50; TRP-249; PRO-302; LYS-358; SER-380;
RP PRO-453; PRO-455 AND ASP-456.
RX PubMed=18551513; DOI=10.1002/ana.21417;
RA Quijano-Roy S., Mbieleu B., Bonnemann C.G., Jeannet P.Y., Colomer J.,
RA Clarke N.F., Cuisset J.M., Roper H., De Meirleir L., D'Amico A.,
RA Ben Yaou R., Nascimento A., Barois A., Demay L., Bertini E.,
RA Ferreiro A., Sewry C.A., Romero N.B., Ryan M., Muntoni F.,
RA Guicheney P., Richard P., Bonne G., Estournet B.;
RT "De novo LMNA mutations cause a new form of congenital muscular
RT dystrophy.";
RL Ann. Neurol. 64:177-186(2008).
RN [90]
RP INVOLVEMENT IN HHS-SLOVENIAN.
RX PubMed=18611980; DOI=10.1136/jmg.2008.060020;
RA Renou L., Stora S., Yaou R.B., Volk M., Sinkovec M., Demay L.,
RA Richard P., Peterlin B., Bonne G.;
RT "Heart-hand syndrome of Slovenian type: a new kind of laminopathy.";
RL J. Med. Genet. 45:666-671(2008).
RN [91]
RP VARIANT CMDHH ARG-59.
RX PubMed=19283854; DOI=10.1002/ajmg.a.32627;
RA McPherson E., Turner L., Zador I., Reynolds K., Macgregor D.,
RA Giampietro P.F.;
RT "Ovarian failure and dilated cardiomyopathy due to a novel lamin
RT mutation.";
RL Am. J. Med. Genet. A 149:567-572(2009).
RN [92]
RP VARIANTS CMD1A PHE-92; LYS-161; LYS-317 AND ARG-523.
RX PubMed=21846512; DOI=10.1016/j.ejmg.2011.07.005;
RA Millat G., Bouvagnet P., Chevalier P., Sebbag L., Dulac A.,
RA Dauphin C., Jouk P.S., Delrue M.A., Thambo J.B., Le Metayer P.,
RA Seronde M.F., Faivre L., Eicher J.C., Rousson R.;
RT "Clinical and mutational spectrum in a cohort of 105 unrelated
RT patients with dilated cardiomyopathy.";
RL Eur. J. Med. Genet. 54:E570-E575(2011).
RN [93]
RP VARIANT HGPS LYS-138.
RX PubMed=21791255; DOI=10.1016/j.ejmg.2011.06.012;
RA Gonzalez-Quereda L., Delgadillo V., Juan-Mateu J., Verdura E.,
RA Rodriguez M.J., Baiget M., Pineda M., Gallano P.;
RT "LMNA mutation in progeroid syndrome in association with strokes.";
RL Eur. J. Med. Genet. 54:E576-E579(2011).
RN [94]
RP VARIANTS EDMD2 SER-39; CYS-45; PRO-150; PRO-189; ARG-190 INS; LEU-206;
RP TRP-249; GLN-249; PRO-268; PRO-271; PRO-294; PRO-295; PRO-303; GLN-355
RP DEL; LYS-358; LYS-361; LYS-386; ASP-449; TRP-453; PRO-454; TYR-461;
RP ARG-467; PRO-527; LYS-528; ARG-528; SER-541; PRO-541; SER-602 AND
RP CYS-644, AND CHARACTERIZATION OF VARIANTS EDMD2 PRO-25; TRP-249;
RP ILE-456 AND PRO-541.
RX PubMed=20848652; DOI=10.1002/humu.21361;
RA Scharner J., Brown C.A., Bower M., Iannaccone S.T., Khatri I.A.,
RA Escolar D., Gordon E., Felice K., Crowe C.A., Grosmann C.,
RA Meriggioli M.N., Asamoah A., Gordon O., Gnocchi V.F., Ellis J.A.,
RA Mendell J.R., Zammit P.S.;
RT "Novel LMNA mutations in patients with Emery-Dreifuss muscular
RT dystrophy and functional characterization of four LMNA mutations.";
RL Hum. Mutat. 32:152-167(2011).
RN [95]
RP VARIANT EDMD3 GLN-225.
RX PubMed=22431096; DOI=10.1002/mus.22324;
RA Jimenez-Escrig A., Gobernado I., Garcia-Villanueva M.,
RA Sanchez-Herranz A.;
RT "Autosomal recessive Emery-Dreifuss muscular dystrophy caused by a
RT novel mutation (R225Q) in the lamin A/C gene identified by exome
RT sequencing.";
RL Muscle Nerve 45:605-610(2012).
CC -!- FUNCTION: Lamins are components of the nuclear lamina, a fibrous
CC layer on the nucleoplasmic side of the inner nuclear membrane,
CC which is thought to provide a framework for the nuclear envelope
CC and may also interact with chromatin. Lamin A and C are present in
CC equal amounts in the lamina of mammals. Plays an important role in
CC nuclear assembly, chromatin organization, nuclear membrane and
CC telomere dynamics. Required for normal development of peripheral
CC nervous system and skeletal muscle and for muscle satellite cell
CC proliferation. Required for osteoblastogenesis and bone formation.
CC Also prevents fat infiltration of muscle and bone marrow, helping
CC to maintain the volume and strength of skeletal muscle and bone.
CC -!- FUNCTION: Prelamin-A/C can accelerate smooth muscle cell
CC senescence. It acts to disrupt mitosis and induce DNA damage in
CC vascular smooth muscle cells (VSMCs), leading to mitotic failure,
CC genomic instability, and premature senescence.
CC -!- SUBUNIT: Homodimer of lamin A and lamin C. Interacts with lamin-
CC associated polypeptides IA, IB and TMPO-alpha, RB1 and with
CC emerin. Interacts with SREBF1, SREBF2, SUN2 and TMEM43 (By
CC similarity). Proteolytically processed isoform A interacts with
CC NARF. Interacts with SUN1. Prelamin-A/C interacts with EMD.
CC Interacts with MLIP; may regulate MLIP localization to the nucleus
CC envelope. Interacts with DMPK; may regulate nuclear envelope
CC stability. Interacts with SUV39H1; the interaction increases
CC stability of SUV39H1.
CC -!- INTERACTION:
CC P18054:ALOX12; NbExp=4; IntAct=EBI-351935, EBI-1633210;
CC Q71DI3:HIST2H3A; NbExp=6; IntAct=EBI-351935, EBI-750650;
CC Q96RG2:PASK; NbExp=2; IntAct=EBI-351935, EBI-1042651;
CC P10215:UL31 (xeno); NbExp=2; IntAct=EBI-351935, EBI-7183650;
CC P10218:UL34 (xeno); NbExp=2; IntAct=EBI-351935, EBI-7183680;
CC P63104:YWHAZ; NbExp=2; IntAct=EBI-351935, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus envelope. Nucleus lamina.
CC Nucleus, nucleoplasm. Note=Farnesylation of prelamin-A/C
CC facilitates nuclear envelope targeting and subsequent cleaveage by
CC ZMPSTE24/FACE1 to remove the farnesyl group produces mature lamin-
CC A/C, which can then be inserted into the nuclear lamina. EMD is
CC required for proper localization of non-farnesylated prelamin-A/C.
CC -!- SUBCELLULAR LOCATION: Isoform C: Nucleus speckle.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=A; Synonyms=Lamin A;
CC IsoId=P02545-1; Sequence=Displayed;
CC Name=C; Synonyms=Lamin C;
CC IsoId=P02545-2; Sequence=VSP_002469, VSP_002470;
CC Name=ADelta10; Synonyms=Lamin ADelta10;
CC IsoId=P02545-3; Sequence=VSP_002468;
CC Name=4;
CC IsoId=P02545-4; Sequence=VSP_045977, VSP_045978, VSP_045979;
CC Note=No experimental confirmation available. Ref.5 (BAG58344)
CC sequence is in conflict in position: 556:G->R;
CC Name=5;
CC IsoId=P02545-5; Sequence=VSP_053503, VSP_053504;
CC Note=No experimental confirmation available;
CC Name=6; Synonyms=Progerin;
CC IsoId=P02545-6; Sequence=VSP_053505;
CC Note=Disease-associated isoform. Polymorphism at codon 608
CC results in activation of a cryptic splice donor site within exon
CC 11, resulting in a truncated protein product that lacks the site
CC for endoproteolytic cleavage;
CC -!- TISSUE SPECIFICITY: In the arteries, prelamin-A/C accumulation is
CC not observed in young healthy vessels but is prevalent in medial
CC vascular smooth muscle cells (VSMCs) from aged individuals and in
CC atherosclerotic lesions, where it often colocalizes with senescent
CC and degenerate VSMCs. Prelamin-A/C expression increases with age
CC and disease. In normal aging, the accumulation of prelamin-A/C is
CC caused in part by the down-regulation of ZMPSTE24/FACE1 in
CC response to oxidative stress.
CC -!- PTM: Increased phosphorylation of the lamins occurs before
CC envelope disintegration and probably plays a role in regulating
CC lamin associations.
CC -!- PTM: Proteolytic cleavage of the C-terminal of 18 residues of
CC prelamin-A/C results in the production of lamin-A/C. The prelamin-
CC A/C maturation pathway includes farnesylation of CAAX motif,
CC ZMPSTE24/FACE1 mediated cleavage of the last three amino acids,
CC methylation of the C-terminal cysteine and endoproteolytic removal
CC of the last 15 C-terminal amino acids. Proteolytic cleavage
CC requires prior farnesylation and methylation, and absence of these
CC blocks cleavage.
CC -!- PTM: Sumoylation is necessary for the localization to the nuclear
CC envelope.
CC -!- PTM: Farnesylation of prelamin-A/C facilitates nuclear envelope
CC targeting.
CC -!- DISEASE: Emery-Dreifuss muscular dystrophy 2, autosomal dominant
CC (EDMD2) [MIM:181350]: A form of Emery-Dreifuss muscular dystrophy,
CC a degenerative myopathy characterized by weakness and atrophy of
CC muscle without involvement of the nervous system, early
CC contractures of the elbows, Achilles tendons and spine, and
CC cardiomyopathy associated with cardiac conduction defects.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Emery-Dreifuss muscular dystrophy 3, autosomal recessive
CC (EDMD3) [MIM:181350]: A form of Emery-Dreifuss muscular dystrophy,
CC a degenerative myopathy characterized by weakness and atrophy of
CC muscle without involvement of the nervous system, early
CC contractures of the elbows, Achilles tendons and spine, and
CC cardiomyopathy associated with cardiac conduction defects.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Cardiomyopathy, dilated 1A (CMD1A) [MIM:115200]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Lipodystrophy, familial partial, 2 (FPLD2) [MIM:151660]:
CC A disorder characterized by the loss of subcutaneous adipose
CC tissue in the lower parts of the body (limbs, buttocks, trunk). It
CC is accompanied by an accumulation of adipose tissue in the face
CC and neck causing a double chin, fat neck, or cushingoid
CC appearance. Adipose tissue may also accumulate in the axillae,
CC back, labia majora, and intraabdominal region. Affected patients
CC are insulin-resistant and may develop glucose intolerance and
CC diabetes mellitus after age 20 years, hypertriglyceridemia, and
CC low levels of high density lipoprotein cholesterol. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Limb-girdle muscular dystrophy 1B (LGMD1B) [MIM:159001]:
CC An autosomal dominant degenerative myopathy with age-related
CC atrioventricular cardiac conduction disturbances, dilated
CC cardiomyopathy, and the absence of early contractures.
CC Characterized by slowly progressive skeletal muscle weakness of
CC the hip and shoulder girdles. Muscle biopsy shows mild dystrophic
CC changes. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2B1 (CMT2B1) [MIM:605588]: A
CC recessive axonal form of Charcot-Marie-Tooth disease, a disorder
CC of the peripheral nervous system, characterized by progressive
CC weakness and atrophy, initially of the peroneal muscles and later
CC of the distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited)
CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of
CC the CMT2 group are characterized by signs of axonal degeneration
CC in the absence of obvious myelin alterations, normal or slightly
CC reduced nerve conduction velocities, and progressive distal muscle
CC weakness and atrophy. Nerve conduction velocities are normal or
CC slightly reduced. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hutchinson-Gilford progeria syndrome (HGPS) [MIM:176670]:
CC Rare genetic disorder characterized by features reminiscent of
CC marked premature aging. Note=The disease is caused by mutations
CC affecting the gene represented in this entry. HGPS is caused by
CC the toxic accumulation of a truncated form of lamin-A/C. This
CC mutant protein, called progerin (isoform 6), acts to deregulate
CC mitosis and DNA damage signaling, leading to premature cell death
CC and senescence. The mutant form is mainly generated by a silent or
CC missense mutation at codon 608 of prelamin A that causes
CC activation of a cryptic splice donor site, resulting in production
CC of isoform 6 with a deletion of 50 amino acids near the C
CC terminus. Progerin lacks the conserved ZMPSTE24/FACE1 cleavage
CC site and therefore remains permanently farnesylated. Thus,
CC although it can enter the nucleus and associate with the nuclear
CC envelope, it cannot incorporate normally into the nuclear lamina
CC (PubMed:12714972).
CC -!- DISEASE: Cardiomyopathy, dilated, with hypergonadotropic
CC hypogonadism (CMDHH) [MIM:212112]: A disorder characterized by the
CC association of genital anomalies, hypergonadotropic hypogonadism
CC and dilated cardiomyopathy. Patients can present other variable
CC clinical manifestations including mental retardation, skeletal
CC anomalies, scleroderma-like skin, graying and thinning of hair,
CC osteoporosis. Dilated cardiomyopathy is characterized by
CC ventricular dilation and impaired systolic function, resulting in
CC congestive heart failure and arrhythmia. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Mandibuloacral dysplasia with type A lipodystrophy (MADA)
CC [MIM:248370]: A disorder characterized by mandibular and
CC clavicular hypoplasia, acroosteolysis, delayed closure of the
CC cranial suture, progeroid appearance, partial alopecia, soft
CC tissue calcinosis, joint contractures, and partial lipodystrophy
CC with loss of subcutaneous fat from the extremities. Adipose tissue
CC in the face, neck and trunk is normal or increased. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Lethal tight skin contracture syndrome (LTSCS)
CC [MIM:275210]: Rare disorder mainly characterized by intrauterine
CC growth retardation, tight and rigid skin with erosions, prominent
CC superficial vasculature and epidermal hyperkeratosis, facial
CC features (small mouth, small pinched nose and micrognathia),
CC sparse/absent eyelashes and eyebrows, mineralization defects of
CC the skull, thin dysplastic clavicles, pulmonary hypoplasia,
CC multiple joint contractures and an early neonatal lethal course.
CC Liveborn children usually die within the first week of life. The
CC overall prevalence of consanguineous cases suggested an autosomal
CC recessive inheritance. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Heart-hand syndrome Slovenian type (HHS-Slovenian)
CC [MIM:610140]: Heart-hand syndrome (HHS) is a clinically and
CC genetically heterogeneous disorder characterized by the co-
CC occurrence of a congenital cardiac disease and limb malformations.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Muscular dystrophy congenital LMNA-related (MDCL)
CC [MIM:613205]: A form of congenital muscular dystrophy. Patients
CC present at birth, or within the first few months of life, with
CC hypotonia, muscle weakness and often with joint contractures.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Note=Defects in LMNA may cause a late-onset
CC cardiocutaneous progeria syndrome characterized by cutaneous
CC manifestations of aging appearing in the third decade of life,
CC cardiac valve calcification and dysfunction, prominent
CC atherosclerosis, and cardiomyopathy, leading to death on average
CC in the fourth decade.
CC -!- MISCELLANEOUS: There are three types of lamins in human cells: A,
CC B, and C.
CC -!- MISCELLANEOUS: The structural integrity of the lamina is strictly
CC controlled by the cell cycle, as seen by the disintegration and
CC formation of the nuclear envelope in prophase and telophase,
CC respectively.
CC -!- SIMILARITY: Belongs to the intermediate filament family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA27173.1; Type=Frameshift; Positions=582;
CC -!- WEB RESOURCE: Name=Human Intermediate Filament Mutation Database;
CC URL="http://www.interfil.org";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/LMNA";
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DR EMBL; X03444; CAA27173.1; ALT_FRAME; mRNA.
DR EMBL; X03445; CAA27174.1; -; mRNA.
DR EMBL; M13451; AAA36164.1; -; mRNA.
DR EMBL; M13452; AAA36160.1; -; mRNA.
DR EMBL; AY847597; AAW32540.1; -; mRNA.
DR EMBL; AY847595; AAW32538.1; -; mRNA.
DR EMBL; AY357727; AAR29466.1; -; mRNA.
DR EMBL; AK295390; BAG58344.1; -; mRNA.
DR EMBL; AL135927; CAI15521.1; -; Genomic_DNA.
DR EMBL; AL135927; CAI15522.1; -; Genomic_DNA.
DR EMBL; AL355388; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL356734; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471121; EAW52997.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW52999.1; -; Genomic_DNA.
DR EMBL; BC000511; AAH00511.1; -; mRNA.
DR EMBL; BC003162; AAH03162.1; -; mRNA.
DR EMBL; BC014507; AAH14507.1; -; mRNA.
DR EMBL; AF381029; AAK59326.1; -; mRNA.
DR PIR; A02961; VEHULA.
DR PIR; A02962; VEHULC.
DR RefSeq; NP_001244303.1; NM_001257374.2.
DR RefSeq; NP_001269553.1; NM_001282624.1.
DR RefSeq; NP_001269554.1; NM_001282625.1.
DR RefSeq; NP_001269555.1; NM_001282626.1.
DR RefSeq; NP_005563.1; NM_005572.3.
DR RefSeq; NP_733821.1; NM_170707.3.
DR RefSeq; NP_733822.1; NM_170708.3.
DR UniGene; Hs.594444; -.
DR PDB; 1IFR; X-ray; 1.40 A; A=435-552.
DR PDB; 1IVT; NMR; -; A=428-549.
DR PDB; 1X8Y; X-ray; 2.20 A; A=305-387.
DR PDB; 2XV5; X-ray; 2.40 A; A/B=328-398.
DR PDB; 2YPT; X-ray; 3.80 A; F/G/H/I=661-664.
DR PDB; 3GEF; X-ray; 1.50 A; A/B/C/D=436-552.
DR PDB; 3V4Q; X-ray; 3.06 A; A=313-386.
DR PDB; 3V4W; X-ray; 3.70 A; A=313-386.
DR PDB; 3V5B; X-ray; 3.00 A; A=313-386.
DR PDBsum; 1IFR; -.
DR PDBsum; 1IVT; -.
DR PDBsum; 1X8Y; -.
DR PDBsum; 2XV5; -.
DR PDBsum; 2YPT; -.
DR PDBsum; 3GEF; -.
DR PDBsum; 3V4Q; -.
DR PDBsum; 3V4W; -.
DR PDBsum; 3V5B; -.
DR DisProt; DP00716; -.
DR ProteinModelPortal; P02545; -.
DR SMR; P02545; 27-119, 313-386, 435-544.
DR DIP; DIP-32948N; -.
DR DIP; DIP-58162N; -.
DR IntAct; P02545; 44.
DR MINT; MINT-5003995; -.
DR STRING; 9606.ENSP00000357283; -.
DR ChEMBL; CHEMBL1293235; -.
DR PhosphoSite; P02545; -.
DR DMDM; 125962; -.
DR REPRODUCTION-2DPAGE; IPI00021405; -.
DR REPRODUCTION-2DPAGE; IPI00216952; -.
DR REPRODUCTION-2DPAGE; P02545; -.
DR SWISS-2DPAGE; P02545; -.
DR PaxDb; P02545; -.
DR PeptideAtlas; P02545; -.
DR PRIDE; P02545; -.
DR DNASU; 4000; -.
DR Ensembl; ENST00000347559; ENSP00000292304; ENSG00000160789.
DR Ensembl; ENST00000361308; ENSP00000355292; ENSG00000160789.
DR Ensembl; ENST00000368300; ENSP00000357283; ENSG00000160789.
DR Ensembl; ENST00000368301; ENSP00000357284; ENSG00000160789.
DR Ensembl; ENST00000448611; ENSP00000395597; ENSG00000160789.
DR Ensembl; ENST00000508500; ENSP00000424977; ENSG00000160789.
DR GeneID; 4000; -.
DR KEGG; hsa:4000; -.
DR UCSC; uc010pgz.2; human.
DR CTD; 4000; -.
DR GeneCards; GC01P156053; -.
DR HGNC; HGNC:6636; LMNA.
DR HPA; CAB004022; -.
DR HPA; HPA006660; -.
DR MIM; 115200; phenotype.
DR MIM; 150330; gene.
DR MIM; 151660; phenotype.
DR MIM; 159001; phenotype.
DR MIM; 176670; phenotype.
DR MIM; 181350; phenotype.
DR MIM; 212112; phenotype.
DR MIM; 248370; phenotype.
DR MIM; 275210; phenotype.
DR MIM; 605588; phenotype.
DR MIM; 610140; phenotype.
DR MIM; 613205; phenotype.
DR neXtProt; NX_P02545; -.
DR Orphanet; 79474; Atypical Werner syndrome.
DR Orphanet; 280365; Autosomal codominant severe lipodystrophic laminopathy.
DR Orphanet; 98853; Autosomal dominant Emery-Dreifuss muscular dystrophy.
DR Orphanet; 264; Autosomal dominant limb-girdle muscular dystrophy type 1B.
DR Orphanet; 98855; Autosomal recessive Emery-Dreifuss muscular dystrophy.
DR Orphanet; 98856; Charcot-Marie-Tooth disease type 2B1.
DR Orphanet; 157973; Congenital muscular dystrophy due to LMNA mutation.
DR Orphanet; 2229; Dilated cardiomyopathy - hypergonadotropic hypogonadism.
DR Orphanet; 300751; Familial dilated cardiomyopathy with conduction defect due to LMNA mutation.
DR Orphanet; 293899; Familial isolated arrhythmogenic ventricular dysplasia, biventricular form.
DR Orphanet; 293888; Familial isolated arrhythmogenic ventricular dysplasia, left dominant form.
DR Orphanet; 293910; Familial isolated arrhythmogenic ventricular dysplasia, right dominant form.
DR Orphanet; 2348; Familial partial lipodystrophy, Dunnigan type.
DR Orphanet; 79084; Familial partial lipodystrophy, Kobberling type.
DR Orphanet; 168796; Heart-hand syndrome, Slovenian type.
DR Orphanet; 740; Hutchinson-Gilford progeria syndrome.
DR Orphanet; 137871; Laminopathy type Decaudain-Vigouroux.
DR Orphanet; 54260; Left ventricular noncompaction.
DR Orphanet; 1662; Lethal restrictive dermopathy.
DR Orphanet; 90153; Mandibuloacral dysplasia with type A lipodystrophy.
DR Orphanet; 99706; Progeria-associated arthropathy.
DR PharmGKB; PA231; -.
DR eggNOG; NOG325506; -.
DR HOVERGEN; HBG013015; -.
DR InParanoid; P02545; -.
DR KO; K12641; -.
DR OMA; HCSGSGD; -.
DR OrthoDB; EOG7MD4PW; -.
DR PhylomeDB; P02545; -.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; LMNA; human.
DR EvolutionaryTrace; P02545; -.
DR GeneWiki; LMNA; -.
DR GenomeRNAi; 4000; -.
DR NextBio; 15692; -.
DR PMAP-CutDB; P02545; -.
DR PRO; PR:P02545; -.
DR ArrayExpress; P02545; -.
DR Bgee; P02545; -.
DR CleanEx; HS_LMNA; -.
DR Genevestigator; P02545; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005882; C:intermediate filament; IEA:UniProtKB-KW.
DR GO; GO:0005638; C:lamin filament; IEA:Ensembl.
DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:UniProtKB.
DR GO; GO:0030951; P:establishment or maintenance of microtubule cytoskeleton polarity; ISS:BHF-UCL.
DR GO; GO:0007077; P:mitotic nuclear envelope disassembly; TAS:Reactome.
DR GO; GO:0007084; P:mitotic nuclear envelope reassembly; TAS:Reactome.
DR GO; GO:0007517; P:muscle organ development; IMP:UniProtKB.
DR GO; GO:0090343; P:positive regulation of cell aging; IDA:UniProtKB.
DR GO; GO:0034504; P:protein localization to nucleus; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0030334; P:regulation of cell migration; ISS:BHF-UCL.
DR GO; GO:0035105; P:sterol regulatory element binding protein import into nucleus; IEA:Ensembl.
DR GO; GO:0055015; P:ventricular cardiac muscle cell development; IEA:Ensembl.
DR InterPro; IPR001664; IF.
DR InterPro; IPR018039; Intermediate_filament_CS.
DR InterPro; IPR001322; Lamin_tail_dom.
DR PANTHER; PTHR23239; PTHR23239; 1.
DR Pfam; PF00038; Filament; 1.
DR Pfam; PF00932; LTD; 1.
DR PROSITE; PS00226; IF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cardiomyopathy;
KW Charcot-Marie-Tooth disease; Coiled coil; Complete proteome;
KW Congenital muscular dystrophy; Direct protein sequencing;
KW Disease mutation; Emery-Dreifuss muscular dystrophy;
KW Intermediate filament; Isopeptide bond;
KW Limb-girdle muscular dystrophy; Lipoprotein; Methylation; Neuropathy;
KW Nucleus; Phosphoprotein; Prenylation; Reference proteome;
KW Ubl conjugation.
FT CHAIN 1 661 Prelamin-A/C.
FT /FTId=PRO_0000398835.
FT CHAIN 1 646 Lamin-A/C.
FT /FTId=PRO_0000063810.
FT PROPEP 647 661 Removed in Lamin-A/C form.
FT /FTId=PRO_0000398836.
FT PROPEP 662 664 Removed in Prelamin-A/C form and in
FT Lamin-A/C form.
FT /FTId=PRO_0000403442.
FT REGION 1 130 Interaction with MLIP.
FT REGION 1 33 Head.
FT REGION 34 383 Rod.
FT REGION 34 70 Coil 1A.
FT REGION 71 80 Linker 1.
FT REGION 81 218 Coil 1B.
FT REGION 219 242 Linker 2.
FT REGION 243 383 Coil 2.
FT REGION 384 664 Tail.
FT MOTIF 417 422 Nuclear localization signal (Potential).
FT SITE 266 266 Heptad change of phase.
FT SITE 325 325 Stutter (By similarity).
FT SITE 330 330 Heptad change of phase.
FT SITE 646 647 Cleavage; by endoprotease.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 3 3 Phosphothreonine.
FT MOD_RES 12 12 Phosphoserine.
FT MOD_RES 18 18 Phosphoserine.
FT MOD_RES 19 19 Phosphothreonine.
FT MOD_RES 22 22 Phosphoserine.
FT MOD_RES 108 108 N6-acetyllysine.
FT MOD_RES 212 212 Phosphoserine.
FT MOD_RES 270 270 N6-acetyllysine.
FT MOD_RES 277 277 Phosphoserine.
FT MOD_RES 301 301 Phosphoserine.
FT MOD_RES 311 311 N6-acetyllysine.
FT MOD_RES 390 390 Phosphoserine.
FT MOD_RES 392 392 Phosphoserine.
FT MOD_RES 395 395 Phosphoserine.
FT MOD_RES 404 404 Phosphoserine.
FT MOD_RES 407 407 Phosphoserine (By similarity).
FT MOD_RES 414 414 Phosphoserine.
FT MOD_RES 431 431 Phosphoserine.
FT MOD_RES 450 450 N6-acetyllysine.
FT MOD_RES 458 458 Phosphoserine.
FT MOD_RES 463 463 Phosphoserine.
FT MOD_RES 496 496 Phosphothreonine (By similarity).
FT MOD_RES 505 505 Phosphothreonine.
FT MOD_RES 510 510 Phosphothreonine (By similarity).
FT MOD_RES 546 546 Phosphoserine (By similarity).
FT MOD_RES 628 628 Phosphoserine.
FT MOD_RES 632 632 Phosphoserine.
FT MOD_RES 636 636 Phosphoserine.
FT MOD_RES 652 652 Phosphoserine.
FT MOD_RES 661 661 Cysteine methyl ester.
FT LIPID 661 661 S-farnesyl cysteine.
FT CROSSLNK 201 201 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO).
FT VAR_SEQ 1 99 Missing (in isoform 5).
FT /FTId=VSP_053503.
FT VAR_SEQ 1 7 METPSQR -> MGNSEGC (in isoform 4).
FT /FTId=VSP_045977.
FT VAR_SEQ 8 119 Missing (in isoform 4).
FT /FTId=VSP_045978.
FT VAR_SEQ 100 119 ARLQLELSKVREEFKELKAR -> MDLEAWDPHLEPDAEAM
FT VDG (in isoform 5).
FT /FTId=VSP_053504.
FT VAR_SEQ 537 566 Missing (in isoform ADelta10).
FT /FTId=VSP_002468.
FT VAR_SEQ 567 572 GSHCSS -> VSGSRR (in isoform C).
FT /FTId=VSP_002469.
FT VAR_SEQ 573 664 Missing (in isoform C).
FT /FTId=VSP_002470.
FT VAR_SEQ 607 656 Missing (in isoform 6).
FT /FTId=VSP_053505.
FT VAR_SEQ 664 664 M -> IQEMGMRWEVEEGRRKVSLSCLP (in isoform
FT 4).
FT /FTId=VSP_045979.
FT VARIANT 10 10 T -> I (in an atypical progeroid patient;
FT diagnosed as Seip syndrome;
FT dbSNP:rs57077886).
FT /FTId=VAR_039745.
FT VARIANT 25 25 R -> G (in EDMD2; dbSNP:rs58327533).
FT /FTId=VAR_039746.
FT VARIANT 25 25 R -> P (in EDMD2; mis-localized in the
FT nucleus; causes nuclear deformations and
FT LMNB1 redistribution; dbSNP:rs61578124).
FT /FTId=VAR_039747.
FT VARIANT 28 28 R -> W (in FPLD2; dbSNP:rs59914820).
FT /FTId=VAR_039748.
FT VARIANT 32 32 Missing (in EDMD2).
FT /FTId=VAR_039749.
FT VARIANT 33 33 E -> D (in CMT2; autosomal dominant form;
FT dbSNP:rs57966821).
FT /FTId=VAR_039750.
FT VARIANT 33 33 E -> G (in EDMD2).
FT /FTId=VAR_039751.
FT VARIANT 35 35 L -> V (in EDMD2; dbSNP:rs56694480).
FT /FTId=VAR_039752.
FT VARIANT 39 39 N -> S (in MDCL and EDMD2).
FT /FTId=VAR_063588.
FT VARIANT 43 43 A -> T (in EDMD2; dbSNP:rs60446065).
FT /FTId=VAR_039753.
FT VARIANT 45 45 Y -> C (in EDMD2; dbSNP:rs58436778).
FT /FTId=VAR_009971.
FT VARIANT 50 50 R -> P (in EDMD2 and MDCL;
FT dbSNP:rs60695352).
FT /FTId=VAR_009972.
FT VARIANT 50 50 R -> S (in EDMD2; dbSNP:rs59931416).
FT /FTId=VAR_039754.
FT VARIANT 57 57 A -> P (in CMDHH; phenotype originally
FT designated as atypical Werner syndrome;
FT dbSNP:rs28928903).
FT /FTId=VAR_017656.
FT VARIANT 59 59 L -> R (in CMDHH).
FT /FTId=VAR_064055.
FT VARIANT 60 60 R -> G (in CMD1A and FPLD2; interacts
FT with itself and with wild-type LMNA and
FT LMNB1; no decrease in the stability
FT compared with wild-type;
FT dbSNP:rs28928900).
FT /FTId=VAR_034706.
FT VARIANT 62 62 R -> G (in FPLD2; dbSNP:rs56793579).
FT /FTId=VAR_039755.
FT VARIANT 63 63 I -> N (in EDMD2).
FT /FTId=VAR_039756.
FT VARIANT 63 63 I -> S (in EDMD2; dbSNP:rs57793737).
FT /FTId=VAR_009974.
FT VARIANT 65 65 E -> G (in EDMD2).
FT /FTId=VAR_039757.
FT VARIANT 85 85 L -> R (in CMD1A; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type; dbSNP:rs28933090).
FT /FTId=VAR_009975.
FT VARIANT 89 89 R -> L (in CMD1A; dramatically aberrant
FT localization with almost no nuclear rim
FT staining and formation of intranuclear
FT foci; dbSNP:rs59040894).
FT /FTId=VAR_039758.
FT VARIANT 92 92 L -> F (in CMD1A).
FT /FTId=VAR_067257.
FT VARIANT 97 97 K -> E (in CMD1A; dbSNP:rs59065411).
FT /FTId=VAR_039759.
FT VARIANT 101 101 R -> P (in CMD1A; dramatically aberrant
FT localization with almost no nuclear rim
FT staining and formation of intranuclear
FT foci).
FT /FTId=VAR_070174.
FT VARIANT 112 112 Missing (in EDMD2).
FT /FTId=VAR_009976.
FT VARIANT 133 133 R -> L (in FPLD2).
FT /FTId=VAR_016913.
FT VARIANT 133 133 R -> P (in EDMD2; dbSNP:rs60864230).
FT /FTId=VAR_017657.
FT VARIANT 138 138 E -> K (in HGPS; might be associated with
FT early and severe strokes).
FT /FTId=VAR_070175.
FT VARIANT 140 140 L -> P (in EDMD2).
FT /FTId=VAR_039760.
FT VARIANT 140 140 L -> R (in HGPS; phenotype originally
FT designated as atypical Werner syndrome;
FT dbSNP:rs60652225).
FT /FTId=VAR_017658.
FT VARIANT 143 143 S -> F (in HGPS; dbSNP:rs58912633).
FT /FTId=VAR_034707.
FT VARIANT 143 143 S -> P (in CMD1A; dbSNP:rs61661343).
FT /FTId=VAR_039761.
FT VARIANT 145 145 E -> K (in HGPS; atypical;
FT dbSNP:rs60310264).
FT /FTId=VAR_017659.
FT VARIANT 150 150 T -> P (in EDMD2; dbSNP:rs58917027).
FT /FTId=VAR_039762.
FT VARIANT 161 161 E -> K (in CMD1A; dbSNP:rs28933093).
FT /FTId=VAR_017660.
FT VARIANT 166 166 R -> P (in CMD1A; dramatically aberrant
FT localization with almost no nuclear rim
FT staining and formation of intranuclear
FT foci).
FT /FTId=VAR_070176.
FT VARIANT 189 189 R -> P (in EDMD2; found also in a patient
FT with limb-girdle muscular dystrophy;
FT sporadic).
FT /FTId=VAR_064962.
FT VARIANT 190 190 R -> Q (in EDMD2 and CMD1A; aberrant
FT localization with decreased nuclear rim
FT staining and increased formation of
FT intranuclear foci).
FT /FTId=VAR_039763.
FT VARIANT 190 190 R -> RR (in EDMD2).
FT /FTId=VAR_064963.
FT VARIANT 190 190 R -> W (in CMD1A; dbSNP:rs59026483).
FT /FTId=VAR_039764.
FT VARIANT 192 192 D -> G (in CMD1A; dramatically increases
FT the size of intranuclear speckles and
FT reduces their number; this phenotype is
FT only partially reversed by coexpression
FT of the G-192 mutation and wild-type
FT lamin-C; precludes insertion of lamin-C
FT into the nuclear envelope when co-
FT transfected with the G-192 LMNA; G-192
FT lamin-C expression totally disrupts the
FT SUMO1 pattern; dbSNP:rs57045855).
FT /FTId=VAR_039765.
FT VARIANT 195 195 N -> K (in CMD1A; dramatically aberrant
FT localization with decreased nuclear rim
FT staining and formation of intranuclear
FT foci; distribution of endogenous LMNA,
FT LMNB1 and LMNB2 are altered in cells
FT expressing this mutant; causes an
FT increased loss of endogenous EMD from the
FT nuclear envelope; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type; dbSNP:rs28933091).
FT /FTId=VAR_009977.
FT VARIANT 196 199 RLQT -> S (in EDMD2).
FT /FTId=VAR_039766.
FT VARIANT 203 203 E -> G (in CMD1A; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type; decreased sumoylation;
FT aberrant localization with decreased
FT nuclear rim staining and formation of
FT intranuclear foci; associated with
FT increased cell death; dbSNP:rs28933092).
FT /FTId=VAR_009978.
FT VARIANT 203 203 E -> K (in CMD1A; decreased sumoylation;
FT aberrant localization with decreased
FT nuclear rim staining and formation of
FT intranuclear foci; associated with
FT increased cell death; dbSNP:rs61195471).
FT /FTId=VAR_039767.
FT VARIANT 206 206 F -> L (in EDMD2).
FT /FTId=VAR_064964.
FT VARIANT 208 208 Missing (in LGMD1B).
FT /FTId=VAR_034708.
FT VARIANT 210 210 I -> S (in CMD1A; dramatically aberrant
FT localization with almost no nuclear rim
FT staining and increased formation of
FT intranuclear foci).
FT /FTId=VAR_070177.
FT VARIANT 215 215 L -> P (in CMD1A; aberrant localization
FT with decreased nuclear rim staining and
FT formation of intranuclear foci).
FT /FTId=VAR_039768.
FT VARIANT 222 222 H -> P (in EDMD2).
FT /FTId=VAR_039769.
FT VARIANT 222 222 H -> Y (in EDMD2; dbSNP:rs28928901).
FT /FTId=VAR_009979.
FT VARIANT 225 225 R -> Q (in EDMD3).
FT /FTId=VAR_067697.
FT VARIANT 230 230 D -> N (in FPLD2).
FT /FTId=VAR_039770.
FT VARIANT 232 232 G -> E (in EDMD2).
FT /FTId=VAR_039771.
FT VARIANT 248 248 L -> P (in EDMD2).
FT /FTId=VAR_039772.
FT VARIANT 249 249 R -> Q (in EDMD2).
FT /FTId=VAR_009980.
FT VARIANT 249 249 R -> W (in MDCL and EDMD2; mislocalized
FT in the nucleus; causes nuclear
FT deformations and LMNB1 redistribution).
FT /FTId=VAR_063589.
FT VARIANT 260 260 K -> N (in CMDA1).
FT /FTId=VAR_039773.
FT VARIANT 261 261 Missing (in EDMD2).
FT /FTId=VAR_009981.
FT VARIANT 267 267 Y -> C (in EDMD2).
FT /FTId=VAR_039774.
FT VARIANT 268 268 S -> P (in EDMD2).
FT /FTId=VAR_064965.
FT VARIANT 271 271 L -> P (in EDMD2).
FT /FTId=VAR_064966.
FT VARIANT 294 294 Q -> P (in EDMD2).
FT /FTId=VAR_009982.
FT VARIANT 295 295 S -> P (in EDMD2).
FT /FTId=VAR_064967.
FT VARIANT 298 298 R -> C (in CMT2B1).
FT /FTId=VAR_017661.
FT VARIANT 300 300 D -> G (probable disease-associated
FT mutation found in a patient with late-
FT onset cardiocutaneous progeria syndrome;
FT abnormal nuclear morphology with single
FT or multple blebs, lobulation and
FT occasional ringed or donut shaped
FT nuclei).
FT /FTId=VAR_070178.
FT VARIANT 302 302 L -> P (in MDCL).
FT /FTId=VAR_063590.
FT VARIANT 303 303 S -> P (in EDMD2).
FT /FTId=VAR_064968.
FT VARIANT 317 317 E -> K (in CMD1A).
FT /FTId=VAR_039775.
FT VARIANT 318 318 A -> T (in CMD1A; no effect on nuclear
FT morphology and lamin A localization).
FT /FTId=VAR_070179.
FT VARIANT 336 336 R -> Q (in EDMD2).
FT /FTId=VAR_009983.
FT VARIANT 343 343 R -> Q (in EDMD2).
FT /FTId=VAR_009984.
FT VARIANT 349 349 R -> L (in CMD1A).
FT /FTId=VAR_039776.
FT VARIANT 355 355 Missing (in EDMD2).
FT /FTId=VAR_064969.
FT VARIANT 358 358 E -> K (in EDMD2 and MDCL; aberrant
FT localization with decreased nuclear rim
FT staining and formation of intranuclear
FT foci; distribution of endogenous LMNA,
FT LMNB1 and LMNB2 are altered in cells
FT expressing this mutant; interacts with
FT itself and with wild-type LMNA and LMNB1;
FT no decrease in the stability compared
FT with wild-type).
FT /FTId=VAR_009985.
FT VARIANT 361 361 E -> K (in EDMD2).
FT /FTId=VAR_064970.
FT VARIANT 371 371 M -> K (in EDMD2; dramatically aberrant
FT localization with decreased nuclear rim
FT staining and formation of intranuclear
FT foci; distribution of endogenous LMNA,
FT LMNB1 and LMNB2 are altered in cells
FT expressing this mutant; causes an
FT increased loss of endogenous EMD from the
FT nuclear envelope; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type).
FT /FTId=VAR_009986.
FT VARIANT 377 377 R -> H (in LGMD1B).
FT /FTId=VAR_016205.
FT VARIANT 377 377 R -> L (in EDMD2 and LGMD1B).
FT /FTId=VAR_039777.
FT VARIANT 380 380 L -> S (in MDCL).
FT /FTId=VAR_063591.
FT VARIANT 386 386 R -> K (in EDMD2; dramatically aberrant
FT localization with decreased nuclear rim
FT staining and formation of intranuclear
FT foci; distribution of endogenous LMNA,
FT LMNB1 and LMNB2 are altered in cells
FT expressing this mutant; causes an
FT increased loss of endogenous EMD from the
FT nuclear envelope; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type).
FT /FTId=VAR_009987.
FT VARIANT 388 388 R -> H (in CMD1A; no effect on nuclear
FT morphology but restricts lamin A to the
FT cytoplasm).
FT /FTId=VAR_070180.
FT VARIANT 399 399 R -> C (in FPLD2 and CMD1A; no effect on
FT nuclear morphology and lamin A
FT localization).
FT /FTId=VAR_039778.
FT VARIANT 435 435 R -> C (in CMD1A).
FT /FTId=VAR_039779.
FT VARIANT 439 439 R -> C (in FPLD2; increase in nuclear
FT blebbing and formation of honeycomb-like
FT structures in the nuclei with no
FT accumulation of prelamin A in skin
FT fibroblasts; causes oligomerization of
FT the C-terminal globular domain of lamins
FT A and C under no-reducing conditions and
FT increases binding affinity for DNA;
FT increases sensitivity to oxidative
FT stress; no significant differences in
FT stability and structure compared with the
FT wild-type).
FT /FTId=VAR_070181.
FT VARIANT 446 446 D -> V (in EDMD2).
FT /FTId=VAR_039780.
FT VARIANT 449 449 G -> D (in EDMD2).
FT /FTId=VAR_064971.
FT VARIANT 453 453 R -> P (in MDCL).
FT /FTId=VAR_063592.
FT VARIANT 453 453 R -> W (in EDMD2; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type).
FT /FTId=VAR_009988.
FT VARIANT 454 454 L -> P (in EDMD2).
FT /FTId=VAR_064972.
FT VARIANT 455 455 R -> P (in MDCL).
FT /FTId=VAR_063593.
FT VARIANT 456 456 N -> D (in MDCL).
FT /FTId=VAR_063594.
FT VARIANT 456 456 N -> I (in EDMD2; mislocalized in the
FT nucleus; does not alter nuclear size or
FT shape).
FT /FTId=VAR_039781.
FT VARIANT 456 456 N -> K (in EDMD2).
FT /FTId=VAR_039782.
FT VARIANT 461 461 D -> Y (in EDMD2).
FT /FTId=VAR_064973.
FT VARIANT 465 465 G -> D (in FPLD2).
FT /FTId=VAR_009989.
FT VARIANT 467 467 W -> R (in EDMD2).
FT /FTId=VAR_064974.
FT VARIANT 469 469 I -> T (in EDMD2).
FT /FTId=VAR_009990.
FT VARIANT 471 471 R -> C (in HGPS; dbSNP:rs28928902).
FT /FTId=VAR_017662.
FT VARIANT 471 471 R -> H (in CMD1A; no effect on nuclear
FT morphology and lamin A localization).
FT /FTId=VAR_070182.
FT VARIANT 481 481 Y -> H (in LGMD1B).
FT /FTId=VAR_039783.
FT VARIANT 482 482 R -> L (in FPLD2).
FT /FTId=VAR_009991.
FT VARIANT 482 482 R -> Q (in FPLD2; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type; dbSNP:rs11575937).
FT /FTId=VAR_009992.
FT VARIANT 482 482 R -> W (in FPLD2; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type; decreases binding affinity for
FT DNA; increases sensitivity to oxidative
FT stress).
FT /FTId=VAR_009993.
FT VARIANT 486 486 K -> N (in FPLD2; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type).
FT /FTId=VAR_009994.
FT VARIANT 520 520 W -> S (in EDMD2; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type).
FT /FTId=VAR_039784.
FT VARIANT 523 523 G -> R (in CMD1A).
FT /FTId=VAR_067258.
FT VARIANT 527 527 R -> C (in HGPS).
FT /FTId=VAR_017663.
FT VARIANT 527 527 R -> H (in MADA).
FT /FTId=VAR_018727.
FT VARIANT 527 527 R -> P (in EDMD2 and FPLD2; interacts
FT with itself and with wild-type LMNA and
FT LMNB1; reduced binding to SUN1; no
FT decrease in the stability compared with
FT wild-type).
FT /FTId=VAR_009995.
FT VARIANT 528 528 T -> K (in EDMD2; interacts with itself
FT and with wild-type LMNA and LMNB1; no
FT decrease in the stability compared with
FT wild-type).
FT /FTId=VAR_009996.
FT VARIANT 528 528 T -> R (in EDMD2).
FT /FTId=VAR_039785.
FT VARIANT 529 529 A -> V (in MADA).
FT /FTId=VAR_034709.
FT VARIANT 530 530 L -> P (in EDMD2; interacts with itself
FT and with wild-type LMNA and LMNB1;
FT reduced binding to SUN1; no decrease in
FT the stability compared with wild-type).
FT /FTId=VAR_009997.
FT VARIANT 541 541 R -> C (in apical left ventricular
FT aneurysm).
FT /FTId=VAR_039786.
FT VARIANT 541 541 R -> H (in EDMD2).
FT /FTId=VAR_039787.
FT VARIANT 541 541 R -> P (in EDMD2; mis-localized in the
FT nucleus; does not alter nuclear size or
FT shape).
FT /FTId=VAR_064975.
FT VARIANT 541 541 R -> S (in EDMD2 and CMD1A; modest and
FT non-specific nuclear membrane
FT alterations; the phenotype is entirely
FT reversed by coexpression of the S-541
FT mutation and wild-type lamin-C).
FT /FTId=VAR_039788.
FT VARIANT 542 542 K -> N (in HGPS).
FT /FTId=VAR_034710.
FT VARIANT 573 573 S -> L (in CMD1A, FPLD2 and MADA).
FT /FTId=VAR_039789.
FT VARIANT 578 578 E -> V (in an atypical progeroid patient;
FT diagnosed as Werner syndrome).
FT /FTId=VAR_039790.
FT VARIANT 582 582 R -> H (in FPLD2; dbSNP:rs57830985).
FT /FTId=VAR_009998.
FT VARIANT 602 602 G -> S (in EDMD2; dbSNP:rs60662302).
FT /FTId=VAR_064976.
FT VARIANT 608 608 G -> S (in HGPS; reduced binding to SUN1;
FT may affect splicing by activating a
FT cryptic splice donor site).
FT /FTId=VAR_017664.
FT VARIANT 624 624 R -> H (in EDMD2).
FT /FTId=VAR_039791.
FT VARIANT 644 644 R -> C (in an atypical progeroid patient;
FT diagnosed as Hutchinson-Gilford progeria
FT syndrome; partially inhibits tail
FT cleavage).
FT /FTId=VAR_039792.
FT MUTAGEN 201 201 K->L: Decreased sumoylation; aberrant
FT localization with decreased nuclear rim
FT staining and formation of intranuclear
FT foci; associated with increased cell
FT death.
FT MUTAGEN 644 644 R->A: Does not affect tail cleavage.
FT MUTAGEN 647 647 L->R: Completely inhibits tail cleavage.
FT MUTAGEN 648 648 L->A: Completely inhibits tail cleavage.
FT MUTAGEN 650 650 N->A: Partially inhibits tail cleavage.
FT MUTAGEN 661 661 C->S: Loss of interaction with NARF.
FT Abolishes farnesylation.
FT CONFLICT 340 340 E -> K (in Ref. 5; BAG58344).
FT HELIX 316 384
FT STRAND 430 436
FT STRAND 438 445
FT STRAND 449 456
FT STRAND 458 460
FT HELIX 464 466
FT STRAND 468 473
FT STRAND 479 482
FT STRAND 494 499
FT HELIX 500 502
FT TURN 508 510
FT STRAND 511 514
FT STRAND 526 531
FT STRAND 537 543
SQ SEQUENCE 664 AA; 74139 MW; E0855F7699F0318B CRC64;
METPSQRRAT RSGAQASSTP LSPTRITRLQ EKEDLQELND RLAVYIDRVR SLETENAGLR
LRITESEEVV SREVSGIKAA YEAELGDARK TLDSVAKERA RLQLELSKVR EEFKELKARN
TKKEGDLIAA QARLKDLEAL LNSKEAALST ALSEKRTLEG ELHDLRGQVA KLEAALGEAK
KQLQDEMLRR VDAENRLQTM KEELDFQKNI YSEELRETKR RHETRLVEID NGKQREFESR
LADALQELRA QHEDQVEQYK KELEKTYSAK LDNARQSAER NSNLVGAAHE ELQQSRIRID
SLSAQLSQLQ KQLAAKEAKL RDLEDSLARE RDTSRRLLAE KEREMAEMRA RMQQQLDEYQ
ELLDIKLALD MEIHAYRKLL EGEEERLRLS PSPTSQRSRG RASSHSSQTQ GGGSVTKKRK
LESTESRSSF SQHARTSGRV AVEEVDEEGK FVRLRNKSNE DQSMGNWQIK RQNGDDPLLT
YRFPPKFTLK AGQVVTIWAA GAGATHSPPT DLVWKAQNTW GCGNSLRTAL INSTGEEVAM
RKLVRSVTVV EDDEDEDGDD LLHHHHGSHC SSSGDPAEYN LRSRTVLCGT CGQPADKASA
SGSGAQVGGP ISSGSSASSV TVTRSYRSVG GSGGGSFGDN LVTRSYLLGN SSPRTQSPQN
CSIM
//

MIM 115200
*RECORD*
*FIELD* NO
115200
*FIELD* TI
#115200 CARDIOMYOPATHY, DILATED, 1A; CMD1A
;;CARDIOMYOPATHY, DILATED, WITH CONDUCTION DEFECT 1; CDCD1;;
read moreCARDIOMYOPATHY, IDIOPATHIC DILATED;;
CARDIOMYOPATHY, FAMILIAL IDIOPATHIC;;
CARDIOMYOPATHY, CONGESTIVE
*FIELD* TX
A number sign (#) is used with this entry because dilated
cardiomyopathy-1A (CMD1A) is caused by heterozygous mutation in the
lamin A/C gene (LMNA; 150330) on chromosome 1q21. Allelic disorders
include the autosomal dominant form of Emery-Dreifuss muscular dystrophy
(181350) and Hutchinson-Gilford progeria syndrome (176670), among
others.

DESCRIPTION

Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and
reduced systolic function. CMD is the most frequent form of
cardiomyopathy and accounts for more than half of all cardiac
transplantations performed in patients between 1 and 10 years of age. A
heritable pattern is present in 20 to 30% of cases. Most familial CMD
pedigrees show an autosomal dominant pattern of inheritance, usually
presenting in the second or third decade of life (summary by Levitas et
al., 2010).

- Genetic Heterogeneity of Dilated Cardiomyopathy

Mutations in many other genes have been found to cause different forms
of dilated cardiomyopathy. These include CMD1C (601493), with or without
left ventricular noncompaction, caused by mutation in the LDB3 gene
(605906) on 10q22-q23; CMD1D (601494), caused by mutation in the TNNT2
gene (191045) on 1q32; CMD1E (601154), caused by mutation in the SCN5A
gene (600163) on 3p; CMD1G (604145), caused by mutation in the TTN gene
(188840) on 2q31; CMD1I (604765), caused by mutation in the DES gene
(125660) on 2q35; CMD1J (605362), caused by mutation in the EYA4 gene
(603550) on 6q23-q24; CMD1L (606685), caused by mutation in the SGCD
gene (601411) on 5q33; CMD1M (607482), caused by mutation in the CSRP3
gene (600824) on 11p15.1; CMD1N (607487), caused by mutation in the TCAP
gene (604488) on 17q12; CMD1O (608569), caused by mutation in the ABCC9
gene (601439) on 12p12.1; CMD1P (609909), caused by mutation in the PLN
gene (172405) on 6q22.1; CMD1R (613424), caused by mutation in the ACTC
gene (102540) on 15q14; CMD1S (613426), caused by mutation in the MYH7
gene (160760) on 14q12; CMD1T (613740), caused by mutation in the TMPO
gene (188380) on chromosome 12q22; CMD1U (613694), caused by mutation in
the PSEN1 gene (104311) on 14q24.3; CMD1V (613697), caused by mutation
in the PSEN2 gene (600759) on 1q31-q42; CMD1W (611407), caused by
mutation in the gene encoding metavinculin (VCL; 193065) on 10q22-q23;
CMD1X (611615), caused by mutation in the gene encoding fukutin (FKTN;
607440) on 9q31; CMD1Y (611878), caused by mutation in the TPM1 gene
(191010) on 15q22.1; CMD1Z (611879), caused by mutation in the TNNC1
gene (191040) on 3p21.3-p14.3; CMD1AA (612158), caused by mutation in
the ACTN2 gene (102573) on 1q42-q43; CMD1BB (612877), caused by mutation
in the DSG2 gene (125671) on 18q12.1-q12.2; CMD1CC (613122), caused by
mutation in the NEXN gene (613121) on 1p31.1; CMD1DD (613172), caused by
mutation in the RBM20 gene (613171) on chromosome 10q25.2; CMD1EE
(613252), caused by mutation in the MYH6 gene (160710) on chromosome
14q12; CMD1FF (613286), caused by mutation in the TNNI3 gene (191044) on
chromosome 19q13.4; CMD1GG (613642), caused by mutation in the SDHA gene
(600857) on chromosome 5p15; and CMD1HH (613881), caused by mutation in
the BAG3 gene (603883) on chromosome 10q25.2-q26.2; CMD1II (615184),
caused by mutation in the CRYAB gene (123590) on chromosome 6q21; CMD1JJ
(615235), caused by mutation in the LAMA4 gene (600133) on chromosome
6q21; CMD1KK (615248), caused by mutation in the MYPN gene (608517) on
chromosome 10q21; CMD1LL (615373), caused by mutation in the PRDM16 gene
(605557) on chromosome 1p36; and CMD1MM (see 615396), caused by mutation
in the MYBPC3 gene (600958) on chromosome 11p11.

Several additional loci for familial dilated cardiomyopathy have been
mapped: CMD1B (600884) on 9q13; CMD1H (604288) on 2q14-q22; CMD1K
(605582) on 6q12-q16; and CMD1Q (609915) on 7q22.3-q31.1.

The symbol CMD1F was formerly used for a disorder later found to be the
same as desmin-related myopathy (601419).

Autosomal recessive forms of dilated cardiomyopathy have been reported,
including CMD2A (611880), caused by mutation in the TNNI3 gene, and
CMD2B (614672), caused by mutation in the GATAD1 gene (614518).

CLINICAL FEATURES

Dilated cardiomyopathy, a disorder characterized by cardiac dilation and
reduced systolic function, represents an outcome of a heterogeneous
group of inherited and acquired disorders. Olson and Keating (1996)
noted that causes include myocarditis, coronary artery disease, systemic
diseases, and myocardial toxins; idiopathic dilated cardiomyopathy in
which these causes are excluded represents approximately one-half of all
cases. Idiopathic dilated cardiomyopathy occurs with a prevalence of
about 36.5 per 100,000; it accounts for more than 10,000 deaths in the
U.S. annually and is the primary indication for cardiac transplantation.
Among cases of idiopathic dilated cardiomyopathy, familial occurrence
accounts for 20 to 25%, with the exception of rare cases resulting from
mutations in dystrophin (e.g., 300377.0021). Familial dilated
cardiomyopathy is characterized by an autosomal dominant pattern of
inheritance with age-related penetrance. It presents with development of
ventricular dilatation and systolic dysfunction usually in the second or
third decade of life.

Whitfield (1961) described a family in which 10 members were suffering
or had died from cardiomyopathy and 6 others were probably affected.
Although both males and females were affected, transmission seemingly
occurred only through the female. Schrader et al. (1961) described 2
sisters with familial idiopathic cardiomegaly. Almost certainly the
mother, who died at age 34, and probably 1 brother, who died at age 16,
had the same condition. In the family reported by Battersby and Glenner
(1961), affected persons were limited to 1 sibship and deposits of a
nonmetachromatic, diastase-resistant, PAS-positive polysaccharide were
described in the myocardium. Undoubtedly heterogeneity exists in the
group of cardiomyopathies. Boyd et al. (1965) suggested that there may
be 3 forms: (1) a form with predominant fibrosis, (2) a form with
predominant hypertrophy (see ventricular hypertrophy, hereditary;
192600), and (3) a form with deposits described above. See amyloidosis
III (176300.0007) for another familial cardiomyopathy. Kariv et al.
(1966) observed 6 affected persons in 3 generations. In 2 of these
persons, Adams-Stokes attacks required an artificial pacemaker. The
affected males showed significant increase in the serum levels of
multiple muscle-derived enzymes. Heterogeneity was suggested by the
finding of normal serum enzyme levels in affected members of a second
family. Rywlin et al. (1969) favored the view that obstructive and
nonobstructive forms of familial cardiopathy are different expressions
of a single entity. Classification into 'hypertrophic' and 'congestive'
clinical types by Goodwin (1970) implies the same. Sommer et al. (1972)
took an opposite view, i.e., that there is a separate nonobstructive
familial cardiomyopathy. They described an Amish family with affected
persons in 3 generations. Severity varied widely. The most severely
affected pursued a rapidly fatal course whereas others manifested mainly
conduction defects compatible with long survival. Machida et al. (1971)
described a Japanese family with affected persons in 2 and perhaps 3
generations with male-to-male transmission. Emanuel et al. (1971)
suggested that both dominant and recessive forms may exist. The
possibility of an autosomal recessive form of congestive cardiomyopathy
was raised by Yamaguchi et al. (1977), who found an astoundingly high
rate of parental consanguinity (about 64%) and a segregation ratio of
0.196 consistent with autosomal recessive inheritance.

Moller et al. (1979) described an autosomal dominant form of congestive
cardiomyopathy. The earliest sign of the disease was arrhythmia and/or
conduction defects. Symptoms of pump failure had their onset in
adulthood. Three members of the extensively affected kindred had died
suddenly. Septal hypertrophy was found in 2 affected persons.

Fragola et al. (1988) studied 44 first-degree relatives of 12 probands
with idiopathic dilated cardiomyopathy. Affected relatives were
identified in 4 of 12 families. In each case, the affected relatives
were sibs. This may be due to a late age of onset for expression of
genetic factors involved in the etiology of this condition.

O'Connell et al. (1984) used endomyocardial biopsy and gallium-67 scans
in patients with dilated cardiomyopathy to demonstrate a subset of
patients with myocardial inflammation. Histologic confirmation was found
at autopsy. A defect in suppressor lymphocyte function was found in 1
patient, who showed improvement with immunosuppressive therapy. In 1
family, 5 persons in 3 generations were affected; in another, a father
and 2 brothers were affected. Battersby and Glenner (1961) reported
striking pericardial effusion in a family with cardiomyopathy. Other
early reports (e.g., Evans, 1949) have commented on inflammatory changes
found at necropsy. Pericardial effusion occurs episodically with the
iron-overload cardiomyopathy of multitransfused thalassemia and occurs
also in the cardiomyopathy of Friedreich ataxia (229300).

Ozick et al. (1984) reported identical twin sisters with congestive
cardiomyopathy and autoimmune thyroid disease. Both had antithyroid
microsomal antibodies and cytolytic antiheart myolemmal antibodies. The
postpartum state may have been a factor in one of the twins; both
cardiomyopathy and autoimmune thyroid disease may become clinically
apparent in the postpartum period. Gardner et al. (1985) evaluated a
kindred in which 12 persons had cardiomegaly with poor ventricular
function and/or dysrhythmia. The disorder was evident by echocardiogram
in a 6-month-old infant. Skeletal muscle biopsies showed subtle
myopathic alterations. The pedigree, spanning 5 generations, was
consistent with autosomal dominant inheritance. Gardner et al. (1987)
described a family in which multiple members in 3 and probably 4
generations had dilated cardiomyopathy with overt clinical onset between
the fourth and seventh decades. Dysrhythmia was frequent. They concluded
that there might be an associated skeletal myopathy manifested by very
mild proximal weakness or detectable only on biopsy. MacLennan et al.
(1987) described 8 affected individuals, 4 of whom were males in 3
generations. Average age at presentation was 39.5 years. Average time to
death from onset of symptoms suggestive of cardiomyopathy in 6 affected
members was 16 months. One member died suddenly after being
asymptomatic. The myocardium showed variation in muscle fiber size and
interstitial fibrosis.

Graber et al. (1986) described a large kindred with an autosomal
dominant form of disease of the cardiac conduction system and of the
myocardium. Stage I occurred in the second and third decades and was
characterized by absence of symptoms, normal heart size, sinus
bradycardia, and premature atrial contractions. Stage II was marked by
first-degree AV block in the third and fourth decades. Stage III
occurred in the fourth and fifth decades and was accompanied by chest
pain, fatigue, lightheadedness, and advanced AV block, followed by the
development of atrial fibrillation or flutter. Stage IV, in the fifth
and sixth decades of life, was characterized by congestive heart failure
and recurrent ventricular arrhythmias. Right ventricular endomyocardial
biopsy specimens showed progressive changes. At autopsy in the proband,
the atrial changes were more severe than the ventricular ones. This
suggested that the disorder discussed in entry 108770 is the same as
this condition. While there was a range in the phenotypic expression of
the inherited gene defect in this kindred, the dilated cardiomyopathy
was less impressive than the dysrhythmia. Arrhythmias were the earliest
manifestation of the disease (in the second to third decade).

Schmidt et al. (1988) studied familial dilated cardiomyopathy in 6
families. The familial nature of the disorder was not readily apparent
in 3 of these families until thorough family investigations were
performed. The authors suggested that the family history should be
reviewed in all patients with dilated cardiomyopathy and that further
investigation of relatives should be performed if there are cases of
unexplained heart disease, sudden unexpected death, or syncopal
episodes. Echocardiography is a convenient noninvasive tool for these
investigations. Early diagnosis is indicated for 2 reasons: treatment of
significant arrhythmias may prevent sudden unexpected death, and genetic
counseling can be provided. In studies of the first-degree relatives of
59 index cases with idiopathic dilated cardiomyopathy, Michels et al.
(1992) found that 18 relatives from 12 families had dilated
cardiomyopathy. Thus, 12 of the 59 index patients (20.3%) had familial
disease. No differences in age, sex, severity of disease, exposure to
selected environmental factors, or electrocardiographic or
echocardiographic features were detected between the index patients with
familial disease and those with nonfamilial disease. A noteworthy
finding was that 22 of 240 healthy relatives (9.2%) with normal ejection
fractions had increased left ventricular diameters during systole or
diastole (or both), as compared with 2 of 112 healthy control subjects
(1.8%) who were studied separately. In a case-control study of
idiopathic dilated cardiomyopathy in Baltimore, a roughly 3-fold
increase in risk was observed among blacks after adjustment for
potential confounding variables (Coughlin et al., 1990). The increased
frequency of dilated cardiomyopathy in black males was the basis in the
past of the designation 'Osler-2 myocarditis'; Osler-2 was the black
male ward at The Johns Hopkins Hospital.

Michels et al. (1993) performed PCR-based assays and Southern blot
analysis of the dystrophin gene (DMD; 300377) in 27 males with
idiopathic dilated cardiomyopathy. Five families had familial disease,
without male-to-male transmission in 4 families. In the fifth family,
there was no evidence of male-to-male transmission when the family was
entered into the study, but on follow-up the index patient's son was
found to have developed the disease. None of the patients had clinical
evidence of skeletal muscle disease or any systemic illness that could
cause heart disease. The mean age of the patients was 50.2 years; the
range of age was 5 to 72 years. No dystrophin gene defects were found.

Csanady et al. (1995) compared 31 familial and 209 nonfamilial cases of
dilated cardiomyopathy. They concluded that the familial form is more
malignant: it occurs at an earlier age and progresses more rapidly than
the nonfamilial form.

For a review of the genetic and clinical heterogeneity of familial
dilated cardiomyopathy, see Seidman and Seidman (2001).

CLINICAL MANAGEMENT

Meune et al. (2006) investigated the efficacy of implantable
cardioverter-defibrillators (ICDs) in the primary prevention of sudden
death in patients with cardiomyopathy due to lamin A/C gene mutations.
Patients referred for permanent cardiac pacing were systematically
offered the implantation of an ICD. The patients were enrolled solely on
the basis of the presence of lamin A/C mutations associated with cardiac
conduction defects. Indications for pacemaker implantation were
progressive conduction block and sinus block. In all, 19 patients were
treated. Meune et al. (2006) concluded that ICD implantation in patients
with lamin A/C mutations who are in need of a pacemaker is effective in
treating possibly lethal tachyarrhythmias, and that implantation of an
ICD, rather than a pacemaker, should be considered for such patients.

MAPPING

Koike et al. (1987) described 2 families with dilated cardiomyopathy. In
1 of these families, the mode of inheritance was autosomal dominant; in
the other, it appeared to be autosomal recessive. In both families, the
pattern of inheritance was consistent with linkage to the HLA locus;
however, because the families were small, the lod scores were low. From
linkage studies in 12 families, Olson et al. (1995) excluded genetic
linkage between the disease phenotype and a 21-cM region spanning the
HLA cluster in at least 60% of the families.

By linkage studies, Kass et al. (1994) demonstrated linkage of the
disease locus to polymorphic loci near the centromere of chromosome 1;
maximum multipoint lod score = 13.2 in the interval between D1S305 and
D1S176. Based on the disease phenotype and the map location, Kass et al.
(1994) speculated that the gap junction protein connexin 40 (121013) is
a candidate for the site of mutations that result in conduction system
disease and dilated cardiomyopathy.

Csanady et al. (1995) compared 31 familial and 209 nonfamilial cases of
dilated cardiomyopathy. They concluded that the familial form is more
malignant: it occurs at an earlier age and progresses more rapidly than
the nonfamilial form.

Among 100 patients with dilated cardiomyopathy, McKenna et al. (1997)
found that familial prevalence was definite in 14 of 56 (25%) and
possible in 25 of 56 (45%). The HLA-DR4 frequency in the 100 patients
with dilated cardiomyopathy was similar to that in 9,000 controls;
however, the DR4 subtype was significantly more common in the 25
probands with a familial tendency to dilated cardiomyopathy than in the
31 probands with nonfamilial dilated cardiomyopathy. McKenna et al.
(1997) concluded that there is an HLA-linked predisposition to familial
dilated cardiomyopathy.

MOLECULAR GENETICS

In 5 of 11 families with autosomal dominant dilated cardiomyopathy and
conduction system defects, Fatkin et al. (1999) identified 5
heterozygous missense mutations in the LMNA gene
(150330.0005-150330.0009). Each mutation caused heritable, progressive
conduction system disease (sinus bradycardia, atrioventricular
conduction block, or atrial arrhythmias) and dilated cardiomyopathy.
Heart failure and sudden death occurred frequently within these
families. No family members with mutations had either joint contractures
or skeletal myopathy. Furthermore, serum creatine kinase levels were
normal in family members with mutations in the lamin rod domain, but
mildly elevated in some family members with a defect in the tail domain
of lamin C. The findings indicated that the lamin A/C intermediate
filament protein plays an important role in cardiac conduction and
contractility. In an editorial accompanying the report of Fatkin et al.
(1999), Graham and Owens (1999) tabulated the chromosomal locations of
the known loci responsible for inherited forms of dilated
cardiomyopathy.

Brodsky et al. (2000) presented a large family with a severe autosomal
dominant dilated cardiomyopathy with an atrioventricular conduction
defect in some affected members. In addition, some affected individuals
had skeletal muscle symptoms varying from minimal weakness to a mild
limb-girdle muscular dystrophy. One individual had a pattern of skeletal
muscle involvement that the authors considered consistent with mild
Emery-Dreifuss muscular dystrophy. Affected individuals were
heterozygous for a single nucleotide deletion in the lamin A/C gene
(150330.0013). The authors highlighted the wide range in phenotype
arising from this mutation.

In 2 families with dilated cardiomyopathy with conduction defects,
Sebillon et al. (2003) identified 2 different mutations in the LMNA gene
(150330.0028, 150330.0029). In 1 family, the phenotype was characterized
by early-onset atrial fibrillation preceding or coexisting with dilated
cardiomyopathy.

Taylor et al. (2003) screened the LMNA gene in 40 families with familial
CMD and 9 patients with sporadic CMD and identified mutations in 3
families (see, e.g., 150330.0017) and 1 sporadic patient (S573L;
150330.0041). There was significant phenotypic variability in the
patients studied, but the presence of skeletal muscle involvement,
supraventricular arrhythmia, conduction defects, and 'mildly' dilated
cardiomyopathy were predictors of LMNA mutations. The LMNA mutation
carriers had a significantly poorer cumulative survival compared with
noncarrier CMD patients, with an event-free survival at age 45 years of
31% versus 75%, respectively.

In affected members of a French family with dilated cardiomyopathy with
conduction defects or atrial/ventricular arrhythmias and skeletal
muscular dystrophy of the quadriceps muscles, Charniot et al. (2003)
identified an arg377-to-his mutation in the LMNA gene (R377H;
150330.0017). The same mutation had been reported in patients with
limb-girdle muscular dystrophy type-1B (159001), a slowly progressive
muscular dystrophy with age-related atrioventricular cardiac conduction
disturbances and the absence of early contractures. Charniot et al.
(2003) suggested that factors other than the R377H mutation may have
influenced the phenotypic expression in this family.

Kimura (2011) reviewed the contribution of genetics in the pathogenesis
of dilated cardiomyopathy and discussed functional aspects of
sarcolemmal, contractile element, Z disc element, sarcoplasmic element,
and nuclear lamina mutations. The author noted that there was no major
disease gene for Japanese CMD patients reported to date.

- Associations Pending Confirmation

Mutation in the ILK gene (see 602366.0001) is a possible cause of CMD,
as is mutation in the ITGB1BP2 gene (see 300332.0001).

ANIMAL MODEL

Elliott et al. (2003) generated HLA-DQ8 transgenic AI-beta knockout NOD
mice that did not show insulitis or diabetes but developed dilated
cardiomyopathy. The constellation of findings of spontaneously arising
destructive focal lymphocytic infiltrates within the myocardium, rising
titers of circulating anticardiac autoantibodies, dilation of the
cardiac chambers, and gradual progression to end-stage heart failure
bore a striking resemblance to clinical features in humans with
idiopathic dilated cardiomyopathy. Elliott et al. (2003) concluded that
this transgenic strain provides a highly relevant animal model for human
autoimmune myocarditis and postinflammatory dilated cardiomyopathy.

Mounkes et al. (2005) generated mice expressing the human N195K
(150330.0007) mutation and observed characteristics consistent with
CMD1A. Continuous electrocardiographic monitoring of cardiac activity
demonstrated that N195K-homozygous mice died at an early age due to
arrhythmia. Immunofluorescence and Western blot analysis showed that
Hf1b/Sp4 (600540), connexin-40 (GJA5; 121013), and connexin-43 (GJA1;
121014) were misexpressed and/or mislocalized in N195K-homozygous mouse
hearts. Desmin staining revealed a loss of organization at sarcomeres
and intercalated disks. Mounkes et al. (2005) hypothesized that
mutations within the LMNA gene may cause cardiomyopathy by disrupting
the internal organization of the cardiomyocyte and/or altering the
expression of transcription factors essential to normal cardiac
development, aging, or function.

*FIELD* SA
Barry and Hall (1962); Biorck and Orinius (1964); Bishop et al. (1962);
Michels et al. (1989)
*FIELD* RF
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2006.

29. Michels, V. V.; Moll, P. P.; Miller, F. A.; Tajik, A. J.; Chu,
J. S.; Driscoll, D. J.; Burnett, J. C.; Rodeheffer, R. J.; Chesebro,
J. H.; Tazelaar, H. D.: The frequency of familial dilated cardiomyopathy
in a series of patients with idiopathic dilated cardiomyopathy. New
Eng. J. Med. 326: 77-82, 1992.

30. Michels, V. V.; Moll, P. P.; Miller, F. A.; Tajik, A. J.; Driscoll,
D. J.; Chu, J. S.; Burnett, J. C.; Chesebro, J. H.; Rodeheffer, R.
J.: Frequency of familial dilated cardiomyopathy in an unselected
series of patients with idiopathic dilated cardiomyopathy. (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A55, 1989.

31. Michels, V. V.; Pastores, G. M.; Moll, P. P.; Driscoll, D. J.;
Miller, F. A.; Burnett, J. C.; Rodeheffer, R. J.; Tajik, J. A.; Beggs,
A. H.; Kunkel, L. M.; Thibodeau, S. N.: Dystrophin analysis in idiopathic
dilated cardiomyopathy. J. Med. Genet. 30: 955-957, 1993.

32. Moller, P.; Lunde, P.; Hovig, T.; Nitter-Hauge, S.: Familial
cardiomyopathy: autosomally, dominantly inherited congestive cardiomyopathy
with two cases of septal hypertrophy in one family. Clin. Genet. 16:
233-243, 1979.

33. Mounkes, L. C.; Kozlov, S. V.; Rottman, J. N.; Stewart, C. L.
: Expression of an LMNA-N195K variant of A-type lamins results in
cardiac conduction defects and death in mice. Hum. Molec. Genet. 14:
2167-2180, 2005.

34. O'Connell, J. B.; Fowles, R. E.; Robinson, J. A.; Subramanian,
R.; Henkin, R. E.; Gunnar, R. M.: Clinical and pathologic findings
of myocarditis in two families with dilated cardiomyopathy. Am. Heart
J. 107: 127-135, 1984.

35. Olson, T. M.; Keating, M. T.: Mapping a cardiomyopathy locus
to chromosome 3p22-p25. J. Clin. Invest. 97: 528-532, 1996.

36. Olson, T. M.; Thibodeau, S. N.; Lundquist, P. A.; Schaid, D. J.;
Michels, V. V.: Exclusion of a primary defect at the HLA locus in
familial idiopathic dilated cardiomyopathy. J. Med. Genet. 32: 876-880,
1995.

37. Ozick, H.; Hollander, G.; Greengart, A.; Shani, J.; Lichstein,
E.: Dilated cardiomyopathy in identical twins. Chest 86: 878-880,
1984.

38. Rywlin, A. M.; Barold, S. S.; Linhart, J. W.; Kramer, H. C.; Meitus,
M. L.; Samet, P.: Idiopathic familial cardiopathy: a study of two
families. J. Genet. Hum. 17: 453-470, 1969.

39. Schmidt, M. A.; Michels, V. V.; Edwards, W. D.; Miller, F. A.
: Familial dilated cardiomyopathy. Am. J. Med. Genet. 31: 135-143,
1988.

40. Schrader, W. H.; Pankey, G. A.; Davis, R. B.; Theologides, A.
: Familial idiopathic cardiomegaly. Circulation 24: 599-606, 1961.

41. Sebillon, P.; Bouchier, C.; Bidot, L. D.; Bonne, G.; Ahamed, K.;
Charron, P.; Drouin-Garraud, V.; Millaire, A.; Desrumeaux, G.; Benaiche,
A.; Charniot, J.-C.; Schwartz, K.; Villard, E.; Komajda, M.: Expanding
the phenotype of LMNA mutations in dilated cardiomyopathy and functional
consequences of these mutations. J. Med. Genet. 40: 560-567, 2003.

42. Seidman, J. G.; Seidman, C.: The genetic basis for cardiomyopathy:
from mutation identification to mechanistic paradigms. Cell 104:
557-567, 2001.

43. Sommer, A.; Sanz, G.; Craenen, J. M.; Newton, W. A., Jr.: Familial
cardiomyopathy. Birth Defects Orig. Art. Ser. VIII(5): 178-181,
1972.

44. Taylor, M. R. G.; Fain, P. R.; Sinagra, G.; Robinson, M. L.; Robertson,
A. D.; Carniel, E.; Di Lenarda, A.; Bohlmeyer, T. J.; Ferguson, D.
A.; Brodsky, G. L.; Boucek, M. M.; Lascor, J.; Moss, A. C.; Li, W.-L.
P.; Stetler, G. L.; Muntoni, F.; Bristow, M. R.; Mestroni, L.; Familial
Dilated Cardiomyopathy Registry Research Group: Natural history
of dilated cardiomyopathy due to lamin A/C gene mutations. J. Am.
Coll. Cardiol. 41: 771-780, 2003. Note: Erratum: J. Am. Coll. Cardiol.
42: 590 only, 2003.

45. Whitfield, A. G. W.: Familial cardiomyopathy. Quart. J. Med. 30:
119-134, 1961.

46. Yamaguchi, M.; Toshima, H.; Yanase, T.; Ikeda, H.; Koga, Y.; Yoshioka,
H.; Ito, M.; Fujino, T.; Yasuda, H.: A family study of idiopathic
cardiomyopathy. Proc. Jpn. Acad. 53 (ser. B): 209-214, 1977.

*FIELD* CS

Cardiac:
Congestive cardiomyopathy;
Conduction defects;
Atrial fibrillation or flutter;
Ventricular arrhythmia;
Congestive heart failure;
Pericardial effusion

Neuro:
Normal neurologic examination;
Adams-Stokes attacks

Lab:
Myocardial deposits of a nonmetachromatic, diastase-resistant, PAS-positive
polysaccharide;
Defect in suppressor lymphocyte function

Inheritance:
Autosomal dominant;
? a recessive form also

*FIELD* CN
Marla J. F. O'Neill - updated: 01/30/2014
Marla J. F. O'Neill - updated: 9/4/2013
Marla J. F. O'Neill - updated: 5/16/2013
Marla J. F. O'Neill - updated: 6/5/2012
Marla J. F. O'Neill - updated: 11/15/2011
Marla J. F. O'Neill - updated: 6/10/2011
Marla J. F. O'Neill - updated: 4/8/2011
Marla J. F. O'Neill - updated: 11/9/2010
Marla J. F. O'Neill - updated: 6/7/2010
Marla J. F. O'Neill - updated: 2/4/2010
George E. Tiller - updated: 11/19/2008
Marla J. F. O'Neill - updated: 6/30/2008
Marla J. F. O'Neill - updated: 3/6/2008
Marla J. F. O'Neill - updated: 11/21/2007
Victor A. McKusick - updated: 11/27/2006
Victor A. McKusick - updated: 2/15/2006
Marla J. F. O'Neill - updated: 10/14/2005
Marla J. F. O'Neill - updated: 2/7/2005
Marla J. F. O'Neill - updated: 6/29/2004
Ada Hamosh - updated: 3/24/2003
Victor A. McKusick - updated: 8/22/2002
Victor A. McKusick - updated: 1/4/2001
Paul Brennan - updated: 4/10/2000
Victor A. McKusick - updated: 12/3/1999
Victor A. McKusick - updated: 9/19/1997

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
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carol: 12/20/1993

MIM 150330
*RECORD*
*FIELD* NO
150330
*FIELD* TI
*150330 LAMIN A/C; LMNA
;;LAMIN A;;
LAMIN C; LMNC
PRELAMIN A, INCLUDED;;
PROGERIN, INCLUDED
read more*FIELD* TX

DESCRIPTION

The LMNA gene encodes lamin A and lamin C. Lamins are structural protein
components of the nuclear lamina, a protein network underlying the inner
nuclear membrane that determines nuclear shape and size. The lamins
constitute a class of intermediate filaments. Three types of lamins, A,
B (see LMNB1; 150340), and C, have been described in mammalian cells
(Fisher et al., 1986).

CLONING

By screening human fibroblast and hepatoma cDNA libraries, Fisher et al.
(1986) isolated cDNAs corresponding to lamin A and lamin C. The lamin A
and C proteins are predicted to have molecular masses of 74 kD and 65
kD, respectively. Fisher et al. (1986) and McKeon et al. (1986) found
that the deduced amino acid sequences from cDNA clones of human lamin A
and C are identical for the first 566 amino acids, but that lamin A
contains an extra 98 amino acids (corresponding to approximately 9 kD)
at the C terminus. Lamin C has 6 unique C-terminal amino acids. Both
lamins A and C contain a 360-residue alpha-helical domain with homology
to a corresponding alpha-helical rod domain that is the structural
hallmark of all intermediate filament proteins. Fisher et al. (1986) and
McKeon et al. (1986) concluded that lamin A and lamin C arise by
alternative splicing from the same gene.

Guilly et al. (1987) detected a 3-kb lamin A mRNA and a 2.1-kb lamin C
mRNA in epithelial HeLa cells, but not in T lymphoblasts. Lamin B was
the only lamin present in T lymphoblasts. Guilly et al. (1987) noted
that the transport of newly synthesized proteins from the cytoplasm into
the nucleus differs from the transport of proteins into other
organelles, such as mitochondria, in that sequences are not cleaved and
remain a permanent feature of the mature polypeptide. Lamin A appears to
be an exception to this rule.

Weber et al. (1989) showed that lamin A is synthesized as a precursor
molecule called prelamin A. Maturation of lamin A involves the removal
of 18 residues from the C terminus, which is accomplished by
isoprenylation and farnesylation involving a C-terminal CAAX
(cysteine-aliphatic-aliphatic-any amino acid) box (Sinensky et al.,
1994).

GENE STRUCTURE

Lin and Worman (1993) demonstrated that the coding region of the lamin
A/C gene spans approximately 24 kb and contains 12 exons. Alternative
splicing within exon 10 gives rise to 2 different mRNAs that code for
prelamin A and lamin C.

MAPPING

Wydner et al. (1996) mapped the LMNA gene to chromosome 1q21.2-q21.3 by
fluorescence in situ hybridization.

Gross (2013) mapped the LMNA gene to chromosome 1q22 based on an
alignment of the LMNA sequence (GenBank GENBANK AY847595) with the
genomic sequence (GRCh37).

GENE FUNCTION

Lloyd et al. (2002) identified proteins interacting with the C-terminal
domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a
yeast 2-hybrid interaction screen. Using this approach, the adipocyte
differentiation factor SREBP1 (184756) was identified as a novel lamin A
interactor. In vitro glutathione S-transferase pull-down and in vivo
coimmunoprecipitation studies confirmed an interaction between lamin A
and both SREBP1a and 1c. A binding site for lamin A was identified in
the N-terminal transcription factor domain of SREBP1, between residues
227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by
FPLD mutations. The authors speculated that fat loss seen in
laminopathies may be caused in part by reduced binding of the adipocyte
differentiation factor SREBP1 to lamin A.

Favreau et al. (2004) analyzed myoblast-to-myotube differentiation in a
mouse myogenic cell line overexpressing wildtype or mutant human lamin
A. In contrast to clones overexpressing wildtype lamin A, those
expressing lamin A with the R453W mutation (150330.0002) differentiated
poorly or not at all, did not exit the cell cycle properly, and were
extensively committed to apoptosis. Clones expressing the R482W mutation
(150330.0011) differentiated normally. Favreau et al. (2004) concluded
that lamin A mutated at arginine-453 fails to build a functional
scaffold and/or fails to maintain the chromatin compartmentation
required for differentiation of myoblasts into myocytes.

Using a novel technique to measure nuclear deformation in response to
biaxial strain applied to cells, Lammerding et al. (2004) found that
Lmna -/- cells showed increased nuclear deformation, defective
mechanotransduction, and impaired viability under mechanical strain
compared to wildtype cells. In addition, activity of nuclear
factor-kappa-B (NFKB; 164011), a mechanical stress-responsive
transcription factor that can act as an antiapoptotic signal, was
impaired in the Lmna -/- cells. The findings suggested that lamin A/C
deficiency is associated with both defective nuclear mechanics and
impaired transcriptional activation.

Broers et al. (2004) used a cell compression device to compare wildtype
and Lmna-knockout mouse embryonic fibroblasts, and found that Lmna-null
cells showed significantly decreased mechanical stiffness and
significantly lower bursting force. Partial rescue of the phenotype by
transfection with either lamin A or lamin C prevented gross nuclear
disruption, but was unable to fully restore mechanical stiffness.
Confocal microscopy revealed that the nuclei of Lmna-null cells
exhibited an isotropic deformation upon indentation, despite an
anisotropic deformation of the cell as a whole. This nuclear behavior
suggested a loss of interaction of the disturbed nucleus with the
surrounding cytoskeleton. Actin-(102610), vimentin-(193060), and
tubulin-(191110) based filaments showed disturbed interaction in
Lmna-null cells. Broers et al. (2004) suggested that in addition to the
loss of nuclear stiffness, the loss of a physical interaction between
nuclear structures (i.e., lamins) and the cytoskeleton may cause more
general cellular weakness; they proposed a potential key function for
lamins in maintaining cellular tensegrity.

Van Berlo et al. (2005) showed that A-type lamins were essential for the
inhibition of fibroblast proliferation by TGF-beta-1 (190180).
TGF-beta-1 dephosphorylated RB1 (614041) through protein phosphatase 2A
(PPP2CA; 176915), both of which were associated with lamin A/C. In
addition, lamin A/C modulated the effect of TGF-beta-1 on collagen
production, a marker of mesenchymal differentiation. Van Berlo et al.
(2005) proposed a role for lamin A/C in control of gene activity
downstream of TGF-beta-1, via nuclear phosphatases such as PPP2CA.

Capanni et al. (2005) showed that the lamin A precursor was specifically
accumulated in lipodystrophy cells. Pre-lamin A was located at the
nuclear envelope and colocalized with SREBP1 Binding of SREBP1 to the
lamin A precursor was detected in patient fibroblasts, as well as in
control fibroblasts, forced to accumulate pre-lamin A by farnesylation
inhibitors. In contrast, SREBP1 did not interact in vivo with mature
lamin A or C in cultured fibroblasts. Inhibition of lamin A precursor
processing in 3T3-L1 preadipocytes resulted in sequestration of SREBP1
at the nuclear rim, thus decreasing the pool of active SREBP1 that
normally activates PPAR-gamma (601487) and causing impairment of
preadipocyte differentiation. This defect could be rescued by treatment
with troglitazone, a known PPAR-gamma ligand activating the adipogenic
program.

Scaffidi and Misteli (2006) showed that the same molecular mechanism
responsible for Hutchinson-Gilford progeria syndrome (HGPS; 176670) is
active in healthy cells. Cell nuclei from old individuals acquire
defects similar to those of HGPS patient cells, including changes in
histone modifications and increased DNA damage. Age-related nuclear
defects are caused by sporadic use, in healthy individuals, of the same
cryptic splice site in lamin A whose constitutive activation causes
HGPS. Inhibition of this splice site reverses the nuclear defects
associated with aging. Scaffidi and Misteli (2006) concluded that their
observations implicate lamin A in physiologic aging.

Human immunodeficiency virus (HIV)-1 (see 609423) protease inhibitors
(PIs) targeting the viral aspartyl protease are a cornerstone of
treatment for HIV infection and disease, but they are associated with
lipodystrophy and other side effects. Coffinier et al. (2007) found that
treatment of human and mouse fibroblasts with HIV-PIs caused an
accumulation of prelamin A. The prelamin A in HIV-PI-treated fibroblasts
migrated more rapidly than nonfarnesylated prelamin A, comigrating with
the farnesylated form found in ZMPSTE24 (606480)-deficient fibroblasts.
HIV-PI-treated heterozygous ZMPSTE24 fibroblasts exhibited an
exaggerated accumulation of farnesyl-prelamin A. Western blot and
enzymatic analysis showed that HIV-PIs inhibited ZMPSTE24 activity and
endoproteolytic processing of a GFP-prelamin A fusion protein, but they
did not affect farnesylation of HDJ2 (DNAJA1; 602837) or activity of
farnesyltransferase (see 134635), ICMT (605851), and RCE1 (605385) in
vitro. Coffinier et al. (2007) concluded that HIV-PIs inhibit ZMPSTE24,
leading to an accumulation of farnesyl-prelamin A, possibly explaining
HIV-PI side effects.

The nuclear envelope LINC (links the nucleoskeleton and cytoskeleton)
complex, which is formed by SUN (e.g., SUN1, 607723) and nesprin (e.g.,
SYNE1, 608441) proteins, provides a direct connection between the
nuclear lamina and the cytoskeleton. Haque et al. (2010) stated that
SUN1 and SUN2 interact with LMNA and that LMNA is required for the
nuclear envelope localization of SUN2, but not SUN1. They found that
LMNA mutations associated with Emery-Dreifuss muscular dystrophy (EDMD2;
181350) and HGPS disrupted interaction of LMNA with mouse Sun1 and human
SUN2. Nuclear localization of SUN1 and SUN2 was not impaired in EDMD2 or
HGPS cell lines. Expression of SUN1, but not SUN2, at the nuclear
envelope was enhanced in some HGPS cells, likely due to increased
interaction of SUN1 with accumulated prelamin A. Haque et al. (2010)
proposed that different perturbations in LMNA-SUN protein interactions
may underlie the opposing effects of EDMD and HGPS mutations on nuclear
and cellular mechanics.

Liu et al. (2011) reported the generation of induced pluripotent stem
cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS
iPSCs showed absence of progerin, and more importantly, lacked the
nuclear envelope and epigenetic alterations normally associated with
premature aging. Upon differentiation of HGPS iPSCs, progerin and its
aging-associated phenotypic consequences were restored. Specifically,
directed differentiation of HGPS iPSCs to vascular smooth muscle cells
led to the appearance of premature senescence phenotypes associated with
vascular aging. Additionally, their studies identified DNA-dependent
protein kinase catalytic subunit (PRKDC; 600899) as a downstream target
of progerin. The absence of nuclear PRKDC holoenzyme correlated with
premature as well as physiologic aging. Because progerin also
accumulates during physiologic aging, Liu et al. (2011) argued that
their results provided an in vitro iPSC-based model to study the
pathogenesis of human premature and physiologic vascular aging.

Chen et al. (2012) showed that cells from Lmna -/- mice, which represent
EDMD2, cells from Lmna(L530P/L530P) mice, which represent HGPS, and
cells from HGPS patients all had overaccumulation of the inner nuclear
envelope SUN1 protein. In wildtype cells, Lmna and Sun1 colocalized at
the nuclear envelope. In Lmna -/- cells, larger amounts of Sun1 were
found at the nuclear envelope and also in the Golgi. The larger amounts
of Sun1 appeared to result from reduced protein turnover. Transfection
of increasing amounts of mouse Sun1 into Lmna-null/Sun1-null murine
cells resulted in increased prevalence of nuclear herniations and
apoptosis, and the herniations appeared to result from Sun1 accumulation
in the Golgi. Loss of the Sun1 gene in both mouse models extensively
rescued cellular, tissue, organ, and lifespan abnormalities. Similarly,
knockdown of overaccumulated SUN1 protein in primary human HGPS cells
corrected nuclear defects and cellular senescence. The findings
indicated that accumulation of SUN1 is a common pathogenetic event in
these disorders.

In mice, Ho et al. (2013) found that lamin A/C-deficient (Lmna-null) and
Lmna(N195K/N195K) (see 150330.0007) mutant cells have impaired nuclear
translocation and downstream signaling of the mechanosensitive
transcription factor megakaryoblastic leukemia-1 (MKL1; 606078), a
myocardin family member that is pivotal in cardiac development and
function. Altered nucleocytoplasmic shuttling of MKL1 was caused by
altered actin dynamics in Lmna-null and Lmna(N195K/N195K) mutant cells.
Ectopic expression of the nuclear envelope protein emerin (300384),
which is mislocalized in Lmna mutant cells and also linked to
Emery-Dreifuss muscular dystrophy (310300) and dilated cardiomyopathy,
restored MKL1 nuclear translocation and rescued actin dynamics in mutant
cells. Ho et al. (2013) concluded that their findings presented a novel
mechanism that could provide insight into the disease etiology for the
cardiac phenotype in many laminopathies, whereby lamin A/C and emerin
regulate gene expression through modulation of nuclear and cytoskeletal
actin polymerization.

MOLECULAR GENETICS

Mutations in the LMNA gene cause a wide range of human diseases. Since
more than 10 different clinical syndromes have been attributed to LMNA
mutations, many of which show overlapping features, attempts at broad
classification have been proposed. Worman and Bonne (2007) suggested
that the disorders may be classified into 4 major types: diseases of
striated and cardiac muscle; lipodystrophy syndromes; peripheral
neuropathy; and premature aging. Benedetti et al. (2007) suggested 2
main groups: (1) neuromuscular and cardiac disorders, and (2)
lipodystrophy and premature aging disorders. The phenotypic
heterogeneity of diseases resulting from a mutation in a single gene can
be explained by the numerous roles of the nuclear lamina, including
maintenance of nuclear shape and structure, as well as functional roles
in transcriptional regulation and heterochromatin organization (review
by Capell and Collins, 2006).

Genschel and Schmidt (2000) compiled a list of 41 known mutations,
predominantly missense, in the LMNA gene. Twenty-three different
mutations had been shown to cause autosomal dominant Emery-Dreifuss
muscular dystrophy (EDMD2; 181350). Three mutations had been reported to
cause autosomal dominant limb-girdle muscular dystrophy (LGMD1B;
159001), 8 mutations were known to result in dilated cardiomyopathy
(CMD1A; 115200), and 7 mutations were reported to cause familial partial
lipodystrophy (FPLD2; 151660). In addition, 1 mutation in LMNA (H222Y;
150330.0014) appeared to be responsible for an autosomal recessive,
atypical form of Emery-Dreifuss muscular dystrophy (EDMD3; see 181350).

- Muscular Dystrophies

In 5 families with autosomal dominant Emery-Dreifuss muscular dystrophy
(EDMD2; 181350), Bonne et al. (1999) identified 4 mutations in the LMNA
gene (150330.0001-150330.0004) that cosegregated with the disease
phenotype. These findings represented the first identification of
mutations in a component of the nuclear lamina as a cause of an
inherited muscle disorder. The authors noted that lamins interact with
integral proteins of the inner nuclear membrane, including emerin
(300384), which is mutated in the X-linked form of Emery-Dreifuss
muscular dystrophy (EDMD1; 310300).

Raffaele di Barletta et al. (2000) showed that heterozygous mutations in
LMNA may cause diverse phenotypes ranging from typical EDMD to no
phenotypic effect. LMNA mutations in patients with autosomal dominant
EDMD occur in the tail and in the 2A rod domain of the protein,
suggesting that unique interactions between lamin A/C and other nuclear
components have an important role in cardiac and skeletal muscle
function. They identified a homozygous LMNA mutation (H222Y;
150330.0014) in 1 patient born of consanguineous unaffected parents,
consistent with autosomal recessive inheritance and a severe atypical
phenotype lacking cardiac features.

Limb-girdle muscular dystrophy type 1B (LGMD1B; 159001) is an autosomal
dominant, slowly progressive limb-girdle muscular dystrophy with
age-related atrioventricular cardiac conduction disturbances and the
absence of early contractures. Muchir et al. (2000) found mutations in
the LMNA gene in 3 LGMD1B families: a missense mutation (150330.0017), a
deletion of a codon (150330.0018), and a splice donor site mutation
(150330.0019). The 3 mutations were identified in all affected members
of the corresponding families and were absent in 100 unrelated control
subjects.

Quijano-Roy et al. (2008) described a form of congenital muscular
dystrophy (MDC) with onset in the first year of life in 15 children
resulting from de novo heterozygous mutations in the LMNA gene (see,
e.g., 150330.0047-150330.0049). Three patients had severe early-onset
disease, with decreased fetal movements in utero, no motor development,
severe hypotonia, diffuse limb and axial muscle weakness and atrophy,
and talipes foot deformities. The remaining 12 children initially
acquired head and trunk control and independent ambulation, but most
lost head control due to neck extensor weakness, a phenotype consistent
with 'dropped head syndrome.' Ten children required ventilatory support.
Cardiac arrhythmias were observed in 4 of the oldest patients, but were
symptomatic only in 1. Quijano-Roy et al. (2008) concluded that the
identified LMNA mutations appeared to correlate with a relatively severe
phenotype, broadening the spectrum of laminopathies. The authors
suggested that this group of patients may define a new disease entity,
which they designated LMNA-related congenital muscular dystrophy
(613205).

Benedetti et al. (2007) reported 27 individuals with mutations in the
LMNA gene resulting in a wide range of neuromuscular disorders.
Phenotypic analysis yielded 2 broad groups of patients. One group
included patients with childhood onset who had skeletal muscle
involvement with predominant scapuloperoneal and facial weakness,
consistent with EDMD or congenital muscular dystrophy. The second group
included patients with later or adult onset who had cardiac disorders or
a limb-girdle myopathy, consistent with LGMD1B. Those in the group with
early onset tended to have missense mutations, whereas those in the
group with adult onset tended to have truncating mutations. Analysis of
the variants showed that those associated with early-onset phenotypes
were primarily found in the Ig-like domain and in coil 2A, which may
interfere with binding to specific ligands. Those associated with later
onset were mostly located in the rod domain and in coil 2B, which was
predicted to affect the surface of lamin A/C dimers and lead to impaired
filament assembly. Benedetti et al. (2007) speculated that there may be
2 different pathogenetic mechanisms associated with neuromuscular
LMNA-related disorders: late-onset phenotypes may arise through loss of
LMNA function secondary to haploinsufficiency, whereas dominant-negative
or toxic gain-of-function mechanisms may underlie the more severe early
phenotypes.

- Dilated Cardiomyopathy and Cardiac Conduction Defects

Fatkin et al. (1999) studied the LMNA gene in 11 families with autosomal
dominant dilated cardiomyopathy and conduction system disease (CMD1A;
115200) linked to a region on chromosome 1 overlapping that of the LMNA
gene. They identified 5 novel missense mutations
(150330.0004-150330.0009): 4 in the alpha-helical rod domain of lamin A,
and 1 in the tail domain of lamin C. No family members with mutations
had joint contractures or skeletal myopathy characteristic of autosomal
dominant Emery-Dreifuss muscular dystrophy. Furthermore, serum creatine
kinase levels were normal in family members with mutations of the lamin
A rod domain, but mildly elevated in some family members with a defect
in the lamin C tail domain. The authors noted that mutations in the rod
domain of the protein led to dilated cardiomyopathy, whereas mutations
in the head or tail domain caused Emery-Dreifuss muscular dystrophy.

Van der Kooi et al. (2002) reported a sporadic patient and 2 unrelated
families with mutations in the LMNA gene who presented with varying
degrees and combinations of muscular dystrophy, partial lipodystrophy,
and cardiomyopathy with conduction defects, presumably due to single
mutations (see 150330.0003 and 150330.0005).

Sebillon et al. (2003) screened the coding sequence of LMNA in DNA
samples from 66 index cases of dilated cardiomyopathy with or without
associated features. They identified a glu161-to-lys mutation (E161K;
150330.0028) in a family with early-onset atrial fibrillation preceding
or coexisting with dilated cardiomyopathy, the previously described
R377H mutation (150330.0017) in the family with quadriceps myopathy
associated with dilated cardiomyopathy previously reported by Charniot
et al. (2003), and a 28insA mutation (150330.0029) leading to a
premature stop codon in a third family with dilated cardiomyopathy with
conduction defects. No mutation in LMNA was found in cases with isolated
dilated cardiomyopathy.

Meune et al. (2006) investigated the efficacy of implantable
cardioverter-defibrillators (ICDs) in the primary prevention of sudden
death in patients with cardiomyopathy due to lamin A/C gene mutations.
Patients referred for permanent cardiac pacing were systematically
offered the implantation of an ICD. The patients were enrolled solely on
the basis of the presence of lamin A/C mutations associated with cardiac
conduction defects. Indications for pacemaker implantation were
progressive conduction block and sinus block. In all, 19 patients were
treated. Meune et al. (2006) concluded that ICD implantation in patients
with lamin A/C mutations who are in need of a pacemaker is effective in
treating possibly lethal tachyarrhythmias, and that implantation of an
ICD, rather than a pacemaker, should be considered for such patients.

Taylor et al. (2003) screened the LMNA gene in 40 families and 9
sporadic patients with CMD with or without muscular dystrophy and
identified mutations in 3 families (see, e.g., 150330.0017) and 1
sporadic patient (S573L; 150330.0041). All mutations involved a
conserved residue, cosegregated with the disease within the families,
and were not found in 300 control chromosomes. LMNA mutation carriers
had a severe and progressive form of CMD with significantly poorer
cumulative survival compared to noncarrier CMD patients.

- Dilated Cardiomyopathy and Hypergonadotropic Hypogonadism

In a 17-year-old Caucasian female with premature ovarian failure and
dilated cardiomyopathy, who had features consistent with atypical Werner
syndrome (see 277700) but who was negative for mutation in the RECQL2
gene (604611), Nguyen et al. (2007) identified heterozygosity for a
missense mutation in the LMNA gene (L59R; 150330.0052). The authors
suggested the diagnosis of a laminopathy, most likely an atypical form
of mandibuloacral dysplasia (see 248370).

In a 15-year-old Caucasian girl with premature ovarian failure and
dilated cardiomyopathy, McPherson et al. (2009) identified
heterozygosity for the L59R mutation in the LMNA gene. McPherson et al.
(2009) noted phenotypic similarities between this patient and the
patient previously reported by Nguyen et al. (2007), who carried the
same mutation, as well as a patient originally described by Chen et al.
(2003) with an adjacent A57P mutation in LMNA (150330.0030). Features
common to these 3 patients included premature ovarian failure, dilated
cardiomyopathy, lipodystrophy, and progressive facial and skeletal
changes involving micrognathia and sloping shoulders, but not
acroosteolysis. Although the appearance of these patients was somewhat
progeroid, none had severe growth failure, alopecia, or rapidly
progressive atherosclerosis, and McPherson et al. (2009) suggested that
the phenotype represents a distinct laminopathy involving dilated
cardiomyopathy and hypergonadotropic hypogonadism (212112).

- Lipodystrophy Disorders

Patients with Dunnigan-type familial partial lipodystrophy, or partial
lipodystrophy type 2 (FPLD2; 151660), are born with normal fat
distribution, but after puberty experience regional and progressive
adipocyte degeneration, often associated with profound insulin
resistance and diabetes. Cao and Hegele (2000) hypothesized that the
analogy between the regional muscle wasting in autosomal dominant
Emery-Dreifuss muscular dystrophy and the regional adipocyte
degeneration in FPLD, in addition to the chromosomal localization of the
FPLD2 locus on 1q21-q22, made LMNA a good candidate gene for FPLD2.
Studies of 5 Canadian probands with familial partial lipodystrophy of
Dunnigan type indicated that each had a novel missense mutation (R482Q;
150330.0010) that cosegregated with the lipodystrophy phenotype and was
absent from 2,000 normal alleles.

Shackleton et al. (2000) identified 5 different missense mutations in
the LMNA gene (see, e.g., 150330.0010-150330.0012) among 10 kindreds and
3 individuals with partial lipodystrophy. All of the mutations occurred
in exon 8, which the authors noted is within the C-terminal globular
domain of lamin A/C. Flier (2000) commented on the significance of LMNA
mutations in partial lipodystrophy.

Vantyghem et al. (2004) characterized the neuromuscular and cardiac
phenotypes of FPLD patients bearing the heterozygous R482W mutation.
Fourteen patients from 2 unrelated families, including 10 affected
subjects, were studied. Clinical and histologic examination showed an
incapacitating, progressive limb-girdle muscular dystrophy in a
42-year-old woman that had been present since childhood, associated with
a typical postpubertal FPLD phenotype. Six of 8 adults presented the
association of calf hypertrophy, perihumeral muscular atrophy, and a
rolling gait due to proximal lower limb weakness. Muscular histology was
compatible with muscular dystrophy in one of them and/or showed a
nonspecific excess of lipid droplets (in 3 cases). Cardiac septal
hypertrophy and atherosclerosis were frequent in FPLD patients. In
addition, a 24-year-old FPLD patient had a symptomatic second-degree
atrioventricular block. Vantyghem et al. (2004) concluded that most
lipodystrophic patients affected by the FPLD-linked R482W mutation show
muscular and cardiac abnormalities.

Mandibuloacral dysplasia (see 248370) is a rare autosomal recessive
disorder characterized by postnatal growth retardation, craniofacial
anomalies, skeletal malformations, and mottled cutaneous pigmentation.
Patients with MAD frequently have partial lipodystrophy and insulin
resistance, which are features seen in FPLD. In all affected members of
5 consanguineous Italian families with MAD, Novelli et al. (2002)
identified a homozygous missense mutation (R527H; 150330.0021) in the
LMNA gene. Patient skin fibroblasts showed nuclei that presented
abnormal lamin A/C distribution and a dysmorphic envelope, demonstrating
the pathogenic effect of the mutation.

In affected members of a consanguineous family from north India,
Plasilova et al. (2004) identified a homozygous missense mutation in the
LMNA gene (150330.0033). The extent of skeletal lesions in this family
were consistent with MAD, but affected individuals also had classic
features of progeria. Plasilova et al. (2004) suggested that autosomal
recessive HGPS and mandibuloacral dysplasia may represent a single
disorder with varying degrees of disease severity.

Decaudain et al. (2007) identified changes in codon 482 of the LMNA gene
(see, e.g., R482Q 150330.0010 and R482W; 150330.0011) in 17 of 277
unrelated adults investigated for lipodystrophy and/or insulin
resistance. All 17 had classic features of FPLD2. Ten additional
patients who fulfilled the International Diabetes Federation diagnostic
criteria for metabolic syndrome were found to have heterozygous LMNA
mutations that were not in codon 482, but affected all 3 domains of the
protein, the N terminal, central rod domain, and C terminal globulin
domain (see, e.g., R399C; 150330.0043). Because the phenotype of these
patients was not typical of FPLD2, the diagnosis of laminopathy was
delayed. Although lipodystrophy was less severe than in typical FPLD2,
common features included calf hypertrophy, myalgia, and muscle cramps or
weakness. Two patients had cardiac conduction disturbances. Metabolic
alterations were prominent, especially insulin resistance and
hypertriglyceridemia.

- Charcot-Marie-Tooth Disease Type 2B1

In affected members of inbred Algerian families with an axonal form of
Charcot-Marie-Tooth disease linked to chromosome 1q21.2-q21.3 (CMT2B1;
605588), De Sandre-Giovannoli et al. (2002) found a shared common
homozygous ancestral haplotype that was suggestive of a founder mutation
and identified a unique mutation in the LMNA rod domain (R298C;
150330.0020). Ultrastructural studies of sciatic nerves of Lmna-null
mice showed a strong reduction of axon density, axonal enlargement, and
the presence of nonmyelinated axons, all of which were highly similar to
the phenotypes of human peripheral axonopathies.

- Hutchinson-Gilford Progeria Syndrome and Other Premature
Aging Syndromes

Eriksson et al. (2003) identified de novo heterozygous point mutations
in lamin A that cause Hutchinson-Gilford progeria syndrome (HGPS;
176670). Eighteen of 20 classic cases of HGPS harbored the identical de
novo single-base substitution resulting in a silent gly-to-gly change at
codon 608 within exon 11 (150330.0022). This change creates an exonic
consensus splice site and activates cryptic splicing, leading to
deletion of 50 codons at the end of prelamin A. This prelamin A still
retains the CAAX box but lacks the site for endoproteolytic cleavage.
Eriksson et al. (2003) suggested that there is at least 1 site for
phosphorylation, ser625, that is deleted in the abnormal lamin A
protein. De Sandre-Giovannoli et al. (2003) independently identified the
heterozygous exon 11 cryptic splice site activation mutation
(1824C-T+1819-1968del; 150330.0022) in 2 HGPS patients. Later cellular
studies (Capell et al., 2005; Glynn and Glover, 2005; Toth et al., 2005)
indicated that Hutchinson-Gilford progeria syndrome results from the
production of a truncated prelamin A, called progerin, which is
farnesylated at its C terminus and accumulates at the nuclear envelope,
causing misshapen nuclei (Yang et al., 2006).

Werner syndrome (277700) is an autosomal recessive progeroid syndrome
caused by mutation in the RECQL2 gene (WRN; 604611). Chen et al. (2003)
reported that of 129 index patients referred to their international
registry for molecular diagnosis of Werner syndrome, 26 (20%) had
wildtype RECQL2 coding regions and were categorized as having 'atypical
Werner syndrome' or 'non-WRN' on the basis of molecular criteria.
Because of some phenotypic similarities between Werner syndrome and
laminopathies including Hutchinson-Gilford progeria, Chen et al. (2003)
sequenced all exons of the LMNA gene in these 26 individuals and found
heterozygosity for novel missense mutations in LMNA in 4 (15%): A57P
(150330.0030), R133L (150330.0027) in 2 persons, and L140R
(150330.0031). Hegele (2003) stated that the clinical designation of
Werner syndrome for each of the 4 patients of Chen et al. (2003), in
whom mutations in the LMNA gene were found, appeared somewhat insecure.
He noted that the comparatively young ages of onset in the patients with
mutant LMNA would be just as consistent with late-onset
Hutchinson-Gilford syndrome as with early-onset Werner syndrome.
Patients with so-called atypical Werner syndrome and mutant LMNA also
expressed components of nonprogeroid laminopathies. Hegele (2003)
suggested that genomic DNA analysis can help draw a diagnostic line that
clarifies potential overlap between older patients with
Hutchinson-Gilford syndrome and younger patients with Werner syndrome,
and that therapies may depend on precise molecular classification.

McPherson et al. (2009) suggested that the patient in whom Chen et al.
(2003) identified an A57P LMNA mutation had a distinct phenotype
involving dilated cardiomyopathy and hypergonadotropic hypogonadism
(212112).

Csoka et al. (2004) screened 13 cell lines from atypical progeroid
patients for mutation in the LMNA gene. They identified 3 novel
heterozygous missense mutations in the LMNA gene in 3 patients: a
13-year-old female with a progeroid syndrome, a 15-year-old male with a
lipodystrophy, and a 20-year-old male with 'atypical progeria.' The
mutations identified in the last 2 patients were the most 5-prime and
3-prime missense mutations, respectively, in LMNA identified to that
time.

Reddel and Weiss (2004) reported that transcription efficiencies of the
mutant and wildtype LMNA alleles were equivalent in HGPS. The mutant
allele gave 2 types of transcripts that encoded truncated and normal
lamin A. Abnormally spliced progerin transcript constituted the majority
(84.5%) of the total steady-state mRNA derived from the mutant allele.
The abnormally spliced progerin transcript was a minority (40%) of all
lamin A transcripts obtained from both alleles. Reddel and Weiss (2004)
concluded that the mutated progerin functions as a dominant negative by
interfering with the structure of the nuclear lamina, intranuclear
architecture, and macromolecular interactions, which collectively would
have a major impact on nuclear function.

Fibroblasts from individuals with HGPS have severe morphologic
abnormalities in nuclear envelope structure. Scaffidi and Misteli (2005)
showed that the cellular disease phenotype is reversible in cells from
individuals with HGPS. Introduction of wildtype lamin A protein did not
rescue the cellular disease manifestations. The mutant LMNA mRNA and
lamin A protein could be efficiently eliminated by correction of the
aberrant splicing event using a modified oligonucleotide targeted to the
activated cryptic splice site. Upon splicing correction, HGPS
fibroblasts assumed normal nuclear morphology, the aberrant nuclear
distribution and cellular levels of lamina-associated proteins were
rescued, defects in heterochromatin-specific histone modifications were
corrected, and proper expression of several misregulated genes was
reestablished. The results established proof of principle for the
correction of the premature aging phenotype in individuals with HGPS.

Huang et al. (2005) designed short hairpin RNAs (shRNA) targeting
mutated pre-spliced or mature LMNA mRNAs and expressed them in HGPS
fibroblasts carrying the 1824C-T mutation (150330.0022). One of the
shRNAs reduced the expression levels of mutant lamin A (so-called LA
delta-50) to 26% or lower. The reduced expression was associated with
amelioration of abnormal nuclear morphology, improvement of
proliferative potential, and reduction in the numbers of senescent
cells.

Moulson et al. (2007) reported 2 unrelated patients with extremely
severe forms of HGPS associated with unusual mutations in the LMNA gene
(150330.0036 and 150330.0040, respectively). Both mutations resulted in
increased use of the cryptic exon 11 donor splice site that is also
observed with the common 1824C-T mutation (150330.0022). As a
consequence, the ratios of mutant progerin mRNA and protein to wildtype
were higher than in typical HGPS patients. The findings indicated that
the level of progerin expression correlates with severity of disease.

Scaffidi and Misteli (2008) found that progerin (150330.0022) expression
in immortalized human skin fibroblasts produced several defects typical
of HGPS. Progerin also caused the spontaneous differentiation of human
mesenchymal stem cells (MSCs) into endothelial cells, and reduced their
differentiation along the adipogenic lineage. Abnormal differentiation
of MSCs appeared to be due to progerin-induced activation of major
downstream effectors of the Notch signaling pathway, including HES1
(139605), HES5 (607348), and HEY1 (602953). Scaffidi and Misteli (2008)
noted that the progerin splice variant of LMNA is present at low levels
in cells from healthy individuals and has been implicated in the normal
aging process. They suggested that progerin-induced defects in Notch
signaling are involved in normal aging and similarly affect adult MSCs
and their differentiation.

- Restrictive Dermopathy

In 2 of 9 fetuses with restrictive dermopathy (275210), a lethal
genodermatosis in which tautness of the skin causes fetal akinesia or
hypokinesia deformation sequence, Navarro et al. (2004) identified
heterozygous splicing mutations in the LMNA gene, resulting in the
complete or partial loss of exon 11 (150330.0036 and 150330.0022,
respectively). In the other 7 patients, they identified a heterozygous
1-bp insertion resulting in a premature stop codon in the zinc
metalloproteinase STE24 gene (ZMPSTE24; 606480). This gene encodes a
metalloproteinase specifically involved in the posttranslational
processing of lamin A precursor. In all patients carrying a ZMPSTE24
mutation, loss of expression of lamin A as well as abnormal patterns of
nuclear sizes and shapes and mislocalization of lamin-associated
proteins was seen. Navarro et al. (2004) concluded that a common
pathogenetic pathway, involving defects of the nuclear lamina and
matrix, is involved in restrictive dermopathy.

Navarro et al. (2005) described 7 previously reported patients and 3 new
patients with restrictive dermopathy who were homozygous or compound
heterozygous for ZMPSTE24 mutations. In all cases there was complete
absence of both ZMPSTE24 and mature lamin A, associated with prelamin A
accumulation. The authors concluded that restrictive dermopathy is
either a primary or a secondary laminopathy, caused by dominant de novo
LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations.
The accumulation of truncated or normal length prelamin A is, therefore,
a shared pathophysiologic feature in recessive and dominant restrictive
dermopathy.

- Heart-Hand Syndrome, Slovenian Type

In a Slovenian family with heart-hand syndrome (610140), originally
reported by Sinkovec et al. (2005), Renou et al. (2008) identified a
splice site mutation in the LMNA gene (150330.0045) that segregated with
disease and was not found in 100 healthy controls. Analysis of
fibroblasts from 2 affected members of the family revealed truncated
lamin A/C protein and nuclear envelope abnormalities, confirming the
pathogenicity of the mutation.

- Other Associations

Hegele et al. (2000) identified a common single-nucleotide polymorphism
(SNP) in LMNA, 1908C/T, which was associated with obesity-related traits
in Canadian Oji-Cree. Hegele et al. (2001) reported association of this
LMNA SNP with anthropometric indices in 186 nondiabetic Canadian Inuit.
They found that physical indices of obesity, such as body mass index,
waist circumference, waist-to-hip circumference ratio, subscapular
skinfold thickness, and subscapular-to-triceps skinfold thickness ratio
were each significantly higher among Inuit subjects with the LMNA 1908T
allele than in subjects with the 1908C/1908C genotype. For each
significantly associated obesity-related trait, the LMNA 1908C/T SNP
genotype accounted for approximately 10 to 100% of the attributable
variation. The results indicated that common genetic variation in LMNA
is an important determinant of obesity-related quantitative traits.

GENOTYPE/PHENOTYPE CORRELATIONS

In 14 of 15 families with familial partial lipodystrophy, Speckman et
al. (2000) identified mutations in exon 8 of the LMNA gene: 5 families
had an R482Q mutation (150330.0010); 7 families had an R482W alteration
(150330.0011), and 1 family had a G465D alteration (150330.0015). The
R482Q and R482W mutations occurred on different haplotypes, indicating
that they probably had arisen more than once. One family with an
atypical form of familial partial lipodystrophy had an R582H mutation
(150330.0016) in exon 11 of the LMNA gene, which the authors noted can
affect the lamin A protein only. Speckman et al. (2000) noted that all
mutations in Dunnigan lipodystrophy affect the globular C-terminal
domain of the lamin A/C protein, whereas mutations responsible for
dilated cardiomyopathy and conduction-system disease are usually
clustered in the rod domain of the protein (Fatkin et al., 1999).
Speckman et al. (2000) could not detect mutations in the LMNA gene in 1
FPLD family that showed linkage to 1q21-q23.

Hegele (2005) used hierarchical cluster analysis to assemble 16
laminopathy phenotypes into 2 classes based on organ system involvement,
and then classified 91 reported causative LMNA mutations according to
their position upstream or downstream of the nuclear localization signal
(NLS) sequence. Contingency analysis revealed that laminopathy class and
LMNA mutation position were strongly correlated (p less than 0.0001),
suggesting that laminopathy phenotype and LMNA genotype are nonrandomly
associated.

Lanktree et al. (2007) analyzed the LMNA gene in 3 unrelated patients
with FPLD2 and identified heterozygosity for 3 different missense
mutations, all affecting only the lamin A isoform and each changing a
conserved residue. Two of the mutations, D230N (150330.0042) and R399C
(150330.0043), were 5-prime to the NLS, which is not typical of LMNA
mutations in FPLD2. The third mutation, S573L (150330.0041), had
previously been identified in heterozygosity in a patient with dilated
cardiomyopathy and conduction defects (CMD1A; 115200) and in
homozygosity in a patient with arthropathy, tendinous calcinosis, and
progeroid features (see 248370). None of the mutations were found in 200
controls of multiple ethnicities. Because heterozygosity for an S573L
mutation can cause cardiomyopathy without lipodystrophy or lipodystrophy
without cardiomyopathy, Lanktree et al. (2007) suggested that additional
factors, genetic or environmental, may contribute to the precise tissue
involvement.

ANIMAL MODEL

Mounkes et al. (2003) attempted to create a mouse model for autosomal
dominant Emery-Dreifuss muscular dystrophy (181350) by introducing a
L530P (150330.0004) mutation in the LMNA gene. Although mice
heterozygous for L530P did not show signs of muscular dystrophy and
remained overtly normal up to 6 months of age, mice homozygous for the
mutation showed phenotypes markedly reminiscent of symptoms observed in
progeria patients. Homozygous Lmna L530P/L530P mice were
indistinguishable from their littermates at birth, but by 4 to 6 days
developed severe growth retardation, dying within 4 to 5 weeks.
Homozygous mutant mice showed a slight waddling gait, suggesting
immobility of joints. Other progeria features of these mutant mice
included micrognathia and abnormal dentition--in approximately half of
the mutants a gap was observed between the lower 2 incisors, which also
appeared yellowed. Mutant mice also had loss of subcutaneous fat,
reduced numbers of eccrine and sebaceous glands, increased collagen
deposition in skin, and decreased hair follicle density. Mounkes et al.
(2003) concluded that Lmna L530P/L530P mice have significant phenotypic
overlap with Hutchinson-Gilford progeria syndrome, including nuclear
envelope abnormalities and decreased doublet capacity and life span of
fibroblasts.

Mounkes et al. (2005) generated mice expressing the human N195K
(150330.0007) mutation and observed characteristics consistent with
CMD1A. Continuous electrocardiographic monitoring of cardiac activity
demonstrated that N195K-homozygous mice died at an early age due to
arrhythmia. Immunofluorescence and Western blot analysis showed that
Hf1b/Sp4 (600540), connexin-40 (GJA5; 121013), and connexin-43 (GJA1;
121014) were misexpressed and/or mislocalized in N195K-homozygous mouse
hearts. Desmin staining revealed a loss of organization at sarcomeres
and intercalated disks. Mounkes et al. (2005) hypothesized that
mutations within the LMNA gene may cause cardiomyopathy by disrupting
the internal organization of the cardiomyocyte and/or altering the
expression of transcription factors essential to normal cardiac
development, aging, or function.

Arimura et al. (2005) created a mouse model of autosomal dominant
Emery-Dreifuss muscular dystrophy expressing an H222P mutation in Lmna.
At adulthood, male homozygous mice displayed reduced locomotion activity
with abnormal stiff walking posture, and all died by 9 months of age.
They also developed dilated cardiomyopathy with hypokinesia and
conduction defects. These skeletal and cardiac muscle features were also
observed in the female homozygous mice, but with a later onset than in
males. Histopathologic analysis of the mice revealed muscle degeneration
with fibrosis associated with dislocation of heterochromatin and
activation of Smad signaling in heart and skeletal muscles.

Varga et al. (2006) created transgenic mice carrying the G608G
(150330.0022)-mutated human LMNA gene and observed the development of a
dramatic defect of the large arteries, consisting of progressive medial
vascular smooth muscle cell loss and replacement with proteoglycan and
collagen followed by vascular remodeling with calcification and
adventitial thickening. In vivo, these arterial abnormalities were
reflected by a blunted initial response to the vasodilator sodium
nitroprusside, consistent with impaired vascular relaxation, and
attenuated blood pressure recovery after infusion. Varga et al. (2006)
noted that although G608G transgenic mice lacked the external phenotype
seen in human progeria, they demonstrated a progressive vascular
abnormality that closely resembled the most lethal aspect of the human
phenotype.

Frock et al. (2006) found that most cultured muscle cells from Lmna
knockout mice exhibited impaired differentiation kinetics and reduced
differentiation potential. Similarly, knockdown of Lmna or emerin (EMD;
300384) expression by RNA interference in normal muscle cells impaired
differentiation potential and reduced expression of muscle-specific
genes, Myod (159970) and desmin (125660). To determine whether impaired
myogenesis was linked to reduced Myod or desmin levels, Frock et al.
(2006) individually expressed these proteins in Lmna-null myoblasts and
found that both increased the differentiation potential of mutant
myoblasts. Frock et al. (2006) concluded that LMNA and emerin are
required for myogenic differentiation, at least in part, through an
effect on expression of critical myoblast proteins.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production
of a truncated prelamin A, called progerin, which is farnesylated at its
C terminus and accumulates at the nuclear envelope, causing misshapen
nuclei (Yang et al., 2006). Farnesyltransferase inhibitors (FTIs) have
been shown to reverse this cellular abnormality (Yang et al., 2005; Toth
et al., 2005; Capell et al., 2005; Mallampalli et al., 2005). Yang et
al. (2006) generated mice with a targeted HGPS mutation (Lmna HG/+) and
observed phenotypes similar to those in human HGPS patients, including
retarded growth, reduced amounts of adipose tissue, micrognathia,
osteoporosis, and osteolytic lesions in bone, which caused spontaneous
rib fractures in the mutant mice. Treatment with an FTI increased
adipose tissue mass, improved body weight curves, reduced the number of
rib fractures, and improved bone mineralization and bone cortical
thickness.

Yang et al. (2008) created knockin mice expressing a nonfarnesylatable
form of progerin. Knockin mice developed the same disease phenotype as
mice expressing farnesylated progerin, although the phenotype was
milder, and embryonic fibroblasts derived from these mice contained
fewer misshapen nuclei. The steady-state level of nonfarnesylated
progerin, but not mRNA, was lower in cultured fibroblasts and whole
tissues, suggesting that the absence of farnesylation may accelerate
progerin turnover.

In a mouse model of EDMD carrying an H222P mutation in the Lmna gene
(Arimura et al., 2005), Muchir et al. (2007) found that activation of
MAPK (see 176948) pathways preceded clinical signs or detectable
molecular markers of cardiomyopathy. Expression of H222P-mutant Lmna in
heart tissue and isolated cardiomyocytes resulted in tissue-specific
activation of MAPKs and downstream target genes. The results suggested
that activation of MAPK pathways plays a role in the pathogenesis of
cardiac disease in EDMD.

Muchir et al. (2009) demonstrated abnormal activation of the
extracellular signal-regulated kinase (ERK) branch of the
mitogen-activated protein kinase (MAPK) signaling cascade in hearts of
Lmna H222P knockin mice, a model of autosomal Emery-Dreifuss muscular
dystrophy. Systemic treatment of Lmna H222P/H222P mice that developed
cardiomyopathy with PD98059, an inhibitor of ERK activation, inhibited
ERK phosphorylation and blocked the activation of downstream genes in
heart. It also blocked increased expression of RNAs encoding natriuretic
peptide precursors and proteins involved in sarcomere organization that
occurred in placebo-treated mice. Histologic analysis and
echocardiography demonstrated that treatment with PD98059 delayed the
development of left ventricular dilatation. PD98059-treated Lmna
H222P/H222P mice had normal cardiac ejection fractions assessed by
echocardiography, whereas placebo-treated mice had a 30% decrease. The
authors emphasized the role of ERK activation in the development of
cardiomyopathy caused by LMNA mutations, and provided further proof of
principle for ERK inhibition as a therapeutic option to prevent or delay
heart failure in humans with Emery-Dreifuss muscular dystrophy and
related disorders caused by mutations in LMNA.

Davies et al. (2010) created knockin mice harboring a mutant Lmna allele
that yielded exclusively nonfarnesylated prelamin A. These mice had no
evidence of progeria but succumbed to cardiomyopathy. Most of the
nonfarnesylated prelamin A in the tissues of these mice was localized at
the nuclear rim, indistinguishable from the lamin A in wildtype mice.
The cardiomyopathy could not be ascribed to an absence of lamin C
because mice expressing an otherwise identical knockin allele yielding
only wildtype prelamin A appeared normal. The authors concluded that
lamin C synthesis is dispensable in mice and that failure to convert
prelamin A to mature lamin A causes cardiomyopathy in the absence of
lamin C.

Choi et al. (2012) found that ERK activation in H222P/H222P mice
specifically upregulated expression of dual-specificity phosphatase-4
(DUSP4; 602747) in cardiac muscle, with much lower Dusp4 induction in
quadriceps muscle, and no Dusp4 induction in tongue, kidney, and liver.
Dusp4 overexpression in cultured C2C12 muscle cells or targeted to mouse
heart resulted in activation of the Akt (see AKT1; 164730)-Mtor (FRAP1;
601231) metabolic signaling pathway, leading to impaired autophagy and
abnormal cardiac metabolism, similar to findings in H222P/H222P mice.

*FIELD* AV
.0001
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
LMNA, GLN6TER

In a family with autosomal dominant Emery-Dreifuss muscular dystrophy
(181350), Bonne et al. (1999) identified a C-to-T transition in exon 1
of the LMNA gene that changed glutamine-6 (CAG) to a stop codon (TAG).

.0002
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
LMNA, ARG453TRP

In a family with autosomal dominant Emery-Dreifuss muscular dystrophy
(181350), Bonne et al. (1999) demonstrated a C-to-T transition in exon 7
of the LMNA gene, resulting in an arg453-to-trp (R453W) substitution.

.0003
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2, INCLUDED
LMNA, ARG527PRO

In 2 families with autosomal dominant Emery-Dreifuss muscular dystrophy
(181350), Bonne et al. (1999) found a G-to-C transversion in the LMNA
gene which, resulting in an arg527-to-pro (R527P) substitution. The
mutation, found in heterozygous state, was demonstrated to be de novo in
both families.

Van der Kooi et al. (2002) reported a woman with limb-girdle muscle
weakness, spinal rigidity, contractures, elevated creatine kinase,
cardiac conduction abnormalities (atrial fibrillation), partial
lipodystrophy (151660), and increased serum triglycerides who had the
R527P mutation. Van der Kooi et al. (2002) also reported a family with
the R527P mutation in which the proband, her father, and her son all
presented with varying degrees of EDMD, lipodystrophy, and cardiac
conduction abnormalities.

Makri et al. (2009) reported 2 sisters with early-onset autosomal
dominant muscular dystrophy most consistent with EDMD. Because the girls
were born of consanguineous Algerian parents, they were at first thought
to have an autosomal recessive congenital muscular dystrophy. However,
genetic analysis identified a heterozygous R527P mutation in the LMNA
gene in both patients that was not present in either unaffected parent.
The results were consistent with germline mosaicism or a recurrent de
novo event. The older sib had a difficult birth and showed congenital
hypotonia, diffuse weakness, and mild initial respiratory and feeding
difficulties. She sat unsupported at age 2 years and walked
independently from age 4 years with frequent falls and a waddling gait.
At 13 years she had a high-arched palate, moderate limb hypotonia, and
weakness of the pelvic muscles. There was proximal limb wasting,
moderate cervical, elbow, and ankle contractures, pes cavus, spinal
rigidity, and lordosis/scoliosis. Her sister had mild hypotonia in early
infancy, walked without support at 24 months, and showed proximal muscle
weakness. There were mild contractures of the elbow and ankles. At age 9
years, she showed adiposity of the neck, trunk and abdomen, consistent
with lipodystrophy. Brain MRI and cognition were normal in both sisters,
and neither had cardiac involvement. Muscle biopsies showed a dystrophic
pattern.

.0004
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
LMNA, LEU530PRO

In a family with autosomal dominant Emery-Dreifuss muscular dystrophy
(181350), Bonne et al. (1999) detected a heterozygous T-to-C transition
in the LMNA gene, resulting in a leu530-to-pro (L530P) substitution.

.0005
CARDIOMYOPATHY, DILATED, 1A
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2, INCLUDED
LMNA, ARG60GLY

In a family with autosomal dominant dilated cardiomyopathy with
conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a
178C-G transversion in the LMNA gene, resulting in an arg60-to-gly
(R60G) substitution.

Van der Kooi et al. (2002) reported a woman with partial lipodystrophy
(151660), hypertriglyceridemia, and cardiomyopathy with conduction
defects who carried the R60G mutation. The patient's mother reportedly
had similar manifestations. The authors noted that lipodystrophy and
cardiac abnormalities were combined manifestations of the same mutation.

.0006
CARDIOMYOPATHY, DILATED, 1A
LMNA, LEU85ARG

In a family with autosomal dominant dilated cardiomyopathy with
conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a
254T-G transversion in the LMNA gene, resulting in a leu85-to-arg (L85R)
substitution.

.0007
CARDIOMYOPATHY, DILATED, 1A
LMNA, ASN195LYS

In a family with autosomal dominant dilated cardiomyopathy with
conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a
585C-G transversion in the LMNA gene, resulting in an asn195-to-lys
(N195K) substitution.

Using cells from the mouse model of Mounkes et al. (2005), Ho et al.
(2013) found that Lmna N195K embryonic fibroblasts and bone
marrow-derived mesenchymal stem cells had impaired nuclear localization
of the mechanosensitive transcription factor MKL1 (606078). Cardiac
sections from Lmna(N195K/N195K) mice had significantly reduced fractions
of cardiomyocytes with nuclear Mkl1, implicating altered Mkl1 signaling
in the development of cardiomyopathy in these animals. Nuclear
accumulation of Mkl1 was substantially lower in Lmna N195K cells than in
wildtype cells. Altered nucleocytoplasmic shuttling of Mkl1 was caused
by altered actin dynamics in Lmna(N195K/N195K) mutant cells. Ectopic
expression of the nuclear envelope protein emerin (300384) restored Mkl1
nuclear translocation and rescued actin dynamics in mutant cells.

.0008
CARDIOMYOPATHY, DILATED, 1A
LMNA, GLU203GLY

In a family with autosomal dominant dilated cardiomyopathy with
conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a
608A-G transition in the LMNA gene, resulting in a glu203-to-gly (E203G)
substitution.

.0009
CARDIOMYOPATHY, DILATED, 1A
LMNA, ARG571SER

In a family with autosomal dominant dilated cardiomyopathy and
conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a
1711C-A transversion in the LMNA gene, resulting in an arg571-to-ser
(R571S) substitution. In this family, the C-terminal of lamin C was
selectively affected by the mutation, and the cardiac phenotype was
relatively milder than that associated with mutations in the rod domain
of the LMNA gene. Furthermore, there was subclinical evidence of
involvement of skeletal muscle. Although affected members of this family
had no skeletal muscle symptoms, some had elevated serum creatine kinase
levels, including 1 asymptomatic family member with the genotype
associated with the disease. The arg571-to-ser mutation affected only
lamin C isoforms, whereas previously described defects causing
Emery-Dreifuss muscular dystrophy (181350) perturbed both lamin A and
lamin C isoforms.

.0010
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, ARG482GLN

In 5 probands from 5 Canadian kindreds with familial partial
lipodystrophy of the Dunnigan type (151660), Cao and Hegele (2000)
demonstrated heterozygosity for a G-to-A transition in exon 8 of the
LMNA gene, predicted to result in an arg484-to-gln (R482Q) substitution.
There were no differences in age, gender, or body mass index in
Q482/R482 heterozygotes compared with R482/R482 homozygotes (normals)
from these families; however, there were significantly more Q482/R482
heterozygotes who had definite partial lipodystrophy and frank diabetes.
Also compared with the normal homozygotes, heterozygotes had
significantly higher serum insulin and C-peptide (see 176730) levels.
The LMNA heterozygotes with diabetes were significantly older than
heterozygotes without diabetes.

Shackleton et al. (2000) found the R482Q mutation in a family with
familial partial lipodystrophy. Hegele et al. (2000) analyzed the
relationship between plasma leptin (164160) and the rare LMNA R482Q
mutation in 23 adult familial partial lipodystrophy (FPLD) subjects
compared with 25 adult family controls with normal LMNA in an extended
Canadian FPLD kindred. They found that the LMNA Q482/R482 genotype was a
significant determinant of plasma leptin, the ratio of plasma leptin to
body mass index (BMI), plasma insulin, and plasma C peptide, but not
BMI. Family members who were Q482/R482 heterozygotes had significantly
lower plasma leptin and leptin:BMI ratio than unaffected R482/R482
homozygotes. Fasting plasma concentrations of insulin and C peptide were
both significantly higher in LMNA Q482/R482 heterozygotes than in
R482/R482 homozygotes. Multivariate regression analysis revealed that
the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%,
respectively, of the attributable variation in log leptin, leptin:BMI
ratio, log insulin, and log C peptide. The authors concluded that a rare
FPLD mutation in LMNA determines the plasma leptin concentration.

Boguslavsky et al. (2006) found that overexpression of wildtype LMNA or
mutant R482Q or R482W (150330.0011) in mouse 3T3-L1 preadipocytes
prevented cellular lipid accumulation, inhibited triglyceride synthesis,
and prevented normal differentiation into adipocytes. In contrast,
embryonic fibroblasts from Lmna-null mice had increased levels of basal
triglyceride synthesis and differentiated into fat-containing cells more
readily that wildtype mouse cells. Mutations at residue 482 are not
predicted to affect the structure of the nuclear lamina, but may change
interactions with other proteins. The findings of this study suggested
that mutations responsible for FPLD are gain-of-function mutations.
Boguslavsky et al. (2006) postulated that mutations that result in gain
of function may cause higher binding affinity to a proadipogenic
transcription factor, thus preventing it from activating target genes;
overexpression of the wildtype protein may result in increased numbers
of molecules with a normal binding affinity. Overexpression of Lmna was
associated with decreased levels of PPARG2 (601487), a nuclear hormone
receptor transcription factor putatively involved in adipogenic
conversion. Lmna-null cells had increased basal phosphorylation of AKT1
(164730), a mediator of insulin signaling.

.0011
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, ARG482TRP

In 6 families and 3 isolated cases of partial lipodystrophy (151660),
Shackleton et al. (2000) found heterozygosity for C-to-T transition in
the LMNA gene, resulting in an arg482-to-trp (R482W) substitution. This
is the same codon as that affected in the R482Q mutation (150330.0010).
R482L (150330.0012) is a third mutation in the same codon causing
partial lipodystrophy.

Schmidt et al. (2001) identified a family with partial lipodystrophy
carrying the R482W mutation in the LMNA gene. Clinically, the loss of
subcutaneous fat and muscular hypertrophy, especially of the lower
extremities, started as early as in childhood. Acanthosis and severe
hypertriglyceridemia developed later in life, followed by diabetes.
Characterization of the lipoprotein subfractions revealed that affected
children present with hyperlipidemia. The presence and severity of
hyperlipidemia seem to be influenced by age, apolipoprotein E genotype,
and the coexistence of diabetes mellitus. In conclusion, dyslipidemia is
an early and prominent feature in the presented lipodystrophic family
carrying the R482W mutation.

.0012
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, ARG482LEU

In a family with partial lipodystrophy (151660), Shackleton et al.
(2000) found that the affected individuals were heterozygous for a
G-to-T transversion in the LMNA gene, resulting in an arg482-to-leu
(R482L) substitution.

.0013
CARDIOMYOPATHY, DILATED, 1A
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT, INCLUDED
LMNA, 1-BP DEL, 959T

In a large family with a severe autosomal dominant dilated
cardiomyopathy with conduction defects (CMD1A; 115200) in which the
majority of affected family members showed signs of mild skeletal muscle
involvement, Brodsky et al. (2000) demonstrated heterozygosity in
affected members for a 1-bp deletion (del959T) deletion in exon 6 of the
LMNA gene. One individual had a pattern of skeletal muscle involvement
that the authors considered consistent with mild Emery-Dreifuss muscular
dystrophy (181350).

.0014
EMERY-DREIFUSS MUSCULAR DYSTROPHY, ATYPICAL, AUTOSOMAL RECESSIVE
LMNA, HIS222TYR

In a 40-year-old man with a severe, atypical form of EDMD (see 181350),
Raffaele di Barletta et al. (2000) found a homozygous 664C-T transition
in the LMNA gene, resulting in a his222-to-tyr (H222Y) amino acid
substitution. Both parents, who were first cousins, were heterozygous
for the mutation and were unaffected. The mutation was not found among
200 control chromosomes. The patient was the only one with a homozygous
LMNA mutation among a larger study of individuals with autosomal
dominant Emery-Dreifuss muscular dystrophy.

.0015
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, GLY465ASP

Speckman et al. (2000) found that 1 of 15 families with familial partial
lipodystrophy of the Dunnigan variety (151660) harbored a gly465-to-asp
(G465D) mutation in exon 8 of the LMNA gene.

.0016
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, ARG582HIS

In a family with an atypical form of familial partial lipodystrophy
(151660), Speckman et al. (2000) identified an arg582-to-his (R582H)
mutation in exon 11 of the LMNA gene. In a follow-up of this same
family, Garg et al. (2001) reported that 2 affected sisters showed less
severe loss of subcutaneous fat from the trunk and extremities with some
retention of fat in the gluteal region and medial parts of the proximal
thighs compared to women with typical FPLD2. Noting that the R582H
mutation interrupts only the lamin A protein, Garg et al. (2001)
suggested that in typical FPLD2, interruption of both lamins A and C
causes a more severe phenotype than that seen in atypical FPLD2, in
which only lamin A is altered.

.0017
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
CARDIOMYOPATHY, DILATED, 1A, INCLUDED
LMNA, ARG377HIS

In a family with limb-girdle muscular dystrophy type 1B (159001), Muchir
et al. (2000) found a G-to-A transition in exon 6 of the LMNA gene,
resulting in a substitution of histidine for arginine-377 (R377H).

Taylor et al. (2003) identified heterozygosity for the R377H mutation in
an American family of British descent with autosomal dominant dilated
cardiomyopathy and mild limb-girdle muscular disease.

Charniot et al. (2003) described a French family with autosomal dominant
severe dilated cardiomyopathy with conduction defects or
atrial/ventricular arrhythmias and a skeletal muscular dystrophy of the
quadriceps muscles. Affected members were found to carry the R377H
mutation, which was shown by transfection experiments in both muscular
and nonmuscular cells to lead to mislocalization of both lamin and
emerin (300384). Unlike previously reported cases of LMNA mutations
causing dilated cardiomyopathy with neuromuscular involvement, cardiac
involvement preceded neuromuscular disease in all affected members.
Charniot et al. (2003) suggested that factors other than the R377H
mutation influenced phenotypic expression in this family. Sebillon et
al. (2003) also reported on this family.

In a German woman with LGMD1B, Rudnik-Schoneborn et al. (2007)
identified a heterozygous R377H mutation in the LMNA gene. Family
history revealed that the patient's paternal grandmother had proximal
muscle weakness and died from heart disease at age 52, and a paternal
aunt had 'walking difficulties' since youth. The patient's father and 4
cousins all had cardiac disease without muscle weakness ranging from
nonspecific 'heart attacks' to dilated cardiomyopathy and arrhythmia.
The only living affected cousin also carried the mutation.

.0018
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
LMNA, 3-BP DEL, EXON 3

In a family with limb-girdle muscular dystrophy type 1B (159001), Muchir
et al. (2000) found a 3-bp deletion (AAG) in exon 3 of the LMNA gene,
resulting in loss of the codon for lysine-208 (delK208).

.0019
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
LMNA, IVS9, G-C, +5

In a family with limb-girdle muscular dystrophy type 1B (159001), Muchir
et al. (2000) found a G-to-C transversion in the splice donor site of
intron 9, leading to retention of intron 9 and a frameshift at position
536. This potentially results in a truncated protein lacking half of the
globular tail domain of lamins A/C.

.0020
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B1
LMNA, ARG298CYS

De Sandre-Giovannoli et al. (2002) found a homozygous arg298-to-cys
(R298C) mutation in the LMNA gene in affected members of Algerian
families with CMT2B1 (605588).

Ben Yaou et al. (2007) identified a homozygous R298C mutation in a
female and 2 male affected members of an Algerian family with CMT2B1.
The 2 males also had X-linked Emery-Dreifuss muscular dystrophy (310300)
and a hemizygous mutation in the EMD gene (300384).

.0021
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL, INCLUDED
LMNA, ARG527HIS

In 5 consanguineous Italian families, Novelli et al. (2002) demonstrated
that individuals with mandibuloacral dysplasia (248370) were homozygous
for an arg527-to-his (R527H) mutation.

In affected members from 2 pedigrees with MADA, Simha et al. (2003)
identified the homozygous R527H mutation.

In a Mexican American boy with MADA born of related parents, Shen et al.
(2003) identified homozygosity for the R527H mutation. The authors noted
that all the patients reported by Novelli et al. (2002) shared a common
disease haplotype, but that the patients reported by Simha et al. (2003)
and their Mexican American patient had different haplotypes, indicating
independent origins of the mutation. The mutation is located within the
C-terminal immunoglobulin-like domain in the center of a beta sheet on
the domain surface of the protein.

Lombardi et al. (2007) identified this mutation in compound
heterozygosity with another missense mutation (150330.0044) in a patient
with an apparent MADA phenotype associated with muscular hyposthenia and
generalized hypotonia.

Garavelli et al. (2009) reported 2 unrelated patients with early
childhood onset of MADA features associated with a homozygous R527H
mutation. One presented at age 5 years, 3 months with bulbous distal
phalanges of fingers and was observed to have dysmorphic craniofacial
features, lipodystrophy type A, and acroosteolysis. The second child,
born of consanguineous Pakistani parents, presented at age 4 years, 2
months with a round face, chubby cheeks, thin nose, lipodystrophy type
A, and short, broad distal phalanges. Garavelli et al. (2009) emphasized
that features of this disorder may become apparent as early as preschool
age and that bulbous fingertips may be a clue to the diagnosis.

.0022
HUTCHINSON-GILFORD PROGERIA SYNDROME
RESTRICTIVE DERMOPATHY, LETHAL, INCLUDED
LMNA, GLY608GLY

In 18 of 20 patients with classic Hutchinson-Gilford progeria syndrome
(176670), Eriksson et al. (2003) found an identical de novo 1824C-T
transition, resulting in a silent gly-to-gly mutation at codon 608
(G608G) within exon 11 of the LMNA gene. This substitution created an
exonic consensus splice donor sequence and results in activation of a
cryptic splice site and deletion of 50 codons of prelamin A. This
mutation was not identified in any of the 16 parents available for
testing.

De Sandre-Giovannoli et al. (2003) identified the exon 11 cryptic splice
site activation mutation (1824C-T+1819-1968del) in 2 HGPS patients.
Immunocytochemical analyses of lymphocytes from 1 patient using specific
antibodies directed against lamin A/C, lamin A, and lamin B1 showed that
most cells had strikingly altered nuclear sizes and shapes, with
envelope interruptions accompanied by chromatin extrusion. Lamin A was
detected in 10 to 20% of HGPS lymphocytes. Only lamin C was present in
most cells, and lamin B1 was found in the nucleoplasm, suggesting that
it had dissociated from the nuclear envelope due to the loss of lamin A.
Western blot analysis showed 25% of normal lamin A levels, and no
truncated form was detected.

Cao and Hegele (2003) confirmed the observations of Eriksson et al.
(2003) using the same cell lines. They referred to this mutation as
2036C-T.

D'Apice et al. (2004) confirmed paternal age effect and demonstrated a
paternal origin of the 2036C-T mutation in 3 families with isolated
cases of Hutchinson-Gilford progeria.

By light and electron microscopy of fibroblasts from HGPS patients
carrying the 1824C-T mutation, Goldman et al. (2004) found significant
changes in nuclear shape, including lobulation of the nuclear envelope,
thickening of the nuclear lamina, loss of peripheral heterochromatin,
and clustering of nuclear pores. These structural defects worsened as
the HGPS cells aged in culture, and their severity correlated with an
apparent accumulation of mutant protein, which Goldman et al. (2004)
designated LA delta-50. Introduction of LA delta-50 into normal cells by
transfection or protein injection induced the same changes. Goldman et
al. (2004) hypothesized that the alterations in nuclear structure are
due to a concentration-dependent dominant-negative effect of LA
delta-50, leading to the disruption of lamin-related functions ranging
from the maintenance of nuclear shape to regulation of gene expression
and DNA replication.

In an infant with restrictive dermopathy (275210), Navarro et al. (2004)
identified the 1824C-T transition in heterozygous state.

In a patient with Hutchinson-Gilford progeria, Wuyts et al. (2005)
identified the G608G mutation. In lymphocyte DNA from the parents,
normal wildtype alleles were observed in the father, but a low signal
corresponding to the mutant allele was detected in the mother's DNA. A
segregation study confirmed that the patient's mutation was transmitted
from the mother, who showed germline and somatic mosaicism without
manifestations of HGPS.

Glynn and Glover (2005) studied the effects of farnesylation inhibition
on nuclear phenotypes in cells expressing normal and G608G-mutant lamin
A. Expression of a GFP-progerin fusion protein in normal fibroblasts
caused a high incidence of nuclear abnormalities (as seen in HGPS
fibroblasts), and resulted in abnormal nuclear localization of
GFP-progerin in comparison with the localization pattern of GFP-lamin A.
Expression of a GFP-lamin A fusion containing a mutation preventing the
final cleavage step, which caused the protein to remain farnesylated,
displayed identical localization patterns and nuclear abnormalities as
in HGPS cells and in cells expressing GFP-progerin. Exposure to a
farnesyltransferase inhibitor (FTI), PD169541, caused a significant
improvement in the nuclear morphology of cells expressing GFP-progerin
and in HGPS cells. Glynn and Glover (2005) proposed that abnormal
farnesylation of progerin may play a role in the cellular phenotype in
HGPS cells, and suggested that FTIs may represent a therapeutic option
for patients with HGPS.

In cells from a female patient with HGPS due to the 1824C-T mutation,
Shumaker et al. (2006) found that the inactive X chromosome showed loss
of histone H3 trimethylation of lys27 (H3K27me3), a marker for
facultative heterochromatin, as well as loss of histone H3
trimethylation of lys9 (H3K9me3), a marker of pericentric constitutive
heterochromatin. Other alterations in epigenetic control included
downregulation of the EZH2 methyltransferase (601573), upregulation of
pericentric satellite III repeat transcripts, and increase in the
trimethylation of H4K20. The epigenetic alterations were observed before
the pathogenic changes in nuclear shape. The findings indicated that the
mutant LMNA protein alters sites of histone methylation known to
regulate heterochromatin and provided evidence that the rapid aging
phenotype of HGPS reflects aspects of normal aging at the molecular
level.

Moulson et al. (2007) demonstrated that HGPS cells with the common
1824C-T LMNA mutation produced about 37.5% of wildtype full-length
transcript, which was higher than previous estimates (Reddel and Weiss,
2004).

Using real-time RT-PCR, Rodriguez et al. (2009) found that progerin
transcripts were expressed in dermal fibroblasts cultured from normal
controls, but at a level more than 160-fold lower than that detected in
dermal fibroblasts cultured from HGPS patients. The level of progerin
transcripts, but not of lamin A or lamin C transcripts, increased in
late-passage cells from both normal controls and HGPS patients.

.0023
HUTCHINSON-GILFORD PROGERIA SYNDROME
LMNA, GLY608SER

In a patient with Hutchinson-Gilford progeria syndrome (176670),
Eriksson et al. (2003) identified a G-to-A transition in the LMNA gene
resulting in a gly-to-ser substitution at codon 608 (G608S). This
mutation was not identified in either parent.

Cao and Hegele (2003) confirmed the observation of Eriksson et al.
(2003) using the same cell line.

.0024
HUTCHINSON-GILFORD PROGERIA SYNDROME, ATYPICAL
LMNA, GLU145LYS

In a patient with somewhat atypical features of progeria (176670),
Eriksson et al. (2003) identified a glu-to-lys substitution at codon 145
(E145K) in exon 2 of the LMNA gene. This mutation was not identified in
either parent. Atypical clinical features, including persistence of
coarse hair over the head, ample subcutaneous tissue over the arms and
legs, and severe strokes beginning at age 4, may subtly distinguish this
phenotype from classic HGPS.

.0025
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL
LMNA, ARG471CYS

In a patient with an apparently typical progeria phenotype (176670) who
was 28 years old at the time that DNA was obtained, Cao and Hegele
(2003) identified compound heterozygosity for 2 missense mutations in
the LMNA gene. One mutation, arg471 to cys (R471C), resulted from a
1623C-T transition. An arg527-to-cys (R527C) substitution (150330.0026),
resulting from a 1791C-T transition, was found on the other allele.
These mutations were not identified in any of 100 control chromosomes.
Parental DNA for this patient and a clinical description of the parents
were not available. Brown (2004) reported that both he and the patient's
physician, Francis Collins, concluded that the patient had
mandibuloacral dysplasia (248370).

Zirn et al. (2008) reported a 7-year-old Turkish girl, born of
consanguineous parents, who was homozygous for the R471C mutation. She
had a phenotype most consistent with an atypical form of MADA, including
lipodystrophy, a progeroid appearance, and congenital muscular dystrophy
with rigid spine syndrome. These latter features were reminiscent of
Emery-Dreifuss muscular dystrophy (181350), although there was no
cardiac involvement. She presented at age 10 months with proximal muscle
weakness, contractures, spinal rigidity, and a dystrophic skeletal
muscle biopsy. Characteristic progeroid features and features of
lipodystrophy and mandibuloacral dysplasia were noted at age 3 years and
became more apparent with age. Zirn et al. (2008) commented on the
severity of the phenotype and emphasized the phenotypic variability in
patients with LMNA mutations.

.0026
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
LMNA, ARG527CYS

See 150330.0025, Cao and Hegele (2003), and Brown (2004).

.0027
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
HUTCHINSON-GILFORD PROGERIA SYNDROME, CHILDHOOD-ONSET, INCLUDED
LMNA, ARG133LEU

In a male patient whose phenotype associated generalized acquired
lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, and
hepatic steatosis (151660), Caux et al. (2003) found a heterozygous
398G-T transversion in exon 2 of the LMNA gene that resulted in an
arg-to-leu change at codon 133 (R133L) in the dimerization rod domain of
lamins A and C. The patient also had hypertrophic cardiomyopathy with
valvular involvement and disseminated whitish papules.
Immunofluorescence microscopic analysis of the patient's cultured skin
fibroblasts revealed nuclear disorganization and abnormal distribution
of A-type lamins, similar to that observed in patients harboring other
LMNA mutations. This observation broadened the clinical spectrum of
laminopathies, pointing out the clinical variability of lipodystrophy
and the possibility of hypertrophic cardiomyopathy and skin involvement.

In 2 unrelated persons with a progeroid syndrome (see 176670), Chen et
al. (2003) found heterozygosity for the R1333L mutation in the LMNA
gene. One was a white Portuguese female who presented at the age of 9
years with short stature. She showed scleroderma-like skin changes and
graying/thinning of hair. Type 2 diabetes developed at the age of 23
years. Hypogonadism, osteoporosis, and voice changes were also present.
The other patient was an African American female in whom the diagnosis
of a progeroid syndrome was made at the age of 18 years.
Scleroderma-like skin, short stature, graying/thinning of hair, and type
2 diabetes at the age of 18 years were features. The deceased father,
paternal aunt, and paternal grandmother of this patient were also
diagnosed with severe insulin-resistant diabetes mellitus, suggesting
that the R133L mutation might have been paternally inherited. It is
noteworthy that a substitution in the same codon, R133P (150330.0032),
was reported in a 40-year-old patient with Emery-Dreifuss muscular
dystrophy who had disease onset at age 7 years and atrial fibrillation
at age 32 years (Brown et al., 2001). Although Chen et al. (2003)
designated these patients as having 'atypical Werner syndrome' (277700),
Hegele (2003) suggested that the patients more likely had late-onset
Hutchinson-Gilford progeria syndrome.

Vigouroux et al. (2003) emphasized that a striking feature in the
patient reported by Caux et al. (2003) was muscular hypertrophy of the
limbs, which contrasts with the muscular atrophy usually present in
Werner syndrome. Muscular hypertrophy, along with insulin-resistant
diabetes and hypertriglyceridemia, is more often associated with
LMNA-linked Dunnigan lipodystrophy. Fibroblasts from their patient
showed nuclear abnormalities identical to those described in Dunnigan
lipodystrophy (Vigouroux et al., 2001).

Jacob et al. (2005) studied the pattern of body fat distribution and
metabolic abnormalities in the 2 patients with atypical Werner syndrome
described by Chen et al. (2003). Patient 1, an African American female,
had normal body fat (27%) by dual energy X-ray absorptiometry (DEXA).
However, magnetic resonance imaging (MRI) revealed relative paucity of
subcutaneous fat in the distal extremities, with preservation of
subcutaneous truncal fat. She had impaired glucose tolerance and
elevated postprandial serum insulin levels. In contrast, patient 2, a
Caucasian female, had only 11.6% body fat as determined by DEXA and had
generalized loss of subcutaneous and intraabdominal fat on MRI. She had
hypertriglyceridemia and severe insulin-resistant diabetes requiring
more than 200 U of insulin daily. Skin fibroblasts showed markedly
abnormal nuclear morphology compared with those from patient 1. Despite
the deranged nuclear morphology, the lamin A/C remained localized to the
nuclear envelope, and the nuclear DNA remained within the nucleus. Jacob
et al. (2005) concluded that atypical Werner syndrome associated with an
R133L mutation in the LMNA gene is phenotypically heterogeneous.
Furthermore, the severity of metabolic complications seemed to correlate
with the extent of lipodystrophy.

.0028
CARDIOMYOPATHY, DILATED, 1A
LMNA, GLU161LYS

Sebillon et al. (2003) described a family with a history of sudden
cardiac death, congestive heart failure, and dilated cardiomyopathy
(CMD1A; 115200). Five affected members had a heterozygous 481G-A
transition in exon 2 of the LMNA gene, resulting in a glu161-to-lys
(E161K) mutation. Dilated cardiomyopathy was present in only 2 patients,
in whom onset of the disease was characterized by congestive heart
failure and atrial fibrillation (at 29 and 44 years, respectively);
heart transplantation was performed in both patients (at 34 and 51 years
of age). In the 3 other affected members, the onset of disease was also
characterized by atrial fibrillation at 22, 49, and 63 years, but
without dilated cardiomyopathy. A 16-year-old male and 12-year-old
female were also heterozygous for the mutation, but had no signs or
symptoms of heart disease. The 5 affected members were a mother and 2
daughters in 1 branch of the family and 2 brothers in another branch.
Two cardiac deaths were reported in the family history: sudden death at
38 years and congestive heart failure at 68 years. No significant
atrioventricular block was observed in the family, except in 1 patient
for whom cardiac pacing was necessary at 67 years of age because of
sinoatrial block coexisting with atrial fibrillation. Sebillon et al.
(2003) concluded that the phenotype in this family was characterized by
early atrial fibrillation preceding or coexisting with dilated
cardiomyopathy, without significant atrioventricular block, and without
neuromuscular abnormalities.

.0029
CARDIOMYOPATHY, DILATED, 1A
LMNA, 1-BP INS, 28A

Sebillon et al. (2003) described a family in which 5 patients with
dilated cardiomyopathy with conduction defects (CMD1A; 115200) were
heterozygous for a 1-bp insertion, 28insA, in exon 1 of the LMNA gene.
Three additional patients were considered as phenotypically affected
with documented dilated cardiomyopathy but were not available for DNA
analysis. In the family history, there were 3 cardiac sudden deaths
before 55 years of age. In the patients with dilated cardiomyopathy, 3
had associated atrioventricular block requiring pacemaker implantation,
1 had premature ventricular beats leading to a cardioverter
defibrillator implantation, and 1 had a mild form of skeletal muscular
dystrophy (mild weakness and wasting of quadriceps muscles, as well as
myogenic abnormalities on electromyogram).

.0030
CARDIOMYOPATHY, DILATED, WITH HYPERGONADOTRIPIC HYPOGONADISM
LMNA, ALA57PRO

In an Iranian female with short stature and a progeroid syndrome (see
176670), Chen et al. (2003) found a heterozygous de novo ala57-to-pro
substitution (A57P) resulting from a 584G-C transversion in the LMNA
gene. Onset occurred in her early teens, and she was 23 years old at
diagnosis. Hypogonadism, osteoporosis, osteosclerosis of digits, and
dilated cardiomyopathy were described. Although Chen et al. (2003)
designated this patient as having 'atypical Werner syndrome' (277700),
Hegele (2003) suggested that the patient more likely had late-onset
Hutchinson-Gilford progeria syndrome.

McPherson et al. (2009) suggested that the patient in whom Chen et al.
(2003) identified an A57P LMNA mutation had a distinct phenotype
involving dilated cardiomyopathy and hypergonadotropic hypogonadism
(212112).

.0031
HUTCHINSON-GILFORD PROGERIA SYNDROME, CHILDHOOD-ONSET
LMNA, LEU140ARG

In a white Norwegian male with a progeroid syndrome (see 176670), Chen
et al. (2003) found a leu140-to-arg (L140R) substitution resulting from
an 834T-G transversion in the LMNA gene. The patient had onset at age 14
of cataracts, scleroderma-like skin, and graying/thinning of hair, as
well as hypogonadism, osteoporosis, soft tissue calcification, and
premature atherosclerosis. Aortic stenosis and insufficiency were also
present. The patient died at the age of 36 years. Although Chen et al.
(2003) designated this patient as having 'atypical Werner syndrome'
(277700), Hegele (2003) suggested that the patient more likely had
late-onset Hutchinson-Gilford progeria syndrome.

.0032
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
LMNA, ARG133PRO

In a 40-year-old patient with Emery-Dreifuss muscular dystrophy (181350)
who had disease onset at age 7 years and atrial fibrillation at age 32
years, Brown et al. (2001) found an arg133-to-pro (R133P) mutation in
the LMNA gene. Chen et al. (2003) noted that the same codon is involved
in the arg133-to-leu (150330.0027) mutation in atypical Werner syndrome.

.0033
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
LMNA, LYS542ASN

In 4 affected members of a consanguineous family from north India with
features of MADA (248370). Plasilova et al. (2004) identified a
homozygous 1626G-C transversion in exon 10 of the LMNA gene, resulting
in a lys542-to-asn (K542N) substitution. The parents and 1 unaffected
daughter were heterozygous for the mutation. Patients in this family
showed uniform skeletal malformations such as acroosteolysis of the
digits, micrognathia, and clavicular aplasia/hypoplasia, characteristic
of mandibuloacral dysplasia. However, the patients also had classic
features of Hutchinson-Gilford progeria syndrome (176670). Plasilova et
al. (2004) suggested that autosomal recessive HGPS and MADA may
represent a single disorder with varying degrees of severity.

.0034
MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
LMNA, SER143PHE

In a young girl with congenital muscular dystrophy and progeroid
features (see 613205), Kirschner et al. (2005) identified a 1824C-T
transition in the LMNA gene, resulting in a de novo heterozygous
missense mutation, ser143 to phe (S143F). The child presented during the
first year of life with myopathy with marked axial weakness, feeding
difficulties, poor head control and axial weakness. Progeroid features,
including growth failure, sclerodermatous skin changes, and osteolytic
lesions, developed later. At routine examination at age 8 years, she was
found to have a mediolateral myocardial infarction.

In cultured skin fibroblasts derived from the patient reported by
Kirschner et al. (2005), Kandert et al. (2007) found dysmorphic nuclei
with blebs and lobulations that accumulated progressively with cell
passage. Immunofluorescent staining showed altered lamin A/C
organization and aggregate formation. There was aberrant localization of
lamin-associated proteins, particularly emerin (EMD; 300384) and
nesprin-2 (SYNE2; 608442), which was reduced or absent from the nuclear
envelope. However, a subset of mutant cells expressing the giant 800-kD
isoform of SYNE2 showed a milder phenotype, suggesting that this isoform
exerts a protective effect. Proliferating cells were observed to express
the 800-kD SYNE2 isoform, whereas nonproliferating cells did not. In
addition, mutant cells showed defects in the intranuclear organization
of acetylated histones and RNA polymerase II compared to control cells.
The findings indicated that the S143F mutant protein affects nuclear
envelope architecture and composition, chromatin organization, gene
expression, and transcription. The findings also implicated nesprin-2 as
a structural reinforcer at the nuclear envelope.

.0035
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
LMNA, TYR259TER

In 9 affected members of Dutch family with limb-girdle muscular
dystrophy type 1B (159001), van Engelen et al. (2005) identified a
777T-A transversion in the LMNA gene, resulting in a tyr259-to-ter
substitution (Y259X). The heterozygous Y259X mutation led to a classic
LGMD1B phenotype. One infant homozygous for the mutation was born of
consanguineous parents who were both affected, and delivered at 30
weeks' gestational age by cesarean section because of decreasing cardiac
rhythm. The infant died at birth from very severe generalized muscular
dystrophy. Cultured skin fibroblasts from the infant showed complete
absence of A-type lamins leading to disorganization of the lamina,
alterations in the protein composition of the inner nuclear membrane,
and decreased life span. Van Engelen et al. (2005) noted that the
fibroblasts from this child showed remarkable similarity, in nuclear
architectural defects and in decreased life span, to the fibroblasts of
homozygous LMNA (L530P/L530P) mice (Mounkes et al., 2003).

.0036
RESTRICTIVE DERMOPATHY, LETHAL
HUTCHINSON-GILFORD PROGERIA SYNDROME, INCLUDED
LMNA, IVS11, G-A, +1

In a premature infant who died at 6 months of age due to restrictive
dermopathy (275210), Navarro et al. (2004) identified a heterozygous
G-to-A transition at position 1 in the intron 11 donor site of the LMNA
gene (IVS11+1G-A), resulting in loss of exon 11 from the transcript. The
patient expressed lamins A and C and a truncated prelamin A.

In a patient with an extremely severe form of HGPS (176670), Moulson et
al. (2007) identified a heterozygous G-to-A transition at the +1
position of the donor splice site of intron 11 in the LMNA gene
(1968+1G-A). RT-PCR studies showed a truncated protein product identical
to that observed in HGPS cell lines with the common 1824C-T mutation
(150330.0022), indicating that the new mutation resulted in the abnormal
use of the same cryptic exon 11 splice site. The findings were in
contrast to those reported by Navarro et al. (2004), who observed
skipping of exon 11 with 1968+1G-A. Further quantitative studies of the
patient's cells by Moulson et al. (2007) found a 4.5-fold increase in
the relative ratio of mutant mRNA and protein to wildtype prelamin A
compared to typical HGPS cells. The findings were confirmed by Western
blot analysis and provided an explanation for the severe phenotype
observed in this patient. He had had abnormally thick and tight skin
observed at 11 weeks of age, and developed more typical but severe
progeroid features over time. He died of infection at age 3.5 years.

.0037
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
LMNA, ALA529VAL

In 2 unrelated Turkish patients with mandibuloacral dysplasia with type
A lipodystrophy (248370), a 21-year-old woman previously described by
Cogulu et al. (2003) and an 18-year-old man, Garg et al. (2005)
identified homozygosity for a 1586C-T transition in the LMNA gene,
resulting in an ala529-to-val (A529V) substitution. Intragenic SNPs
revealed a common haplotype spanning 2.5 kb around the mutated
nucleotide in the parents of both patients, suggesting ancestral origin
of the mutation. The female patient had no breast development despite
normal menstruation, a phenotype different from that seen in women with
the R527H mutation (150330.0021).

.0038
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B
LMNA, GLN493TER

In a German woman with LGMD1B (159001), Rudnik-Schoneborn et al. (2007)
identified a heterozygous 1477C-T transition in exon 8 of the LMNA gene,
resulting in a gln493-to-ter (Q493X) substitution. She presented with
slowly progressive proximal muscle weakness beginning in the lower
extremities and later involving the upper extremities. EMG showed both
neurogenic and myopathic defects in the quadriceps muscle. At age 53
years, she was diagnosed with atrioventricular conduction block and
arrhythmia requiring pacemaker implantation. Family history showed that
her mother had walking difficulties from age 40 years and died of a
heart attack at age 54. Six other deceased family members had suspected
cardiomyopathy without muscle involvement.

.0039
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, IVS8, G-C, +5

Morel et al. (2006) reported 2 sisters, the children of
nonconsanguineous Punjabi parents, with familial partial lipodystrophy
type 2 (FPLD2; 151660). The first presented with acanthosis nigricans at
age 5 years, diabetes with insulin resistance, hypertension, and
hypertriglyceridemia at age 13 years, and partial lipodystrophy starting
at puberty. Her sister and their mother had a similar metabolic profile
and physical features, and their mother died of vascular disease at age
32 years. LMNA sequencing showed that the sisters were each heterozygous
for a novel G-to-C mutation at the intron 8 consensus splice donor site,
which was absent from the genomes of 300 healthy individuals. The
retention of intron 8 in mRNA predicted a prematurely truncated lamin A
isoform (516 instead of 664 amino acids) with 20 nonsense 3-prime
terminal residues. The authors concluded that this was the first LMNA
splicing mutation to be associated with FPLD2, and that it causes a
severe clinical and metabolic phenotype.

.0040
HUTCHINSON-GILFORD PROGERIA SYNDROME
LMNA, VAL607VAL

In a patient with a severe form of HGPS (176670), Moulson et al. (2007)
identified a de novo heterozygous 1821G-A transition in exon 11 of the
LMNA gene, resulting in a val607-to-val (V607V) substitution. The
1821G-A mutation favored the use of the same cryptic splice site as the
common 1824C-T mutation (150330.0022) and produced the same resultant
progerin product. However, the ratio of mutant to wildtype mRNA and
protein was increased in the patient compared to typical HGPS cells. The
patient had flexion contractures, thick and tight skin, and other severe
progeroid features. He died of infection at 26 days of age.

.0041
CARDIOMYOPATHY, DILATED, 1A
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL, INCLUDED;;
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2, INCLUDED
LMNA, SER573LEU

In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with
conduction defects (CMD1A; 115200), Taylor et al. (2003) identified
heterozygosity for a 1718C-T transition in exon 11 of the LMNA gene,
resulting in a ser573-to-leu substitution at a highly conserved residue,
predicted to affect the carboxyl tail of the lamin A isoform. The
mutation was not found in the proband's 2 unaffected offspring or in 300
control chromosomes, but her unaffected 60-year-old sister also carried
the mutation.

Van Esch et al. (2006) analyzed the LMNA gene in a 44-year-old male of
European descent with arthropathy, tendinous calcifications, and a
progeroid appearance (see 248370) and identified homozygosity for the
S573L mutation. Progeroid features included a small pinched nose, small
lips, micrognathia with crowded teeth, cataract, and alopecia. He also
had generalized lipodystrophy, and sclerodermatous skin. The arthropathy
affected predominantly the distal femora and proximal tibia in the knee
with tendinous calcifications. However, he had normal clavicles and no
evidence of acroosteolysis. The authors concluded that he had a novel
phenotype. The patient's unaffected 15-year-old son was heterozygous for
the mutation, which was not found in 450 control chromosomes. The
authors noted that the patient had no evidence of cardiomyopathy and his
70-year-old mother, an obligate heterozygote, had no known cardiac
problems.

In a 75-year-old European male with partial lipodystrophy (151660),
Lanktree et al. (2007) identified heterozygosity for the S573L mutation
in the LMNA gene.

.0042
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, ASP230ASN

In a 46-year-old South Asian female with partial lipodystrophy (151660),
Lanktree et al. (2007) identified heterozygosity for a 688G-A transition
in exon 4 of the LMNA gene, resulting in an asp230-to-asn (D230N)
substitution at a conserved residue located 5-prime to the nuclear
localization signal. The mutation, predicted to affect only the lamin A
isoform, was not found in 200 controls of multiple ethnic backgrounds.

.0043
LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2
LMNA, ARG399CYS

In a 50-year-old European female with partial lipodystrophy (151660),
Lanktree et al. (2007) identified heterozygosity for a 1195C-T
transition in exon 7 of the LMNA gene, resulting in an arg399-to-cys
(R399C) substitution at a conserved residue located 5-prime to the
nuclear localization signal. The mutation, predicted to affect only the
lamin A isoform, was not found in 200 controls of multiple ethnic
backgrounds.

Decaudain et al. (2007) identified a heterozygous R399 mutation in a
woman with severe metabolic syndrome. She was diagnosed with
insulin-resistant diabetes at age 32. Chronic hyperglycemia led to
retinopathy, peripheral neuropathy, and renal failure. She had severe
hypertriglyceridemia and diffuse atherosclerosis, requiring coronary
artery bypass at age 49. Physical examination revealed android fat
distribution with lipoatrophy of lower limbs and calves hypertrophy
without any muscle weakness. Her mother and a brother had diabetes and
died several years earlier.

.0044
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL
LMNA, VAL440MET

In a 27-year-old Italian woman with a mandibuloacral dysplasia type A
(MADA; 248370)-like phenotype, Lombardi et al. (2007) found compound
heterozygosity for missense mutations in the LMNA cDNA: a G-to-A
transition at position 1318 in exon 7 that gave rise to a val-to-met
substitution at codon 440 (V440M), and an R527H substitution
(150330.0021). Each healthy parent was a simple heterozygote for one or
the other mutation. The apparent MADA phenotype was associated with
muscular hyposthenia and generalized hypotonia. Clavicular hypoplasia
and metabolic imbalances were absent. Lombardi et al. (2007)
hypothesized that lack of homozygosity for the R527H mutation attenuated
the MADA phenotype, while the V440M mutation may have contributed to
both the muscle phenotype and the pathogenic effect of the single R527H
mutation.

.0045
HEART-HAND SYNDROME, SLOVENIAN TYPE
LMNA, IVS9AS, T-G, -12

In affected members of a Slovenian family with heart-hand syndrome
(610140), originally reported by Sinkovec et al. (2005), Renou et al.
(2008) identified heterozygosity for a T-G transversion in intron 9 of
the LMNA gene (IVS9-12T-G), predicted to cause a frameshift and
premature termination in exon 10, with the addition of 14 new amino
acids at the C terminus. The mutation was not found in unaffected family
members or in 100 healthy controls. Analysis of fibroblasts from 2
affected individuals confirmed the presence of truncated protein and
revealed aberrant localization of lamin A/C accumulated in intranuclear
foci as well as dysmorphic nuclei with nuclear envelope herniations.

.0046
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY
LMNA, ALA529THR

In a 56-year-old Japanese woman, born of consanguineous parents, with
mandibuloacral dysplasia and type A lipodystrophy (248370), Kosho et al.
(2007) identified a homozygous 1585G-A transition in exon 9 of the LMNA
gene, resulting in an ala529-to-thr (A529T) substitution. The authors
stated that she was the oldest reported patient with the disorder. In
addition to classic MAD with lipodystrophy type A phenotype, including
progeroid appearance, acroosteolysis of the distal phalanges, and loss
of subcutaneous fat in the limbs, she had severe progressive destructive
skeletal and osteoporotic changes. Vertebral collapse led to paralysis.
However, Kosho et al. (2007) also noted that other factors may have
contributed to the severe osteoporosis observed in this patient. Another
mutation in this codon, A529V (150330.0037), results in a similar
phenotype.

.0047
MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
LMNA, LEU380SER

In a 7-year-old boy with a LNMA-related congenital muscular dystrophy
(613205), Quijano-Roy et al. (2008) identified a de novo heterozygous
mutation in exon 6 of the LMNA gene, resulting in a leu380-to-ser
(L380S) substitution. He showed decreased movements in utero, hypotonia,
talipes foot deformities, no head or trunk control, distal joint
contractures, respiratory insufficiency, and paroxysmal atrial
tachycardia. Serum creatine kinase was increased, and muscle biopsy
showed dystrophic changes.

.0048
MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
LMNA, ARG249TRP

In a 9-year-old girl with congenital muscular dystrophy (613205),
Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in
exon 4 of the LMNA gene, resulting in an arg249-to-trp (R249W)
substitution. She presented at age 3 to 6 months with axial weakness and
talipes foot deformities. She lost head support at 9 months, had
respiratory insufficiency, joint contractures, and axial and limb muscle
weakness. A de novo heterozygous R249W mutation was also identified in
an unrelated 3-year-old boy with congenital LGMD1B who showed decreased
movements in utero, hypotonia, distal contractures, no head or trunk
control, and respiratory insufficiency. Both patients had increased
serum creatine kinase and showed myopathic changes on EMG studies.

.0049
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT
MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED, INCLUDED;;
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B, INCLUDED
LMNA, GLU358LYS

Mercuri et al. (2004) identified a de novo heterozygous 1072G-A
transition in exon 5 of the LMNA gene, resulting in a glu358-to-lys
(E358K) substitution in 5 unrelated patients with muscular dystrophy.
Three patients had the common phenotype of autosomal dominant
Emery-Dreifuss muscular dystrophy (181350), 1 had early-onset LGMD1B
(159001), and the last had had a more severe disorder consistent with
congenital muscular dystrophy (613205). The mutation was not identified
in 150 controls. The patient with LGMD1B also had cardiac conduction
abnormalities, respiratory failure, and features of lipodystrophy
(151660). Mercuri et al. (2004) commented on the extreme phenotypic
variability associated with this mutation.

In 4 unrelated patients with LMNA-related congenital muscular dystrophy,
Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in
exon 6 of the LMNA gene, resulting in a glu358-to-lys (E358K)
substitution. Three patients presented before 1 year of age with
hypotonia and later developed head drop with neck muscle weakness. There
was delayed motor development with early loss of ambulation, distal limb
contractures, axial and limb muscle weakness, respiratory insufficiency
requiring mechanical ventilation, increased serum creatine kinase, and
dystrophic changes on muscle biopsy. One patient developed ventricular
tachycardia at age 20 years. The fourth patient with congenital LGMD1B
had decreased fetal movements and presented at age 3 to 6 months with
hypotonia, loss of head control, and delayed motor development.

.0050
MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
LMNA, 3-BP DEL, 94AAG

In an 18-month-old boy with LMNA-related congenital muscular dystrophy
(613205), D'Amico et al. (2005) identified a de novo heterozygous 3-bp
deletion (94delAAG) in exon 1 of the LMNA gene, resulting in the
deletion of lys32. Although he had normal early motor development, he
showed prominent neck extensor weakness resulting in a 'dropped head'
phenotype at age 1 year. He was able to stand independently but had some
difficulty walking.

.0051
VARIANT OF UNKNOWN SIGNIFICANCE
LMNA, ARG644CYS

This variant is classified as a variant of unknown significance because
its contribution to various phenotypes has not been confirmed.

An arg644-to-cys (R644C) mutation in the LMNA gene has been found in
several different phenotypic presentations (Genschel et al., 2001;
Mercuri et al., 2005; Rankin et al., 2008); however, the pathogenicity
of the mutation has not been confirmed (Moller et al., 2009).

In a German patient with dilated cardiomyopathy with no history history
of conduction system disease (see 152000), Genschel et al. (2001)
identified heterozygosity for a 1930C-T transition in exon 11 of the
LMNA gene resulting in an R644C substitution in the C-terminal domain of
lamin A. The authors noted that the mutation is solely within lamin A,
but not lamin C, whereas previously reported mutations causing dilated
cardiomyopathy are located more in the rod domain of the protein.

Mercuri et al. (2005) identified heterozygosity for the R644C mutation
in 4 patients with skeletal and cardiac muscle involvement of varying
severity. In 1 patient, the mutation was found in the affected brother
and the unaffected father, and was not found in the affected mother. The
mutation was not found in 100 unrelated control subjects.

Rankin et al. (2008) described 9 patients in 8 families with the same
mutation. Patients 1 and 2 presented with lipodystrophy and insulin
resistance; patient 1 also had focal segmental glomerulosclerosis.
Patient 3 presented with motor neuropathy, patient 4 with arthrogryposis
and dilated cardiomyopathy with left ventricular noncompaction, patient
5 with severe scoliosis and contractures, patient 6 with limb-girdle
weakness, and patient 7 with hepatic steatosis and insulin resistance.
Patients 8 and 9 were brothers who had proximal weakness and
contractures. The same LMNA was identified in 9 unaffected individuals
in these 9 families, but was not detected in 200 German and 300 British
controls. Rankin et al. (2008) suggested that extreme phenotypic
diversity and low penetrance are associated with the R644C mutation.

.0052
CARDIOMYOPATHY, DILATED, WITH HYPERGONADOTRIPIC HYPOGONADISM
LMNA, LEU59ARG

In a 17-year-old Caucasian female with dilated cardiomyopathy and
ovarian failure (212112), Nguyen et al. (2007) identified heterozygosity
for a de novo 176T-C transition in exon 1 of the LMNA gene, predicted to
result in a leu59-to-arg (L59R) substitution. Analysis of nuclear
morphology in patient fibroblasts showed more irregularity and variation
than that of control fibroblasts, with denting, blebbing, and irregular
margins. The mutation was not found in the unaffected parents or in 116
population-based controls.

In a 15-year-old Caucasian girl with dilated cardiomyopathy and ovarian
failure who died from an arrhythmia while awaiting cardiac
transplantation, McPherson et al. (2009) identified heterozygosity for
the L59R mutation in the LMNA gene. The mutation was presumed to be de
novo, although the unaffected parents declined DNA testing. The patient
also had a healthy older sister, and there was no family history of
cardiomyopathy or hypogonadism.

.0053
CARDIOMYOPATHY, DILATED, 1A
LMNA, ARG541GLY

In 2 sibs with dilated cardiomyopathy (CMD1A; 115200), Malek et al.
(2011) identified a heterozygous 1621C-G transversion in exon 10 of the
LMNA gene, resulting in an arg541-to-gly (R541G) substitution in the
C-terminal tail region. The 23-year-old male proband had a history of
paroxysmal atrioventricular nodal reentrant tachycardia and was found by
echocardiogram to have dilation of the left ventricle and global
hypokinesis. Cardiac MRI showed discrete regional areas of akinesis with
muscle thinning in the left ventricle and marked hypertrabeculation in
dysfunctional regions, as well as evidence of fibrosis. The proband's
sister had sinus bradycardia and supraventricular and ventricular
arrhythmias, but normal echocardiogram and cardiac MRI. The sibs' father
and paternal aunt had both died of dilated cardiomyopathy. In vitro
functional expression studies showed that the R541G mutant resulted in
the formation of abnormal lamin aggregates, most of which were
sickle-shaped, suggesting aberrant formation of the inner nuclear lamina
from misassembled lamin dimers.

*FIELD* SA
Krohne and Benavente (1986); Lebel and Raymond (1987)
*FIELD* RF
1. Arimura, T.; Helbling-Leclerc, A.; Massart, C.; Varnous, S.; Niel,
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Hutchinson-Gilford progeria syndrome. J. Med. Genet. 41: 609-614,
2004.

85. Quijano-Roy, S.; Mbieleu, B.; Bonnemann, C. G.; Jeannet, P.-Y.;
Colomer, J.; Clarke, N. F.; Cuisset, J.-M.; Roper, H.; De Meirleir,
L.; D'Amico, A.; Yaou, R. B.; Nascimento, A.; and 12 others: De
novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann.
Neurol. 64: 177-186, 2008.

86. Raffaele di Barletta, M.; Ricci, E.; Galluzzi, G.; Tonali, P.;
Mora, M.; Morandi, L.; Romorini, A.; Voit, T.; Orstavik, K. H.; Merlini,
L.; Trevisan, C.; Biancalana, V.; Housmanowa-Petrusewicz, I.; Bione,
S.; Ricotti, R.; Schwartz, K.; Bonne, G.; Toniolo, D.: Different
mutations in the LMNA gene cause autosomal dominant and autosomal
recessive Emery-Dreifuss muscular dystrophy. Am. J. Hum. Genet. 66:
1407-1412, 2000.

87. Rankin, J.; Auer-Grumbach, M.; Bagg, W.; Colclough, K.; Duong,
N. T.; Fenton-May, J.; Hattersley, A.; Hudson, J.; Jardine, P.; Josifova,
D.; Longman, C.; McWilliam, R.; Owen, K.; Walker, M.; Wehnert, M.;
Ellard, S.: Extreme phenotypic diversity and nonpenetrance in families
with the LMNA gene mutation R644C. Am. J. Med. Genet. 146A: 1530-1542,
2008.

88. Reddel, C. J.; Weiss, A. S.: Lamin A expression levels are unperturbed
at the normal and mutant alleles but display partial splice site selection
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2004.

89. Renou, L.; Stora, S.; Yaou, R. B.; Volk, M.; Sinkovec, M.; Demay,
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666-671, 2008.

90. Rodriguez, S.; Coppede, F.; Sagelius, H.; Eriksson, M.: Increased
expression of the Hutchinson-Gilford progeria syndrome truncated lamin
A transcript during cell aging. Europ. J. Hum. Genet. 17: 928-937,
2009.

91. Rudnik-Schoneborn, S.; Botzenhart, E.; Eggermann, T.; Senderek,
J.; Schoser, B. G. H.; Schroder, R.; Wehnert, M.; Wirth, B.; Zerres,
K.: Mutations of the LMNA gene can mimic autosomal dominant proximal
spinal muscular atrophy. Neurogenetics 8: 137-142, 2007.

92. Scaffidi, P.; Misteli, T.: Lamin A-dependent nuclear defects
in human aging. Science 312: 1059-1063, 2006.

93. Scaffidi, P.; Misteli, T.: Lamin A-dependent misregulation of
adult stem cells associated with accelerated ageing. Nature Cell
Biol. 10: 452-459, 2008.

94. Scaffidi, P.; Misteli, T.: Reversal of the cellular phenotype
in the premature aging disease Hutchinson-Gilford progeria syndrome. Nature
Med. 11: 440-445, 2005.

95. Schmidt, H. H.-J.; Genschel, J.; Baier, P.; Schmidt, M.; Ockenga,
J.; Tietge, U. J. F.; Propsting, M.; Buttner, C.; Manns, M. P.; Lochs,
H.; Brabant, G.: Dyslipemia in familial partial lipodystrophy caused
by an R482W mutation in the LMNA gene. J. Clin. Endocr. Metab. 86:
2289-2295, 2001.

96. Sebillon, P.; Bouchier, C.; Bidot, L. D.; Bonne, G.; Ahamed, K.;
Charron, P.; Drouin-Garraud, V.; Millaire, A.; Desrumeaux, G.; Benaiche,
A.; Charniot, J.-C.; Schwartz, K.; Villard, E.; Komajda, M.: Expanding
the phenotype of LMNA mutations in dilated cardiomyopathy and functional
consequences of these mutations. J. Med. Genet. 40: 560-567, 2003.

97. Shackleton, S.; Lloyd, D. J.; Jackson, S. N. J.; Evans, R.; Niermeijer,
M. F.; Singh, B. M.; Schmidt, H.; Brabant, G.; Kumar, S.; Durrington,
P. N.; Gregory, S.; O'Rahilly, S.; Trembath, R. C.: LMNA, encoding
lamin A/C, is mutated in partial lipodystrophy. Nature Genet. 24:
153-156, 2000.

98. Shen, J. J.; Brown, C. A.; Lupski, J. R.; Potocki, L.: Mandibuloacral
dysplasia caused by homozygosity for the R527H mutation in lamin A/C. J.
Med. Genet. 40: 854-857, 2003.

99. Shumaker, D. K.; Dechat, T.; Kohlmaier, A.; Adam, S. A.; Bozovsky,
M. R.; Erdos, M. R.; Eriksson, M.; Goldman, A. E.; Khuon, S.; Collins,
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100. Simha, V.; Agarwal, A. K.; Oral, E. A.; Fryns, J.-P.; Garg, A.
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2821-2824, 2003.

101. Sinensky, M.; Fantle, K.; Trujillo, M.; McLain, T.; Kupfer, A.;
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102. Sinkovec, M.; Petrovic, D.; Volk, M.; Peterlin, B.: Familial
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103. Speckman, R. A.; Garg, A.; Du, F.; Bennett, L.; Veile, R.; Arioglu,
E.; Taylor, S. I.; Lovett, M.; Bowcock, A. M.: Mutational and haplotype
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Erratum: Am. J. Hum. Genet. 67: 775 only, 2000.

104. Taylor, M. R. G.; Fain, P. R.; Sinagra, G.; Robinson, M. L.;
Robertson, A. D.; Carniel, E.; Di Lenarda, A.; Bohlmeyer, T. J.; Ferguson,
D. A.; Brodsky, G. L.; Boucek, M. M.; Lascor, J.; Moss, A. C.; Li,
W.-L. P.; Stetler, G. L.; Muntoni, F.; Bristow, M. R.; Mestroni, L.;
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Am. Coll. Cardiol. 41: 771-780, 2003. Note: Erratum: J. Am. Coll.
Cardiol. 42: 590 only, 2003.

105. Toth, J. I.; Yang, S. H.; Qiao, X.; Beigneux, A. P.; Gelb, M.
H.; Moulson, C. L.; Miner, J. H.; Young, S. G.; Fong, L. G.: Blocking
protein farnesyltransferase improves nuclear shape in fibroblasts
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12873-12878, 2005.

106. Van Berlo, J. H.; Voncken, J. W.; Kubben, N.; Broers, J. L. V.;
Duisters, R.; van Leeuwen, R. E. W.; Crijns, H. J. G. M.; Ramaekers,
F. C. S.; Hutchison, C. J.; Pinto, Y. M.: A-type lamins are essential
for TGF-beta-1 induced PP2A to dephosphorylate transcription factors. Hum.
Molec. Genet. 14: 2839-2849, 2005.

107. van der Kooi, A. J.; Bonne, G.; Eymard, B.; Duboc, D.; Talim,
B.; Van der Valk, M.; Reiss, P.; Richard, P.; Demay, L.; Merlini,
L.; Schwartz, K.; Busch, H. F. M.; de Visser, M.: Lamin A/C mutations
with lipodystrophy, cardiac abnormalities, and muscular dystrophy. Neurology 59:
620-623, 2002.

108. van Engelen, B. G. M.; Muchir, A.; Hutchison, C. J.; van der
Kooi, A. J.; Bonne, G.; Lammens, M.: The lethal phenotype of a homozygous
nonsense mutation in the lamin A/C gene. Neurology 64: 374-376,
2005.

109. Van Esch, H.; Agarwal, A. K.; Debeer, P.; Fryns, J.-P.; Garg,
A.: A homozygous mutation in the lamin A/C gene associated with a
novel syndrome of arthropathy, tendinous calcinosis, and progeroid
features. J. Clin. Endocr. Metab. 91: 517-521, 2006.

110. Vantyghem, M. C.; Pigny, P.; Maurage, C. A.; Rouaix-Emery, N.;
Stojkovic, T.; Cuisset, J. M.; Millaire, A.; Lascols, O.; Vermersch,
P.; Wemeau, J. L.; Capeau, J.; Vigouroux, C.: Patients with familial
partial lipodystrophy of the Dunnigan type due to a LMNA R482W mutation
show muscular and cardiac abnormalities. J. Clin. Endocr. Metab. 89:
5337-5346, 2004.

111. Varga, R.; Eriksson, M.; Erdos, M. R.; Olive, M.; Harten, I.;
Kolodgie, F.; Capell, B. C.; Cheng, J.; Faddah, D.; Perkins, S.; Avallone,
H.; San, H.; Qu, X.; Ganesh, S.; Gordon, L. B.; Virmani, R.; Wight,
T. N.; Nabel, E. G.; Collins, F. S.: Progressive vascular smooth
muscle cell defects in a mouse model of Hutchinson-Gilford progeria
syndrome. Proc. Nat. Acad. Sci. 103: 3250-3255, 2006.

112. Vigouroux, C.; Auclair, M.; Dubosclard, E.; Pouchelet, M.; Capeau,
J.; Courvalin, J.-C.; Buendia, B.: Nuclear envelope disorganization
in fibroblasts from lipodystrophic patients with heterozygous R482Q/W
mutations in the lamin A/C gene. J. Cell Sci. 114: 4459-4468, 2001.

113. Vigouroux, C.; Caux, F. Capeau, J.; Christin-Maitre, S.; Cohen,
A.: LMNA mutations in atypical Werner's syndrome. (Letter) Lancet 362:
1585 only, 2003.

114. Weber, K.; Plessmann, U.; Traub, P.: Maturation of nuclear lamin
A involves a specific carboxy-terminal trimming, which removes the
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of the nuclear lamina. FEBS Lett. 257: 411-414, 1989.

115. Worman, H. J.; Bonne, G.: 'Laminopathies': a wide spectrum of
human diseases. Exp. Cell Res. 313: 2121-2133, 2007.

116. Wuyts, W.; Biervliet, M.; Reyniers, E.; D'Apice, M. R.; Novelli,
G.; Storm, K.: Somatic and gonadal mosaicism in Hutchinson-Gilford
progeria. Am. J. Med. Genet. 135A: 66-68, 2005.

117. Wydner, K. L.; McNeil, J. A.; Lin, F.; Worman, H. J.; Lawrence,
J. B.: Chromosomal assignment of human nuclear envelope protein genes
LMNA, LMNB1, and LBR by fluorescence in situ hybridization. Genomics 32:
474-478, 1996.

118. Yang, S. H.; Andres, D. A.; Spielmann, H. P.; Young, S. G.; Fong,
L. G.: Progerin elicits disease phenotypes of progeria in mice whether
or not it is farnesylated. J. Clin. Invest. 118: 3291-3300, 2008.

119. Yang, S. H.; Bergo, M. O.; Toth, J. I.; Qiao, X.; Hu, Y.; Sandoval,
S.; Meta, M.; Bendale, P.; Gelb, M. H.; Young, S. G.; Fong, L. G.
: Blocking protein farnesyltransferase improves nuclear blebbing in
mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome
mutation. Proc. Nat. Acad. Sci. 102: 10291-10296, 2005.

120. Yang, S. H.; Meta, M.; Qiao, X.; Frost, D.; Bauch, J.; Coffinier,
C.; Majumdar, S.; Bergo, M. O.; Young, S. G.; Fong, L. G.: A farnesyltransferase
inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford
progeria syndrome mutation. J. Clin. Invest. 116: 2115-2121, 2006.

121. Zirn, B.; Kress, W.; Grimm, T.; Berthold, L. D.; Neubauer, B.;
Kuchelmeister, K.; Muller, U.; Hahn, A.: Association of homozygous
LMNA mutation R471C with new phenotype: mandibuloacral dysplasia,
progeria, and rigid spine muscular dystrophy. Am. J. Med. Genet. 146A:
1049-1054, 2008.

*FIELD* CN
George E. Tiller - updated: 9/10/2013
George E. Tiller - updated: 8/23/2013
Ada Hamosh - updated: 7/11/2013
Patricia A. Hartz - updated: 6/10/2013
Matthew B. Gross - updated: 3/26/2013
Cassandra L. Kniffin - updated: 10/3/2012
Ada Hamosh - updated: 6/7/2011
Cassandra L. Kniffin - updated: 2/14/2011
Marla J. F. O'Neill - updated: 10/19/2010
Cassandra L. Kniffin - updated: 10/13/2010
Paul J. Converse - updated: 9/20/2010
Patricia A. Hartz - updated: 8/10/2010
Patricia A. Hartz - updated: 7/27/2010
Cassandra L. Kniffin - updated: 4/7/2010
Nara Sobreira - updated: 1/8/2010
Cassandra L. Kniffin - updated: 1/5/2010
Cassandra L. Kniffin - updated: 11/2/2009
George E. Tiller - updated: 8/3/2009
Cassandra L. Kniffin - updated: 7/9/2009
Patricia A. Hartz - updated: 6/30/2009
George E. Tiller - updated: 5/13/2009
George E. Tiller - updated: 4/22/2009
George E. Tiller - updated: 4/16/2009
Cassandra L. Kniffin - updated: 3/5/2009
Marla J. F. O'Neill - updated: 2/19/2009
George E. Tiller - updated: 11/19/2008
Paul J. Converse - updated: 10/27/2008
John A. Phillips, III - updated: 9/23/2008
George E. Tiller - updated: 6/5/2008
Cassandra L. Kniffin - updated: 1/30/2008
Marla J. F. O'Neill - updated: 11/21/2007
Cassandra L. Kniffin - updated: 11/7/2007
George E. Tiller - updated: 10/31/2007
Cassandra L. Kniffin - updated: 10/16/2007
John A. Phillips, III - updated: 7/17/2007
George E. Tiller - updated: 6/13/2007
Cassandra L. Kniffin - updated: 5/2/2007
John A. Phillips, III - updated: 4/9/2007
John A. Phillips, III - updated: 3/22/2007
Marla J. F. O'Neill - updated: 3/8/2007
Ada Hamosh - updated: 8/1/2006
Cassandra L. Kniffin - updated: 6/26/2006
Patricia A. Hartz - updated: 3/28/2006
Marla J. F. O'Neill - updated: 3/22/2006
Marla J. F. O'Neill - updated: 2/15/2006
Victor A. McKusick - updated: 2/1/2006
Marla J. F. O'Neill - updated: 7/5/2005
Marla J. F. O'Neill - updated: 6/1/2005
George E. Tiller - updated: 5/19/2005
Victor A. McKusick - updated: 5/11/2005
John A. Phillips, III - updated: 4/13/2005
Victor A. McKusick - updated: 3/15/2005
Victor A. McKusick - updated: 2/22/2005
Victor A. McKusick - updated: 2/17/2005
Marla J. F. O'Neill - updated: 11/3/2004
Patricia A. Hartz - updated: 10/27/2004
Victor A. McKusick - updated: 10/12/2004
Cassandra L. Kniffin - reorganized: 5/3/2004
Cassandra L. Kniffin - updated: 4/15/2004
Victor A. McKusick - updated: 2/25/2004
Patricia A. Hartz - updated: 2/17/2004
Victor A. McKusick - updated: 2/9/2004
Victor A. McKusick - updated: 1/20/2004
Cassandra L. Kniffin - updated: 1/6/2004
Victor A. McKusick - updated: 10/22/2003
Victor A. McKusick - updated: 10/1/2003
John A. Phillips, III - updated: 8/25/2003
Victor A. McKusick - updated: 6/11/2003
Ada Hamosh - updated: 5/28/2003
Ada Hamosh - updated: 4/29/2003
Ada Hamosh - updated: 4/23/2003
Ada Hamosh - updated: 4/16/2003
Cassandra L. Kniffin - updated: 12/16/2002
George E. Tiller - updated: 10/28/2002
Victor A. McKusick - updated: 8/16/2002
Victor A. McKusick - updated: 3/21/2002
John A. Phillips, III - updated: 11/6/2001
John A. Phillips, III - updated: 10/4/2001
John A. Phillips, III - updated: 7/16/2001
John A. Phillips, III - updated: 3/16/2001
Victor A. McKusick - updated: 1/2/2001
George E. Tiller - updated: 8/16/2000
Victor A. McKusick - updated: 7/20/2000
Victor A. McKusick - updated: 4/13/2000
Paul Brennan - updated: 4/10/2000
Victor A. McKusick - updated: 1/28/2000
Victor A. McKusick - updated: 12/14/1999
Victor A. McKusick - updated: 12/3/1999
Victor A. McKusick - updated: 2/23/1999
Alan F. Scott - updated: 4/22/1996

*FIELD* CD
Victor A. McKusick: 1/5/1988

*FIELD* ED
carol: 09/18/2013
tpirozzi: 9/10/2013
tpirozzi: 8/23/2013
alopez: 7/11/2013
mgross: 6/10/2013
alopez: 6/10/2013
mgross: 3/26/2013
carol: 10/17/2012
carol: 10/16/2012
ckniffin: 10/3/2012
carol: 6/5/2012
alopez: 4/12/2012
alopez: 10/11/2011
terry: 10/4/2011
carol: 6/17/2011
alopez: 6/9/2011
terry: 6/7/2011
terry: 3/9/2011
wwang: 3/2/2011
ckniffin: 2/14/2011
carol: 12/7/2010
carol: 10/19/2010
wwang: 10/19/2010
ckniffin: 10/13/2010
mgross: 9/20/2010
mgross: 8/16/2010
terry: 8/10/2010
mgross: 8/6/2010
terry: 7/27/2010
wwang: 4/13/2010
ckniffin: 4/7/2010
ckniffin: 2/24/2010
carol: 1/15/2010
ckniffin: 1/11/2010
carol: 1/8/2010
carol: 1/6/2010
ckniffin: 1/5/2010
wwang: 11/5/2009
ckniffin: 11/2/2009
wwang: 8/3/2009
ckniffin: 7/9/2009
alopez: 7/7/2009
terry: 6/30/2009
wwang: 6/25/2009
terry: 6/3/2009
terry: 5/13/2009
wwang: 5/7/2009
terry: 4/22/2009
alopez: 4/16/2009
wwang: 3/11/2009
ckniffin: 3/5/2009
carol: 2/24/2009
wwang: 2/23/2009
terry: 2/19/2009
wwang: 11/19/2008
mgross: 10/27/2008
alopez: 9/23/2008
wwang: 6/11/2008
terry: 6/5/2008
wwang: 2/1/2008
ckniffin: 1/30/2008
carol: 11/26/2007
terry: 11/21/2007
wwang: 11/20/2007
ckniffin: 11/7/2007
alopez: 11/6/2007
terry: 10/31/2007
wwang: 10/25/2007
ckniffin: 10/16/2007
terry: 9/20/2007
alopez: 7/17/2007
wwang: 6/14/2007
terry: 6/13/2007
wwang: 6/8/2007
wwang: 5/11/2007
ckniffin: 5/2/2007
carol: 4/9/2007
alopez: 3/22/2007
wwang: 3/12/2007
terry: 3/8/2007
wwang: 8/9/2006
alopez: 8/3/2006
terry: 8/1/2006
wwang: 7/5/2006
ckniffin: 6/26/2006
wwang: 3/29/2006
terry: 3/28/2006
wwang: 3/22/2006
wwang: 2/23/2006
terry: 2/15/2006
alopez: 2/15/2006
terry: 2/3/2006
terry: 2/1/2006
terry: 10/12/2005
wwang: 7/8/2005
terry: 7/5/2005
alopez: 6/13/2005
wwang: 6/8/2005
wwang: 6/1/2005
tkritzer: 5/25/2005
terry: 5/19/2005
wwang: 5/18/2005
wwang: 5/11/2005
wwang: 4/13/2005
wwang: 3/22/2005
wwang: 3/18/2005
terry: 3/16/2005
terry: 3/15/2005
carol: 3/8/2005
wwang: 3/7/2005
terry: 2/22/2005
terry: 2/21/2005
terry: 2/17/2005
joanna: 2/9/2005
carol: 12/8/2004
tkritzer: 12/7/2004
tkritzer: 11/4/2004
terry: 11/3/2004
mgross: 10/27/2004
tkritzer: 10/15/2004
terry: 10/12/2004
terry: 6/28/2004
tkritzer: 5/10/2004
carol: 5/4/2004
carol: 5/3/2004
ckniffin: 4/29/2004
ckniffin: 4/28/2004
ckniffin: 4/27/2004
ckniffin: 4/15/2004
cwells: 3/4/2004
tkritzer: 2/26/2004
terry: 2/25/2004
cwells: 2/23/2004
terry: 2/17/2004
cwells: 2/16/2004
terry: 2/9/2004
carol: 1/21/2004
terry: 1/20/2004
tkritzer: 1/13/2004
ckniffin: 1/6/2004
terry: 11/11/2003
tkritzer: 10/24/2003
alopez: 10/22/2003
tkritzer: 10/22/2003
tkritzer: 10/7/2003
tkritzer: 10/1/2003
alopez: 8/25/2003
alopez: 7/7/2003
tkritzer: 6/25/2003
tkritzer: 6/24/2003
terry: 6/11/2003
alopez: 5/28/2003
terry: 5/28/2003
alopez: 5/9/2003
alopez: 4/30/2003
terry: 4/29/2003
alopez: 4/25/2003
alopez: 4/23/2003
joanna: 4/23/2003
alopez: 4/16/2003
terry: 4/16/2003
ckniffin: 4/10/2003
tkritzer: 2/28/2003
carol: 1/3/2003
tkritzer: 12/23/2002
ckniffin: 12/16/2002
cwells: 11/19/2002
terry: 11/15/2002
cwells: 10/28/2002
tkritzer: 8/23/2002
tkritzer: 8/22/2002
terry: 8/16/2002
alopez: 4/19/2002
carol: 4/2/2002
alopez: 3/27/2002
terry: 3/21/2002
mcapotos: 12/21/2001
alopez: 11/6/2001
cwells: 10/8/2001
cwells: 10/4/2001
cwells: 7/20/2001
cwells: 7/16/2001
alopez: 3/16/2001
cwells: 1/11/2001
terry: 1/2/2001
alopez: 8/16/2000
mcapotos: 7/24/2000
mcapotos: 7/20/2000
mcapotos: 6/30/2000
carol: 5/9/2000
alopez: 5/8/2000
terry: 4/13/2000
alopez: 4/10/2000
alopez: 2/1/2000
terry: 1/28/2000
alopez: 12/14/1999
carol: 12/14/1999
mgross: 12/3/1999
terry: 12/3/1999
alopez: 3/1/1999
alopez: 2/26/1999
terry: 2/23/1999
terry: 4/22/1996
mark: 4/22/1996
mark: 12/7/1995
carol: 10/1/1993
carol: 8/14/1992
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 2/3/1990
ddp: 10/27/1989

MIM 151660
*RECORD*
*FIELD* NO
151660
*FIELD* TI
#151660 LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2; FPLD2
;;FPL2;;
LIPODYSTROPHY, FAMILIAL PARTIAL, DUNNIGAN TYPE;;
read moreLIPODYSTROPHY, FAMILIAL, OF LIMBS AND LOWER TRUNK;;
LIPODYSTROPHY, REVERSE PARTIAL;;
LIPOATROPHIC DIABETES
*FIELD* TX
A number sign (#) is used with this entry because familial partial
lipodystrophy type 2 (FPLD2) is caused by heterozygous mutation in the
gene encoding lamin A/C (LMNA; 150330) on chromosome 1q21.

DESCRIPTION

Familial partial lipodystrophy is a metabolic disorder characterized by
abnormal subcutaneous adipose tissue distribution beginning in late
childhood or early adult life. Affected individuals gradually lose fat
from the upper and lower extremities and the gluteal and truncal
regions, resulting in a muscular appearance with prominent superficial
veins. In some patients, adipose tissue accumulates on the face and
neck, causing a double chin, fat neck, or cushingoid appearance.
Metabolic abnormalities include insulin-resistant diabetes mellitus with
acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual
abnormalities occur infrequently. Familial partial lipodystrophy may
also be referred to as lipoatrophic diabetes mellitus, but the essential
feature is loss of subcutaneous fat (review by Garg, 2004).

The disorder may be misdiagnosed as Cushing disease (see 219080)
(Kobberling and Dunnigan, 1986; Garg, 2004).

- Genetic Heterogeneity of Familial Partial Lipodystrophy

Familial partial lipodystrophy is a clinically and genetically
heterogeneous disorder. Types 1 and 2 were originally described as
clinical subtypes: type 1 (FPLD1; 608600), characterized by loss of
subcutaneous fat confined to the limbs (Kobberling et al., 1975), and
FPLD2, characterized by loss of subcutaneous fat from the limbs and
trunk (Dunnigan et al., 1974; Kobberling and Dunnigan, 1986). No genetic
basis for FPLD1 has yet been delineated. FPLD3 (604367) is caused by
mutation in the PPARG gene (601487) on chromosome 3p25; FPLD4 (613877)
is caused by mutation in the PLIN1 gene (170290) on chromosome 15q26;
and FPLD5 (615238) is caused by mutation in the CIDEC gene (612120) on
chromosome 3p25.

CLINICAL FEATURES

Dunnigan et al. (1974) described an autosomal dominant disorder in 2
families from the same region of northern Scotland. Features were
symmetric lipoatrophy of the trunk and limbs with rounded, full face,
tuberoeruptive xanthomata, acanthosis nigricans, and insulin-resistant
hyperinsulinism. In 1 family, 6 females, 3 of whom were personally
examined by the authors, were affected in 4 generations. In the other
family, which was probably related to the first, 6 females in 3
generations were affected. This syndrome is distinct from congenital
generalized lipodystrophy (see 608594), from progressive partial
lipodystrophy (see 613779), which is a sporadic disorder associated with
decreased levels of complement component C3, and from the acquired
generalized lipodystrophy described by Lawrence (1946).

Greene et al. (1970) and Ozer et al. (1973) described a condition of fat
accumulation around the neck, shoulders, upper back, and genitalia
associated with lean muscular limbs, phlebectasia, insulin resistance,
hyperglycemia, and type IV hyperlipoproteinemia. Affected members in the
family of Greene et al. (1970) also had hyperuricemia. Successive
generations were affected, but only females appeared to have the
full-blown disorder.

Davidson and Young (1975) reported a family with familial partial
lipodystrophy characterized by absence of subcutaneous fat from the
limbs and lower trunk with sparing of the face and upper trunk. Although
lipodystrophy was not seen in males, 5 males were diabetic. The authors
suggested X-linked dominant inheritance of the disorder. See also the
pedigree analysis of Wettke-Schafer and Kantner (1983), who discussed
the possibility of X-linked dominant inheritance with lethality in
hemizygous males.

Burn and Baraitser (1986) reported a family in which 5 members,
including 1 male, were affected with familial partial lipodystrophy in
an autosomal dominant pattern of inheritance. Clinical features included
lipoatrophy of the limbs and trunk, with sparing of the face and neck.
Affected members had muscular definition with variable muscular
hypertrophy and prominent peripheral veins. Acanthosis nigricans and
xanthomata were present. Laboratory studies showed hyperinsulinemia,
hyperlipidemia, and insulin resistance.

Reardon et al. (1990) described partial lipodystrophy in a 2-year-old
boy. There was complete absence of fat on the body and limbs, but the
face and feet were spared and the hands were puffy. Classification of
the case was considered difficult, but the distribution of loss of
subcutaneous fat corresponded to that of FPLD type 2 (Dunnigan type)
described in adults.

To investigate whether there is a unique pattern of fat distribution in
men and women with FPLD, Garg et al. (1999) performed whole-body
magnetic resonance imaging (MRI) in 1 male and 3 female patients from 2
pedigrees. MRI studies confirmed the clinical findings of near-total
absence of subcutaneous fat from all extremities. Reduction in
subcutaneous adipose tissue from the truncal area was more prominent
anteriorly than posteriorly. Increased fat stores were observed in the
neck and face. The authors concluded that FPLD results in a
characteristic absence of subcutaneous fat from the extremities, with
preservation of intermuscular fat stores.

The clinical features in families studied by Jackson et al. (1998)
included a dramatic absence of adipose tissue in the limbs and trunk,
more evident in females than in males, with fat retained on the face, in
the retroorbital space, and at periserous sites. Jackson et al. (1998)
noted that a syndrome with similar metabolic abnormalities, including
insulin resistance, hyperinsulinemia, and dyslipidemia, has been
referred to as 'metabolic syndrome X' (Reaven, 1988); see 605552.

Garg (2000) compared the anthropometric variables and prevalence of
diabetes mellitus, dyslipidemia, hypertension, and atherosclerotic
vascular disease among 17 postpubertal males and 22 females with FPLD
from 8 pedigrees. All individuals completed a questionnaire, and fasting
blood was analyzed for glucose, insulin, and lipoprotein concentrations.
Both affected men and women had similar patterns of fat loss. Compared
with the affected men, women had a higher prevalence of diabetes (18%
and 50%, respectively; P = 0.05) and atherosclerotic vascular disease
(12% and 45%, respectively; P = 0.04), and had higher serum
triglycerides (median values, 2.27 and 4.25 mmol/L, respectively; P =
0.02) and lower HDL cholesterol concentrations (age-adjusted means, 0.94
and 0.70 mmol/L, respectively; P = 0.04). The prevalence of both
hypertension and fasting serum insulin concentrations were similar. Garg
(2000) concluded that females with FPLD are more severely affected with
metabolic complications of insulin resistance than are males.

The common insulin resistance syndrome of obesity, dyslipidemia,
hyperglycemia, and hypertension has a well-recognized association with
atherosclerosis. Hegele (2001) studied the prevalence of coronary artery
disease in a group of individuals with Dunnigan-type familial partial
lipodystrophy, all of whom had mutations in the LMNA gene. All
individuals had insulin resistance, with significantly more type II
diabetes mellitus, hypertension, and dyslipidemia than in normal family
control subjects. Eight of 23 individuals (35%) had identifiable
endpoints of coronary artery disease (angina pectoris, myocardial
infarction, or coronary artery bypass surgery); 1 of these individuals
had also developed occlusive peripheral vascular disease. Only 1 control
individual had coronary artery disease. Hegele (2001) concluded that
Dunnigan-type familial partial lipodystrophy represents a single-gene
model for the more common insulin resistance syndrome.

Caux et al. (2003) reported a 27-year-old man with generalized
lipodystrophy, hepatic steatosis, insulin-resistant diabetes,
hypertrophic cardiomyopathy, and leukomelanodermic papules. He had been
diagnosed with hepatic steatosis at the age of 21 years,
hypertriglyceridemia at 22 years, and diabetes at 25 years. The
patient's appearance included square jaw, thin lips, high forehead,
marked thinning of the eyebrows, pectus excavatum, and narrow shoulders.
Generalized atrophy of subcutaneous fat resulted in sunken cheeks and
muscular pseudohypertrophy of the 4 limbs. Multiple whitish papules on
pigmented skin were present on the neck, trunk, and upper limbs and to a
lesser extent on the lower limbs. The patient mentioned that his
subcutaneous body fat progressively disappeared from the age of 14
years, after the onset of puberty. The development of the skin lesions
occurred simultaneously. No acanthosis nigricans was present. Gray hair
had been present since the age of 17 years. Muscular strength was
normal, and no neurologic defects were detected. Cardiac involvement
included concentric hypertrophy of the left ventricle without cavity
dilatation, associated with thickened and regurgitant valves, aortic
fibrotic nodules, and calcification of the posterior annulus. Doppler
echocardiographic findings were similar to those described in aged
patients. Abdominal MRI revealed an absence of body fat at both the
subcutaneous and visceral levels. Osteopoikilosis, acroosteolysis,
hypoplastic clavicles, wide sutures, and mandibular hypoplasia,
previously described in mandibuloacral dysplasia (MAD; 248370), were not
identified by bone x-rays. Typical symptoms of Werner syndrome (277700),
such as cataracts, short stature, and skeletal anomalies, were absent.
Family members were unaffected, and no consanguinity was reported.
Genetic analysis identified a heterozygous mutation in the LMNA gene
(R133L; 150330.0027). Vigouroux et al. (2003) emphasized that a striking
feature in the patient reported by Caux et al. (2003) was muscular
hypertrophy of the limbs, which contrasts with the muscular atrophy
usually present in Werner syndrome. Muscular hypertrophy, along with
insulin-resistant diabetes and hypertriglyceridemia, is more often
associated with LMNA-linked Dunnigan lipodystrophy. Fibroblasts from
this patient showed nuclear abnormalities identical to those described
in Dunnigan lipodystrophy (Vigouroux et al., 2001).

Spuler et al. (2007) reported 13 FPLD2 patients with neuromuscular
involvement. Twelve had muscle hypertrophy, 9 had severe myalgias, and 8
had multiple nerve entrapment syndromes. Skeletal muscle biopsies showed
marked hypertrophy of type 1 and type 2 muscle fibers and nonspecific
myopathic changes. Sural nerve biopsies showed numerous paranodal myelin
swellings, or tomacula. Skeletal muscle myostatin (MSTN; 601788) mRNA
was decreased in patients compared to controls, but no MSTN gene
mutations were detected. FPLD2 muscle specimens had a large number of
SMAD (see, e.g., 601595) molecules adhered to the nuclear membrane and
not found within the nucleus, compared to normal muscle or muscle from a
patient with a non-FPLD LMNA disease. Spuler et al. (2007) concluded
that neuromuscular features of FPLD2 may result from disrupted SMAD-MSTN
signaling.

Vantyghem et al. (2008) compared the fertility and occurrence of
obstetric complications of women with familial partial lipodystrophy due
to LMNA mutations with those of nonaffected relatives, women from the
general population, and women with polycystic ovary syndrome (PCOS).
Data were obtained from clinical follow-up of 7 families with patients
exhibiting mutations in LMNA (14 affected among 48 women). The mean
number of live children per woman was 1.7 in affected patients versus
2.8 in nonaffected relatives. Fifty-four percent of LMNA-mutated women
exhibited a clinical phenotype of PCOS, 28% suffered from infertility,
50% experienced at least one miscarriage, 36% developed gestational
diabetes, and 14% experienced eclampsia and fetal death. Vantyghem et
al. (2008) concluded that in these LMNA-linked lipodystrophic patients,
the prevalence of PCOS, infertility, and gestational diabetes was higher
than in the general population. Moreover, the prevalence of gestational
diabetes and miscarriages was higher in lipodystrophic LMNA-mutated
women than previously reported in PCOS women with similar body mass
index. Women with lipodystrophies due to LMNA mutations are at high risk
of infertility, gestational diabetes, and obstetrical complications and
require reinforced gynecologic and obstetric care.

INHERITANCE

Although X-linked dominant inheritance had been suggested, affected
pedigrees reported by Robbins et al. (1982), Jackson et al. (1997), and
Peters et al. (1998) showed clear autosomal dominant inheritance.

MAPPING

In a genomewide scan using highly polymorphic short tandem repeats
(STRs) in individuals from 5 well-characterized FPLD pedigrees, Peters
et al. (1998) mapped the disease locus to 1q21-q22. The maximum 2-point
lod score obtained with a highly polymorphic microsatellite at D1S2624
at theta (max) = 0.0 was 5.84. Multipoint linkage analysis yielded a
peak lod score of 8.25 between D1S305 and D1S1600. There was no evidence
for genetic heterogeneity in these pedigrees.

Anderson et al. (1999) performed linkage and haplotype analysis with
highly polymorphic microsatellite markers on a large, multigenerational
Caucasian kindred of German ancestry with the Dunnigan form of familial
partial lipodystrophy. The family showed affected members through at
least 4 generations. The results yielded a maximum 2-point lod score of
4.96 at theta = 0 for marker D1S2721 and a maximum multipoint lod score
of 6.27 near the same marker. The results of the haplotype analysis
supported the minimal candidate region reported by Peters et al. (1998).

Jackson et al. (1998) ascertained 2 multigenerational families, with a
combined total of 18 individuals with partial lipodystrophy. A
genomewide linkage search using microsatellite markers provided
conclusive evidence of linkage to 1q21 (D1S498, maximum lod score = 6.89
at theta = 0.00), with no evidence of heterogeneity. Haplotype and
multipoint analysis supported the location of the locus (which they
symbolized PLD, for partial lipodystrophy) within a 21.2-cM chromosomal
region flanked by markers D1S2881 and D1S484.

MOLECULAR GENETICS

In 5 Canadian FPLD families, Cao and Hegele (2000) identified
heterozygosity for a mutation in the lamin A/C gene (R482Q;
150330.0010). There were no differences in age, gender, or body mass
index in Q482/R482 heterozygotes compared with R482/R482 homozygotes
(normals) from these families; however, there were significantly more
Q482/R482 heterozygotes who had definite partial lipodystrophy and frank
diabetes. Also compared with the normal homozygotes, heterozygotes had
significantly higher serum insulin and C-peptide (see 176730) levels.
The LMNA heterozygotes with diabetes were significantly older than
heterozygotes without diabetes.

In 6 families and 3 isolated cases of partial lipodystrophy, Shackleton
et al. (2000) found heterozygosity for an R482W missense mutation in the
LMNA gene (150330.0011), in the same codon as the R482Q mutation found
in Canadian families by Cao and Hegele (2000). Shackleton et al. (2000)
identified a third mutation in that codon, R482L (150330.0012), in
another family with partial lipodystrophy.

Speckman et al. (2000) analyzed the LMNA gene in 15 families with
partial lipodystrophy and identified the R482Q mutation in 5, the R482W
mutation in 7, and a G465D mutation (150330.0015) in 1.

Schmidt et al. (2001) identified a family with partial lipodystrophy
carrying the R482W missense mutation in the LMNA gene. Clinically, the
loss of subcutaneous fat and muscular hypertrophy, especially of the
lower extremities, started as early as in childhood. Acanthosis and
severe hypertriglyceridemia developed later in life, followed by
diabetes. Characterization of the lipoprotein subfractions revealed that
affected children present with hyperlipidemia. The presence and severity
of hyperlipidemia seem to be influenced by age, apolipoprotein E
genotype, and the coexistence of diabetes mellitus.

Lanktree et al. (2007) analyzed the LMNA gene in 3 unrelated patients
with FPLD2 and identified heterozygosity for 3 different missense
mutations, all affecting only the lamin A isoform and each changing a
conserved residue. Two of the mutations, D230N (150330.0042) and R399C
(150330.0043), respectively, were 5-prime to the NLS, which is not
typical of LMNA mutations in FPLD2.

GENOTYPE/PHENOTYPE CORRELATIONS

In a family with an atypical form of FPLD, Speckman et al. (2000)
identified an R582H mutation (150220.0016) in the LMNA gene. In a
follow-up of this same family, Garg et al. (2001) reported that 2
affected sisters showed less severe loss of subcutaneous fat from the
trunk and extremities with some retention of fat in the gluteal region
and medial parts of the proximal thighs compared to women with typical
FPLD2. Neither of the sisters with atypical FPLD2 had acanthosis
nigricans or hirsutism, and only 1 had diabetes mellitus, borderline
hypertriglyceridemia, and irregular menstrual periods. The sisters also
tended to have lower serum triglycerides and higher HDL cholesterol
concentrations compared to those with typical FPLD2. Both types had
similar excess of fat deposition in the neck, face, intraabdominal, and
intermuscular regions. Noting that the R582H mutation interrupts only
the lamin A protein, Garg et al. (2001) suggested that in typical FPLD2,
interruption of both lamins A and C causes a more severe phenotype than
that seen in atypical FPLD2, in which only lamin A is altered.

PATHOGENESIS

Araujo-Vilar et al. (2009) studied 7 patients from 1 kindred with FPLD2
caused by an R482W mutation in the LMNA gene (150330.0011). Two had type
2 diabetes mellitus. As a group, the patients with FPLD2 were found to
have significantly higher insulin resistance compared to 10 controls.
The expression of LMNA in abdominal and peripheral adipose tissues was
similar in both groups. In patients with FPLD2, thigh adipose tissue,
but not abdomen adipose tissue, showed significantly decreased
expression of PPARG2 (601487), RB1 (614041), cyclin D3 (CCND3; 123834),
and LPL (609708) (67%, 25%, 38%, and 66%, respectively) compared to
controls. There was an accumulation of prelamin A in the nuclear
envelope of peripheral adipose tissue of patients with FPLD2. Electron
microscopic analysis of adipocytes of patients with FPLD2 showed defects
in the peripheral heterochromatin and a nuclear fibrous dense lamina.
Collectively, the findings indicated that transcriptional activity of
several genes involved in adipogenesis is altered in affected tissues of
patients with FPLD2.

*FIELD* RF
1. Anderson, J. L.; Khan, M.; David, W. S.; Mahdavi, Z.; Nuttall,
F. Q.; Krech, E.; West, S. G.; Vance, J. M.; Pericak-Vance, M. A.;
Nance, M. A.: Confirmation of linkage of hereditary partial lipodystrophy
to chromosome 1q21-22. Am. J. Med. Genet. 82: 161-165, 1999.

2. Araujo-Vilar, D.; Lattanzi, G.; Gonzalez-Mendez, B.; Costa-Freitas,
A. T.; Prieto, D.; Columbaro, M.; Mattioli, E.; Victoria, B.; Martinez-Sanchez,
N.; Ramazanova, A.; Fraga, M.; Beiras, A.; Forteza, J.; Dominguez-Gerpe,
L.; Calvo, C.; Lado-Abeal, J.: Site-dependent differences in both
prelamin A and adipogenic genes in subcutaneous adipose tissue of
patients with type 2 familial partial lipodystrophy. J. Med. Genet. 46:
40-48, 2009.

3. Burn, J.; Baraitser, M.: Partial lipoatrophy with insulin resistant
diabetes and hyperlipidaemia (Dunnigan syndrome). J. Med. Genet. 23:
128-130, 1986.

4. Cao, H.; Hegele, R. A.: Nuclear lamin A/C R482Q mutation in Canadian
kindreds with Dunnigan-type familial partial lipodystrophy. Hum.
Molec. Genet. 9: 109-112, 2000.

5. Caux, F.; Dubosclard, E.; Lascols, O.; Buendia, B.; Chazouilleres,
O.; Cohen, A.; Courvalin, J.-C.; Laroche, L.; Capeau, J.; Vigouroux,
C.; Christin-Maitre, S.: A new clinical condition linked to a novel
mutation in lamins A and C with generalized lipoatrophy, insulin-resistant
diabetes, disseminated leukomelanodermic papules, liver steatosis,
and cardiomyopathy. J. Clin. Endocr. Metab. 88: 1006-1013, 2003.

6. Davidson, M. B.; Young, R. T.: Metabolic studies in familial partial
lipodystrophy of the lower trunk and extremities. Diabetologia 11:
561-568, 1975.

7. Dunnigan, M. G.; Cochrane, M.; Kelly, A.; Scott, J. W.: Familial
lipoatrophic diabetes with dominant transmission: a new syndrome. Quart.
J. Med. 43: 33-48, 1974.

8. Garg, A.: Acquired and inherited lipodystrophies. New Eng. J.
Med. 350: 1220-1234, 2004.

9. Garg, A.: Gender differences in the prevalence of metabolic complications
in familial partial lipodystrophy (Dunnigan variety). J. Clin. Endocr.
Metab. 85: 1776-1782, 2000.

10. Garg, A.; Peshock, R. M.; Fleckenstein, J. L.: Adipose tissue
distribution pattern in patients with familial partial lipodystrophy
(Dunnigan variety). J. Clin. Endocr. Metab. 84: 170-174, 1999.

11. Garg, A.; Vinaitheerthan, M.; Weatherall, P. T.; Bowcock, A. M.
: Phenotypic heterogeneity in patients with familial partial lipodystrophy
(Dunnigan variety) related to the site of missense mutations in lamin
A/C gene. J. Clin. Endocr. Metab. 86: 59-65, 2001.

12. Greene, M. L.; Glueck, C. J.; Fujimoto, W. Y.; Seegmiller, J.
E.: Benign symmetric lipomatosis (Launosis-Bensaude adenolipomatosis)
with gout and hyperlipoproteinemia. Am. J. Med. 48: 239-246, 1970.

13. Hegele, R. A.: Premature atherosclerosis associated with monogenic
insulin resistance. Circulation 103: 2225-2229, 2001.

14. Jackson, S. N.; Howlett, T. A.; McNally, P. G.; O'Rahilly, S.;
Trembath, R. C.: Dunnigan-Kobberling syndrome: an autosomal dominant
form of partial lipodystrophy. Quart. J. Med. 90: 27-36, 1997.

15. Jackson, S. N. J.; Pinkney, J.; Bargiotta, A.; Veal, C. D.; Howlett,
T. A.; McNally, P. G.; Corral, R.; Johnson, A.; Trembath, R. C.:
A defect in the regional deposition of adipose tissue (partial lipodystrophy)
is encoded by a gene at chromosome 1q. Am. J. Hum. Genet. 63: 534-540,
1998.

16. Kobberling, J.; Dunnigan, M. G.: Familial partial lipodystrophy:
two types of an X linked dominant syndrome, lethal in the hemizygous
state. J. Med. Genet. 23: 120-127, 1986.

17. Kobberling, J.; Willms, B.; Kattermann, R.; Creutzfeldt, W.:
Lipodystrophy of the extremities: a dominantly inherited syndrome
associated with lipoatrophic diabetes. Humangenetik 29: 111-120,
1975.

18. Lanktree, M.; Cao, H.; Rabkin, S. W.; Hanna, A.; Hegele, R. A.
: Novel LMNA mutations seen in patients with familial partial lipodystrophy
subtype 2 (FPLD2; MIM 151660) (Letter) Clin. Genet. 71: 183-186,
2007.

19. Lawrence, R. D.: Lipodystrophy and hepatomegaly with diabetes,
lipaemia, and other metabolic disturbances: a case throwing new light
on the action of insulin. Lancet 247: 724-731 and 773-775, 1946.
Note: Originally Volume I.

20. Ozer, F. L.; Lichtenstein, J. R.; Kwiterovich, P. O., Jr.; McKusick,
V. A.: New genetic variety of lipodystrophy. (Abstract) Clin. Res. 21:
533 only, 1973.

21. Peters, J. M.; Barnes, R.; Bennett, L.; Gitomer, W. M.; Bowcock,
A. M.; Garg, A.: Localization of the gene for familial partial lipodystrophy
(Dunnigan variety) to chromosome 1q21-22. Nature Genet. 18: 292-295,
1998.

22. Reardon, W.; Temple, I. K.; Mackinnon, H.; Leonard, J. V.; Baraitser,
M.: Partial lipodystrophy syndromes--a further male case. Clin.
Genet. 38: 391-395, 1990.

23. Reaven, G. M.: Role of insulin resistance in human disease. Diabetes 37:
1595-1607, 1988.

24. Robbins, D. C.; Horton, E. S.; Tulp, O.; Sims, E. A. H.: Familial
partial lipodystrophy: complications of obesity in the non-obese? Metabolism 31:
445-452, 1982.

25. Schmidt, H. H.-J.; Genschel, J.; Baier, P.; Schmidt, M.; Ockenga,
J.; Tietge, U. J. F.; Propsting, M.; Buttner, C.; Manns, M. P.; Lochs,
H.; Brabant, G.: Dyslipemia in familial partial lipodystrophy caused
by an R482W mutation in the LMNA gene. J. Clin. Endocr. Metab. 86:
2289-2295, 2001.

26. Shackleton, S.; Lloyd, D. J.; Jackson, S. N. J.; Evans, R.; Niermeijer,
M. F.; Singh, B. M.; Schmidt, H.; Brabant, G.; Kumar, S.; Durrington,
P. N.; Gregory, S.; O'Rahilly, S.; Trembath, R. C.: LMNA, encoding
lamin A/C, is mutated in partial lipodystrophy. Nature Genet. 24:
153-156, 2000.

27. Speckman, R. A.; Garg, A.; Du, F.; Bennett, L.; Veile, R.; Arioglu,
E.; Taylor, S. I.; Lovett, M.; Bowcock, A. M.: Mutational and haplotype
analyses of families with familial partial lipodystrophy (Dunnigan
variety) reveal recurrent missense mutations in the globular C-terminal
domain of lamin A/C. Am. J. Hum. Genet. 66: 1192-1198, 2000. Note:
Erratum: Am. J. Hum. Genet. 67: 775 only, 2000.

28. Spuler, S.; Kalbhenn, T.; Zabojszcza, J.; van Landeghem, F. K.
H.; Ludtke, A.; Wenzel, K.; Koehnlein, M.; Schuelke, M.; Ludemann,
L.; Schmidt, H. H.: Muscle and nerve pathology in Dunnigan familial
partial lipodystrophy. Neurology 68: 677-683, 2007.

29. Vantyghem, M. C.; Vincent-Desplanques, D.; Defrance-Faivre, F.;
Capeau, J.; Fermon, C.; Valat, A. S.; Lascols, O.; Hecart, A. C.;
Pigny, P.; Delemer, B.; Vigouroux, C.; Wemeau, J. L.: Fertility and
obstetrical complications in women with LMNA-related familial partial
lipodystrophy. J. Clin. Endocr. Metab. 93: 2223-2229, 2008.

30. Vigouroux, C.; Auclair, M.; Dubosclard, E.; Pouchelet, M.; Capeau,
J.; Courvalin, J. C.; Buendia, B.: Nuclear envelope disorganization
in fibroblasts from lipodystrophic patients with heterozygous R482Q/W
mutations in the lamin A/C gene. J. Cell Sci. 114: 4459-4468, 2001.

31. Vigouroux, C.; Caux, F. Capeau, J.; Christin-Maitre, S.; Cohen,
A.: LMNA mutations in atypical Werner's syndrome. (Letter) Lancet 362:
1585 only, 2003.

32. Wettke-Schafer, R.; Kantner, G.: X-linked dominant inherited
diseases with lethality in hemizygous males. Hum. Genet. 64: 1-23,
1983.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Normal or increased facial adipose tissue;
Round, full face;
[Neck];
Normal or increased adipose tissue around the neck

CARDIOVASCULAR:
[Vascular];
Prominent superficial veins;
Atherosclerosis;
Hypertension

ABDOMEN:
[Liver];
Hepatomegaly;
Hepatic steatosis;
[Pancreas];
Pancreatitis, acute in some

GENITOURINARY:
[External genitalia, female];
Labial pseudohypertrophy;
Polycystic ovary disease (uncommon)

SKIN, NAILS, HAIR:
[Skin];
Prominent superficial veins;
Xanthomata;
Acanthosis nigricans (uncommon);
[Hair];
Hirsutism (uncommon)

MUSCLE, SOFT TISSUE:
Partial lipodystrophy (abnormal distribution of subcutaneous adipose
tissue);
Loss of subcutaneous truncal adipose tissue;
Loss of subcutaneous adipose tissue in limbs;
Loss of adipose tissue occurs around puberty;
No lipodystrophy in face and neck;
Muscular appearance;
Muscular hypertrophy;
Myalgia;
Increased intramuscular fat;
Increased intraabdominal fat;
Skeletal muscle biopsy shows hypertrophy of type 1 and 2 muscle fibers;
Nonspecific myopathic changes

NEUROLOGIC FEATURES:
[Peripheral nervous system];
Nerve compression;
Nerve entrapment syndromes;
Enlarged peripheral nerves;
Tomaculae (paranodal myelin swellings)

ENDOCRINE FEATURES:
Insulin-resistant diabetes mellitus (onset around puberty)

LABORATORY ABNORMALITIES:
Hyperglycemia;
Hyperinsulinemia;
Increased serum triglycerides;
Decreased HDL cholesterol

MISCELLANEOUS:
Onset of clinical features around puberty

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0003)

*FIELD* CN
Cassandra L. Kniffin - updated: 12/7/2007
Cassandra L. Kniffin - revised: 5/5/2004

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 04/13/2011
joanna: 3/19/2008
ckniffin: 12/7/2007
joanna: 3/8/2007
joanna: 3/14/2005
ckniffin: 5/5/2004
joanna: 3/28/2003
alopez: 3/6/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 2/13/2009
John A. Phillips, III - updated: 1/9/2009
Cassandra L. Kniffin - updated: 12/7/2007
Marla J. F. O'Neill - updated: 11/21/2007
Cassandra L. Kniffin - reorganized: 5/3/2004
Victor A. McKusick - updated: 3/14/2003
Paul Brennan - updated: 3/6/2002
John A. Phillips, III - updated: 2/9/2001
Victor A. McKusick - updated: 12/14/1999
John A. Phillips, III - updated: 11/24/1999
Victor A. McKusick - updated: 2/14/1999
Victor A. McKusick - updated: 7/16/1998
Victor A. McKusick - updated: 2/24/1998

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 05/21/2013
ckniffin: 5/20/2013
carol: 6/17/2011
carol: 4/14/2011
ckniffin: 4/14/2011
carol: 1/6/2010
ckniffin: 1/5/2010
wwang: 6/1/2009
ckniffin: 2/13/2009
terry: 1/29/2009
alopez: 1/9/2009
wwang: 1/7/2008
ckniffin: 12/7/2007
carol: 11/27/2007
carol: 11/26/2007
terry: 11/21/2007
carol: 5/3/2004
ckniffin: 4/29/2004
ckniffin: 4/27/2004
carol: 5/28/2003
carol: 3/28/2003
tkritzer: 3/24/2003
terry: 3/14/2003
alopez: 3/6/2002
carol: 2/6/2002
carol: 6/14/2001
mgross: 5/31/2001
terry: 2/9/2001
carol: 1/12/2001
alopez: 12/14/1999
carol: 12/14/1999
alopez: 11/24/1999
carol: 2/19/1999
carol: 2/15/1999
carol: 2/14/1999
terry: 8/5/1998
terry: 7/16/1998
alopez: 2/27/1998
terry: 2/25/1998
terry: 2/24/1998
alopez: 6/2/1997
mimadm: 11/5/1994
terry: 7/15/1994
warfield: 4/12/1994
carol: 11/11/1993
supermim: 3/16/1992
carol: 12/13/1990

MIM 159001
*RECORD*
*FIELD* NO
159001
*FIELD* TI
#159001 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1B; LGMD1B
;;MUSCULAR DYSTROPHY, PROXIMAL, TYPE 1B
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
autosomal dominant limb-girdle muscular dystrophy type 1B (LGMD1B) is
caused by mutation in the gene encoding lamin A/C (LMNA; 150330).
Allelic disorders with overlapping phenotypes include autosomal dominant
Emery-Dreifuss muscular dystrophy (181350) and dilated cardiomyopathy
type 1A (CMD1A; 115200).

For a phenotypic description and a discussion of genetic heterogeneity
of autosomal dominant LGMD, see LGMD1A (159000).

CLINICAL FEATURES

Van der Kooi et al. (1996, 1997) described the clinical picture of 3
families with autosomal dominant LGMD associated with cardiac
involvement. In affected individuals, symmetric weakness started in the
proximal lower-limb muscles before the age of 20 years. In the third or
fourth decade, upper-limb muscles gradually became affected as well.
Early contractures of the spine were absent, and contractures of elbows
and Achilles tendons were either minimal or late, distinguishing this
disorder from Emery-Dreifuss muscular dystrophy. Serum creatine kinase
activity was normal to moderately elevated. EMG and muscle biopsy were
consistent with mild muscular dystrophy. Cardiologic abnormalities were
found in 62.5% of the patients, including atrioventricular conduction
disturbances and dysrhythmias, presenting as bradycardia, syncopal
attacks necessitating pacemaker implantation, and sudden cardiac death
at the age of approximately 50 years. Two patients had dilated
cardiomyopathy. In nearly all patients, neuromuscular symptomatology
preceded cardiologic involvement. Van der Kooi et al. (1997) commented
that the cardiologic abnormalities in these families, consisting
predominantly of AV conduction disturbances, resembled closely the
disorder in the family reported by Graber et al. (1986) (see CMD1A;
115200).

Mercuri et al. (2004) reported a 30-year-old woman with a severe form of
LGMD1B. She was noted to be hypotonic at birth and had feeding
difficulties, but motor development was within the normal range,
although she was never able to run. At age 7 years, she had generalized
hypotonia, waddling gait, and severe limb muscle wasting and weakness.
The weakness progressed rapidly in early adulthood, and she became
wheelchair-bound in her mid-twenties. Examination at age 30 showed
marked midface hypoplasia with a broad nasal bridge. She also had
features of lipodystrophy (FPLD2; 151660), with increased subcutaneous
adipose tissue in the back and facial region and extremely thin
extremities. Contractures were present in the elbows, finger flexors,
spine, and Achilles tendons. Cardiac involvement included recurrent
atrial fibrillation and a brady/tachy syndrome. She also had respiratory
insufficiency. Genetic analysis showed a de novo heterozygous mutation
in the LMNA gene (E358K; 150330.0049).

Rudnik-Schoneborn et al. (2007) reported 2 unrelated German women with
LGMD1B who were initially diagnosed with adult-onset proximal spinal
muscular atrophy (e.g., 271150 and 182980). The first patient developed
proximal muscle weakness in her thirties, followed by cardiac arrhythmia
and dilated cardiomyopathy in her late fifties. Family history revealed
that the paternal grandmother had proximal muscle weakness and died from
heart disease at age 52, and a paternal aunt had 'walking difficulties'
since youth. The patient's father and 4 cousins all had cardiac disease
without muscle weakness ranging from nonspecific 'heart attacks' to
dilated cardiomyopathy and arrhythmia. The second patient presented with
slowly progressive proximal muscle weakness beginning in the lower
extremities and later involving the upper extremities. EMG showed both
neurogenic and myopathic defects in the quadriceps muscle. At age 53
years, she was diagnosed with atrioventricular conduction block and
arrhythmia requiring pacemaker implantation. Family history showed that
her mother had walking difficulties from age 40 years and died of a
heart attack at age 54. Six other deceased family members had suspected
cardiomyopathy without muscle involvement. In both patients, genetic
analysis confirmed a heterozygous mutation in the LMNA gene (150330.0017
and 150330.0038, respectively).

Benedetti et al. (2007) reported 27 individuals with mutations in the
LMNA gene resulting in a wide range of neuromuscular disorders.
Phenotypic analysis yielded 2 broad groups of patients. One group
included patients with childhood onset who had skeletal muscle
involvement with predominant scapuloperoneal and facial weakness,
consistent with EDMD or congenital muscular dystrophy. The second group
included patients with later or adult onset who had cardiac disorders or
a limb-girdle myopathy, consistent with LGMD1B. Features common to both
groups included involvement of the neck or paravertebral muscles and an
age-dependent development of cardiomyopathy, most after age 25 years.
Both groups also had an increased frequency of sudden death in the
family. Genetic analysis showed that the group with childhood onset
tended to have missense mutations, whereas the group with adult onset
tended to have truncating mutations. Benedetti et al. (2007) speculated
that there may be 2 different pathogenetic mechanisms associated with
neuromuscular LMNA-related disorders: late-onset phenotypes may arise
through loss of LMNA function secondary to haploinsufficiency, whereas
dominant-negative or toxic gain-of-function mechanisms may underly the
more severe early phenotypes.

MAPPING

Van der Kooi et al. (1997) demonstrated linkage in their 3 families to
chromosome 1q11-q21, with a combined maximum 2-point lod score greater
than 12 at theta = 0.0. The concomitant presence of mild muscular
dystrophy indicated a difference between the cardiomyopathy disorder in
the family of Graber et al. (1986) and LGMD1B. However, the authors
suggested that they could be allelic disorders. They mentioned
connexin-40 (121013) as a potential candidate gene.

MOLECULAR GENETICS

In 3 LGMD1B families linked to markers on chromosome 1q11-q21, Muchir et
al. (2000) identified mutations in the LMNA gene: a missense mutation
(150330.0017), a deletion of a codon (150330.0018), and a splice donor
site mutation (150330.0019). The 3 mutations were identified in all
affected members of the corresponding families and were absent in 100
unrelated control subjects. The authors thus demonstrated that LGMD1B,
Emery-Dreifuss muscular dystrophy, and dilated cardiomyopathy type 1 are
allelic disorders.

The clinical and histologic phenotypes of an LGMD1B family, including a
newborn child with a homozygous LMNA Y259X mutation (150330.0035) were
described by van Engelen et al. (2005). The heterozygous Y259 mutation
led to the classic LGMD1B phenotype, while the homozygous mutation
caused a lethal phenotype.

Charniot et al. (2003) described a French family with autosomal dominant
severe dilated cardiomyopathy with conduction defects or
atrial/ventricular arrhythmias and a skeletal muscular dystrophy of the
quadriceps muscles. Cardiac involvement preceded neuromuscular disease
in all affected patients, whereas in previously reported cases with both
cardiac and neuromuscular involvement, the neuromuscular disorders had
preceded cardiac abnormalities. Twenty-nine members of the family were
examined, of whom 11 were classified as affected and 4 had both cardiac
and peripheral muscle symptoms. Average age at onset of cardiac symptoms
was 40 years. Bilateral motor deficit of the quadriceps deteriorated
progressively, without involvement of other muscles. Affected members
were found to have an arg377-to-his mutation in the LMNA gene (R377H;
150330.0017), which had been reported in patients with limb-girdle
muscular dystrophy type 1B by Muchir et al. (2000). Charniot et al.
(2003) suggested that factors other than the R377H mutation may have
influenced the phenotypic expression in this family.

*FIELD* RF
1. Benedetti, S.; Menditto, I.; Degano, M.; Rodolico, C.; Merlini,
L.; D'Amico, A.; Palmucci, L.; Berardinelli, A.; Pegoraro, E.; Trevisan,
C. P.; Morandi, L.; Moroni, I.; and 15 others: Phenotypic clustering
of lamin A/C mutations in neuromuscular patients. Neurology 69:
1285-1292, 2007.

2. Charniot, J.-C.; Pascal, C.; Bouchier, C.; Sebillon, P.; Salama,
J.; Duboscq-Bidot, L.; Peuchmaurd, M.; Desnos, M.; Artigou, J.-Y.;
Komajda, M.: Functional consequences of an LMNA mutation associated
with a new cardiac and non-cardiac phenotype. Hum. Mutat. 21: 473-481,
2003.

3. Graber, H. L.; Unverferth, D. V.; Baker, P. B.; Ryan, J. M.; Baba,
N.; Wooley, C. F.: Evolution of a hereditary cardiac conduction and
muscle disorder: a study involving a family with six generations affected. Circulation 74:
21-35, 1986.

4. Mercuri, E.; Poppe, M.; Quinlivan, R.; Messina, S.; Kinali, M.;
Demay, L.; Bourke, J.; Richard, P.; Sewry, C.; Pike, M.; Bonne, G.;
Muntoni, F.; Bushby, K.: Extreme variability of phenotype in patients
with an identical missense mutation in the lamin A/C Gene: from congenital
onset with severe phenotype to milder classic Emery-Dreifuss variant. Arch.
Neurol. 61: 690-694, 2004.

5. Muchir, A.; Bonne, G.; van der Kooi, A. J.; van Meegen, M.; Baas,
F.; Bolhuis, P. A.; de Visser, M.; Schwartz, K.: Identification of
mutations in the gene encoding lamins A/C in autosomal dominant limb
girdle muscular dystrophy with atrioventricular conduction disturbances
(LGMD1B). Hum. Molec. Genet. 9: 1453-1459, 2000.

6. Rudnik-Schoneborn, S.; Botzenhart, E.; Eggermann, T.; Senderek,
J.; Schoser, B. G. H.; Schroder, R.; Wehnert, M.; Wirth, B.; Zerres,
K.: Mutations of the LMNA gene can mimic autosomal dominant proximal
spinal muscular atrophy. Neurogenetics 8: 137-142, 2007.

7. van der Kooi, A. J.; Ledderhof, T. M.; de Voogt, W. G.; Res, J.
C. J.; Bouwsma, G.; Troost, D.; Busch, H. F. M.; Becker, A. E.; de
Visser, M.: A newly recognized autosomal dominant limb girdle muscular
dystrophy with cardiac involvement. Ann. Neurol. 39: 636-642, 1996.

8. van der Kooi, A. J.; van Meegen, M.; Ledderhof, T. M.; McNally,
E. M.; de Visser, M.; Bolhuis, P. A.: Genetic localization of a newly
recognized autosomal dominant limb-girdle muscular dystrophy with
cardiac involvement (LGMD1B) to chromosome 1q11-21. Am. J. Hum. Genet. 60:
891-895, 1997.

9. van Engelen, B. G. M.; Muchir, A.; Hutchison, C. J.; van der Kooi,
A. J.; Bonne, G.; Lammens, M.: The lethal phenotype of a homozygous
nonsense mutation in the lamin A/C gene. Neurology 64: 374-376,
2005.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Atrioventricular conduction disturbances;
Bradycardia;
Dilated cardiomyopathy;
Sudden cardiac death

SKELETAL:
[Limbs];
Mild joint contractures with sparing of the elbows

MUSCLE, SOFT TISSUE:
Hip girdle muscle weakness (usually presenting symptom);
Shoulder girdle muscle weakness;
Muscle biopsy shows mild dystrophic changes;
EMG shows myopathic changes

LABORATORY ABNORMALITIES:
Increased serum creatine kinase

MISCELLANEOUS:
Onset before age 20 years;
Slowly progressive;
Muscle symptoms precede cardiac symptoms;
Genetic heterogeneity (see LGMD1A 159000 for overview);
Allelic disorders with overlapping phenotypes include autosomal dominant
Emery-Dreifuss muscular dystrophy (181350), dilated cardiomyopathy
type 1A (115200), and congenital muscular dystrophy (613205).

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0017)

*FIELD* CN
Cassandra L. Kniffin - updated: 01/05/2010
Cassandra L. Kniffin - updated: 7/9/2009
Cassandra L. Kniffin - revised: 6/6/2003

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
ckniffin: 01/05/2010
joanna: 11/23/2009
ckniffin: 7/9/2009
ckniffin: 1/12/2005
joanna: 1/23/2004
ckniffin: 6/6/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 1/5/2010
Cassandra L. Kniffin - updated: 7/9/2009
Cassandra L. Kniffin - updated: 5/15/2007
Victor A. McKusick - updated: 5/10/2005
Cassandra L. Kniffin - reorganized: 6/11/2003
George E. Tiller - updated: 8/16/2000
Victor A. McKusick - updated: 6/12/1997

*FIELD* CD
Victor A. McKusick: 12/17/1993

*FIELD* ED
carol: 01/06/2010
ckniffin: 1/5/2010
wwang: 8/3/2009
ckniffin: 7/9/2009
carol: 2/24/2009
wwang: 6/8/2007
wwang: 5/17/2007
ckniffin: 5/15/2007
wwang: 5/11/2005
terry: 5/10/2005
terry: 7/28/2003
carol: 6/11/2003
ckniffin: 6/6/2003
alopez: 8/16/2000
mark: 6/16/1997
alopez: 6/13/1997
terry: 6/12/1997
alopez: 6/2/1997
mimadm: 12/2/1994
carol: 12/17/1993

MIM 176670
*RECORD*
*FIELD* NO
176670
*FIELD* TI
#176670 HUTCHINSON-GILFORD PROGERIA SYNDROME; HGPS
;;PROGERIA
PROGERIA SYNDROME, CHILDHOOD-ONSET, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because both classic
infantile-onset and later childhood-onset Hutchinson-Gilford progeria
syndrome (HGPS) can be caused by de novo heterozygous mutation in the
lamin A gene (LMNA; 150330) on chromosome 1q22.

DESCRIPTION

Hutchinson-Gilford progeria syndrome is a rare disorder characterized by
short stature, low body weight, early loss of hair, lipodystrophy,
scleroderma, decreased joint mobility, osteolysis, and facial features
that resemble aged persons. Cardiovascular compromise leads to early
death. Cognitive development is normal. Onset is usually within the
first year of life (review by Hennekam, 2006). The designation
Hutchinson-Gilford progeria syndrome appears to have been first used by
DeBusk (1972).

A subset of patients with heterozygous mutations in the LMNA gene and a
phenotype similar to HGPS have shown onset of the disorder in late
childhood or in the early teenage years, and have longer survival than
observed in classic HGPS (Chen et al., 2003; Hegele, 2003).

Other disorders with a less severe, but overlapping phenotype include
mandibuloacral dysplasia (MADA; 248370), an autosomal disorder caused by
homozygous or compound heterozygous mutations in the LMNA gene, dilated
cardiomyopathy with hypergonadotropic hypogonadism (212112), caused by
heterozygous mutation in the LMNA gene, and Werner syndrome (277700), an
autosomal recessive progeroid syndrome caused by homozygous or compound
heterozygous mutations in the RECQL2 gene (604611).

CLINICAL FEATURES

Hastings Gilford (1904) gave the name progeria to this disorder in an
article in which he also assigned the term ateleiosis to a pituitary
growth hormone deficiency (262400). He provided no photographs of
progeria and indicated that 'only two well-marked instances have so far
been recorded.' Death from angina pectoris at age 18 years was noted.
Jonathan Hutchinson (1886) had previously written about the disorder
(McKusick, 1952). Hutchinson's report was accompanied by a photograph of
his patient at the age of 15.5 years showing the stereotypic phenotype
of this disorder. Hutchinson emphasized the lack of hair but the other
features were evident: disproportionately large head, 'pinched' facial
features, lipodystrophy, incomplete extension at the knees and elbows
indicating stiffness of joints, and generally a senile appearance.

Paterson (1922) recorded the cases of 2 possibly affected brothers whose
parents were first cousins. Photographs were not published and the
diagnosis is not completely certain. The full report was simply the
following: 'A boy, aged 8 years. Condition has been present since
birth... There are 4 children in the family; the girls are unaffected,
both boys are affected. The senile condition of the skin and facies
should be noted. The vessels show arteriosclerosis. (There is almost
complete absence of subcutaneous fat.)'

Ogihara et al. (1986) described a Japanese patient with progeria who
survived to age 45, dying of myocardial infarction. Clinically, he
seemed typical except for the unusually long survival. According to
reviews of the literature, the age at death ranges from 7 to 27.5 years,
with a median age of 13.4 years. Dyck et al. (1987) reported coronary
artery bypass surgery and percutaneous transluminal angioplasty in a
14-year-old girl with this disorder.

The 2 brothers reported as having progeria by Parkash et al. (1990)
probably had mandibuloacral dysplasia (MADA; 248370). Fatunde et al.
(1990) described a family in which 3 of 6 sibs had progeria. A seventh
sib, who had died before the time of study, may have been affected.

Rodriguez et al. (1999) reported a severe prenatal form of progeria in a
female fetus at 35 weeks' gestation. The patient was born by cesarean
section. Severe growth retardation and oligohydramnios had been detected
at 32 weeks by ultrasonography. This was the first patient reported in
the English literature; 3 cases of neonatal HGPS had been reported in
France (De Martinville et al., 1980; Labeille et al., 1987). All 4
patients died early, 2 on the first day of life and the others at 6 and
20 months of age, respectively. Unlike classic HGPS, however, none of
the 4 presented clinical signs of coronary occlusion. Faivre et al.
(1999) concluded that the patient reported by Rodriguez et al. (1999)
could not in fact have had Hutchinson-Gilford progeria syndrome. They
also thought it unlikely that the infant had Wiedemann-Rautenstrauch
syndrome, also known as neonatal progeroid syndrome (264090). Rodriguez
and Perez-Alonso (1999) defended the 'diagnosis of progeria syndrome
[as] the only one possible.'

De Paula Rodrigues et al. (2002) reported details of the involvement of
bones and joints in a seemingly typical example of progeria in an
8-year-old girl.

Hennekam (2006) provided an exhaustive review of the phenotype of HGPS,
based on data from 10 of his own cases and 132 cases from the
literature.

Merideth et al. (2008) comprehensively studied 15 children between 1 and
17 years of age, representing nearly half of the world's known patients
with Hutchinson-Gilford progeria syndrome. The previously described
features were documented. Previously unrecognized findings included
prolonged prothrombin times, elevated platelet counts and serum
phosphorus levels, low-frequency conductive hearing loss, and functional
oral deficits. Growth impairment was not related to inadequate
nutrition, insulin unresponsiveness, or growth hormone deficiency.
Growth hormone treatment in a few patients increased height growth by
10% and weight growth by 50%. Cardiovascular studies revealed
diminishing vascular function with age, including elevated blood
pressure, reduced vascular compliance, decreased ankle-brachial indices,
and adventitial thickening. The ankle-brachial index was used to measure
the difference in blood pressure between the legs and arms in 11
children. The index was abnormal in 2 patients, indicating arterial
disease in the legs.

- Childhood-Onset HGPS

Chen et al. (2003) found that 26 (20%) of 129 probands referred to their
international registry for molecular diagnosis of the autosomal
recessive progeroid disorder Werner syndrome (277700) did not have
mutations in the RECQL2 gene (604611). Sequencing of the LMNA gene in
these individuals found that 4 (15%) had heterozygous mutations: A57P
(150330.0030), R133L (in 2 persons) (150330.0027), and L140R
(150330.0031), all of which altered relatively conserved residues within
lamin A/C. Fibroblasts from the patient with the L140R mutation had a
substantially enhanced proportion of nuclei with altered morphology and
mislocalized lamins. These individuals had a more severe phenotype than
those with RECQL2-associated Werner syndrome. Although Chen et al.
(2003) designated these patients as having 'atypical Werner syndrome,'
Hegele (2003) suggested that the patients more likely had late-onset
Hutchinson-Gilford progeria syndrome. Hegele (2003) reviewed the
clinical features of the 4 patients with LMNA mutations reported by Chen
et al. (2003), and stated that the designation of 'atypical Werner
syndrome' appeared somewhat insecure. He noted that the comparatively
young ages of onset in the patients with mutant LMNA would be just as
consistent with late-onset HGPS as with early-onset Werner syndrome.
These patients also expressed features of nonprogeroid laminopathies,
including insulin resistance (FPLD2; 151660), dilated cardiomyopathy
(115200), and phalangeal osteosclerosis (MADA; 248370). Hegele (2003)
suggested that genomic DNA analysis can help draw a diagnostic line that
clarifies potential overlap between older patients with
Hutchinson-Gilford syndrome and younger patients with Werner syndrome,
and that therapies may depend on precise molecular classification.

McPherson et al. (2009) noted phenotypic similarities between the
patient studied by Chen et al. (2003) with the A57P LMNA mutation and 2
unrelated patients with heterozygosity for an adjacent mutation in the
LMNA gene, L59R (150330.0052). Features common to these 3 patients
included premature ovarian failure, dilated cardiomyopathy,
lipodystrophy, and progressive facial and skeletal changes involving
micrognathia and sloping shoulders, but not acroosteolysis. Although the
appearance of these patients was somewhat progeroid, none had severe
growth failure, alopecia, or rapidly progressive atherosclerosis, and
McPherson et al. (2009) suggested that the phenotype represents a
distinct laminopathy (dilated cardiomyopathy and hypergonadotropic
hypogonadism, 212112).

BIOCHEMICAL FEATURES

In cultured skin fibroblasts of patients with progeria, Goldstein and
Moerman (1978) demonstrated an increased fraction of heat-labile enzymes
and other altered proteins. Freshly obtained cells, namely,
erythrocytes, showed similar heat-lability of G6PD and
6-phosphogluconate dehydrogenases in a girl with progeria. Both parents
showed intermediate values, consistent with recessive inheritance.
Normal HLA antigens were found by Brown et al. (1980).

Cao et al. (2011) reported the effect of rapamycin on the cellular
phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished
nuclear blebbing, delayed the onset of cellular senescence, and enhanced
the degradation of progerin in HGPS cells. Rapamycin also decreased the
formation of insoluble progerin aggregates and induced clearance through
autophagic mechanisms in normal fibroblasts. Cao et al. (2011) concluded
that their findings suggested an additional mechanism for the beneficial
effects of rapamycin on longevity and encouraged the hypothesis that
rapamycin treatment could provide clinical benefit for children with
HGPS.

INHERITANCE

The majority of patients with HGPS have de novo heterozygous dominant
mutations in the LMNA gene. Presumably, patients with the disorder do
not survive long enough to reproduce (Eriksson et al., 2003; Cao and
Hegele, 2003).

DeBusk (1972) maintained that of 19 cases reported to that date in which
consanguinity was sought, in only 3 were the parents related. He
suggested that progeria could conceivably be dominant and the rare
instances of affected sibs be the result of germinal mosaicism.

DeBusk (1972) and Jones et al. (1975) reported a paternal age effect,
supporting autosomal dominant inheritance. In 20 cases in which parental
age was known, the mean paternal and maternal ages were 35.6 and 28.8
years, respectively, and the median ages 31 and 28, respectively. In 7
U.S. cases, the mean paternal age was 37.1. On the basis of the paternal
age effect, the low frequency of parental consanguinity, and the report
of progeric monozygotic twins of 14 normal sibs, Brown (1979) favored
autosomal dominant inheritance, with most cases resulting from a de
novo, new, mutation.

In a patient with Hutchinson-Gilford progeria, Wuyts et al. (2005)
identified a heterozygous mutation in the LMNA gene (G608G;
150330.0022). In lymphocyte DNA from the parents, normal wildtype
alleles were observed in the father, but a low signal corresponding to
the mutant allele was detected in the mother's DNA. A segregation study
confirmed that the patient's mutation was transmitted from the mother,
who showed germline and somatic mosaicism without clinical
manifestations of HGPS.

- Reports Suggesting Autosomal Recessive Inheritance

Recessive inheritance was suggested by the report from Egypt of affected
sisters, children of first cousins (Gabr et al., 1960). Erecinski et al.
(1961) described photographically typical progeria in 2 brothers. Among
the 9 offspring of 2 sisters, Rava (1967) found 6 affected.

Maciel (1988) reported an inbred Brazilian family in which presumed
Hutchinson-Gilford progeria syndrome had occurred in members of 2
sibships related as first cousins once removed. Although autosomal
recessive inheritance was unmistakable, the disorder was not
definitively HGPS.

Khalifa (1989) described a consanguineous Libyan family in which 2 males
and 1 female in 2 sibships related as cousins had seemingly typical
Hutchinson-Gilford progeria. Repeated nonhealing fractures were the
presenting manifestation in the proband.

Verstraeten et al. (2006) reported a 2-year-old Dutch boy with features
of HGPS who was compound heterozygous for 2 mutations in the LMNA gene.
After the age of 1 year, he showed failure to thrive, poor growth, and
hair loss. Clinical features included prominent forehead, prominent
veins, narrow nasal bridge, small mouth, lipodystrophy, and dental
crowding. He also had significant shortening of the distal phalanges
with osteolysis and tufting, as well as osteoresorption of the distal
ends of the clavicles. Some of these features were more consistent with
mandibuloacral dysplasia. Fibroblasts derived from the patient showed
irregularly shaped nuclei with blebs, honeycomb figures, large and
poorly defined protrusions, and intra/trans-nuclear tubule-like
structures. There was no accumulation of prelamin A, as usually observed
in typical HGPS. A clinically unaffected sister was heterozygous for 1
of the mutations, and each clinically unaffected parent was heterozygous
for 1 of the mutations. A smaller percentage of fibroblasts derived from
the parents showed the nuclear abnormalities that were present in the
proband.

CYTOGENETICS

Brown et al. (1990) described identical twins with progeria who
developed heart failure at the age of 8 and died within 1 month of each
other. Cytogenetic analysis showed an inverted insertion in the long arm
of chromosome 1 in 70% of cells. Brown et al. (1990) suggested that a
gene for progeria may be located on chromosome 1. Evidence for possible
bioinactive growth hormone was presented with a suggestion of treatment
of progeria with growth hormone.

In a 9-year-old patient with a classic clinical picture of
Hutchinson-Gilford progeria, Luengo et al. (2002) found an interstitial
deletion of chromosome 1q23. Because a perturbation in glycosylation in
connective tissue had been demonstrated in patients with this condition,
they suggested that the defect may reside in the B4GALT3 gene (604014),
which maps to 1q23.

Lewis (2003) suggested that the defect causing progeria might reside in
the proline/arginine-rich end leucine-rich repeat protein gene (PRELP;
601914), which maps to chromosome 1q32 and is a small leucine-rich
proteoglycan that binds type I collagen to basement membranes and type
II collagen to cartilage.

POPULATION GENETICS

Hennekam (2006) stated that the incidence of HGPS was 1 per 8 million
newborns in the US between 1915 and 1967 and 1 per 4 million newborns in
the Netherlands between 1900 and 2005. Patients have been reported from
all continents and all ethnic backgrounds.

MOLECULAR GENETICS

Eriksson et al. (2003) reported de novo point mutations in lamin A
(150330) causing Hutchinson-Gilford progeria syndrome. The HGPS gene was
initially localized to chromosome 1q by observing 2 cases of uniparental
isodisomy of 1q, and 1 case with a 6-Mb paternal interstitial deletion.
Eighteen of 20 classic cases of HGPS harbored the identical de novo
single-base substitution, a C-to-T transition resulting in a silent
gly-to-gly change at codon 608 within exon 11 (G608G; 150330.0022). One
additional case was identified with a different substitution within the
same codon (150330.0023). Both of these mutations were shown to result
in activation of a cryptic splice site within exon 11 of the lamin A
gene, resulting in production of a protein product that deletes 50 amino
acids near the C terminus. This prelamin A still retains the CAAX box
but lacks the site for endoproteolytic cleavage. Immunofluorescence of
HGPS fibroblasts with antibodies directed against lamin A revealed that
many cells showed visible abnormalities of the nuclear membrane.

Cao and Hegele (2003) studied cell lines from 7 HGPS probands. Five
carried the common mutation within exon 11 of LMNA, which they termed
2036C-T (150330.0022). In 1 of 7 patients, they identified the G608S
mutation (150330.0023). Cao and Hegele (2003) confirmed the findings of
Eriksson et al. (2003) using the same cell lines. In 1 patient with an
HGPS phenotype who was 28 years old at the time that DNA was obtained,
Cao and Hegele (2003) identified compound heterozygosity for 2 missense
mutations in the LMNA gene (150330.0025 and 150330.0026); this patient
was later determined (Brown, 2004) to have mandibuloacral dysplasia.

De Sandre-Giovannoli et al. (2003) identified the exon 11 cryptic splice
site activation mutation (1824C-T+1819-1968del; 150330.0022) in 2 HGPS
patients. Immunocytochemical analyses of lymphocytes from 1 patient
using specific antibodies directed against lamin A/C, lamin A, and lamin
B1 showed that most cells had strikingly altered nuclear sizes and
shapes, with envelope interruptions accompanied by chromatin extrusion.
Lamin A was detected in 10 to 20% of HGPS lymphocytes. Only lamin C was
present in most cells, and lamin B1 was found in the nucleoplasm,
suggesting that it had dissociated from the nuclear envelope due to the
loss of lamin A. Western blot analysis showed 25% of normal lamin A
levels, and no truncated form was detected.

In 4 affected members of a consanguineous family from north India,
Plasilova et al. (2004) with features of both MADA (248370) and HGPS
resulting from a homozygous missense mutation in the LMNA gene
(150330.0033). Plasilova et al. (2004) suggested that autosomal
recessive HGPS and MADA may represent a single disorder with varying
degrees of severity.

GENOTYPE/PHENOTYPE CORRELATIONS

Moulson et al. (2007) reported 2 unrelated patients with extremely
severe forms of HGPS associated with unusual mutations in the LMNA gene.
(150330.0036 and 150330.0040, respectively). Both mutations resulted in
increased use of the cryptic exon 11 donor splice site observed with the
common 1824C-T mutation (150330.0022). As a consequence, the ratios of
mutant progerin mRNA and protein to wildtype were higher than in typical
HGPS patients. The findings indicated that the level of progerin
expression correlates to the severity of the disease.

PATHOGENESIS

By light and electron microscopy of fibroblasts from HGPS patients
carrying the 1824C-T mutation, Goldman et al. (2004) found significant
changes in nuclear shape, including lobulation of the nuclear envelope,
thickening of the nuclear lamina, loss of peripheral heterochromatin,
and clustering of nuclear pores. These structural defects worsened as
the HGPS cells aged in culture, and their severity correlated with an
apparent accumulation of mutant protein, which Goldman et al. (2004)
designated LA delta-50. Goldman et al. (2004) concluded that expression
of LA delta-50 has an age-dependent, cumulative, and ultimately
devastating effect on nuclear architecture and function that is
responsible for premature aging in HGPS patients.

Glynn and Glover (2005) studied the effects of farnesylation inhibition
on nuclear phenotypes in cells expressing normal and 1824C-T mutant
lamin A. Expression of a GFP-progerin fusion protein in normal
fibroblasts caused a high incidence of nuclear abnormalities (as seen in
HGPS fibroblasts), and resulted in abnormal nuclear localization of
GFP-progerin in comparison with the localization pattern of GFP-lamin A.
Expression of a GFP-lamin A fusion containing a mutation preventing the
final cleavage step, which caused the protein to remain farnesylated,
displayed identical localization patterns and nuclear abnormalities as
in HGPS cells and in cells expressing GFP-progerin. Exposure to a
farnesyltransferase inhibitor (FTI), PD169541, caused a significant
improvement in the nuclear morphology of cells expressing GFP-progerin
and in HGPS cells. Glynn and Glover (2005) proposed that abnormal
farnesylation of progerin may play a role in the cellular phenotype in
HGPS cells, and suggested that FTIs may represent a therapeutic option
for patients with HGPS.

Using various mechanical measurements, including photobleaching assays,
biophysical analysis under hypo- and hyperosmotic conditions, and
micropipette aspiration, Dahl et al. (2006) demonstrated that the lamina
in HGPS cells has a reduced ability to rearrange after mechanical stress
compared to wildtype cells. In response to dynamic changes in the cell,
mutant LMNA associated more tightly with the nuclear lamina than
wildtype LMNA. Polarization microscopy studies showed that the lamins in
HGPS nuclei were birefringent, forming orientationally ordered
microdomains with reduced deformability. Dahl et al. (2006) suggested
that the altered mechanical properties of HGPS cells may lead to
misexpression of mechanosensitive genes.

Hennekam (2006) noted that the HGPS-like disorder,
mandibuloacrodysplasia with type B lipodystrophy (MADB; 608612), and
restrictive dermopathy (275210) are both caused by mutation in the
ZMPSTE24 gene (606480), resulting in abnormal posttranslational
processing of lamin A. The author suggested that patients with atypical
progeria may have ZMPSTE24 mutation.

Wang et al. (2006) found that cultured HGPS fibroblasts showed early
accelerated growth followed by rapid decline in proliferation in later
passages compared to normal cells. HGPS fibroblasts had shrunken cell
bodies with coarse cell membranes starting from early passages and
showed loss of cell-to-cell growth inhibition with cell clustering. HPGS
nuclei also showed multiple morphologic abnormalities compared to normal
fibroblasts. Using microarray, RT-PCR, and Western blot analysis, Wang
et al. (2006) found significantly increased (approximately 100-fold)
expression of the ANK3 gene (600465) in fibroblast cell lines from a
patient with HGPS compared to a normal control cell line.

Varela et al. (2008) found that combined treatment of HGPS cells with
both statins and aminobisphosphonates resulted in improved nuclear
morphology and decreased accumulation of prelamin A. The mechanism of
treatment involved the inhibition of farnesyl pyrophosphate synthesis
and prevention of cross-prenylation of prelamin A.

Liu et al. (2011) reported the generation of induced pluripotent stem
cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS
iPSCs showed absence of progerin, and more importantly, lacked the
nuclear envelope and epigenetic alterations normally associated with
premature aging. Upon differentiation of HGPS iPSCs, progerin and its
aging-associated phenotypic consequences were restored. Specifically,
directed differentiation of HGPS iPSCs to vascular smooth muscle cells
led to the appearance of premature senescence phenotypes associated with
vascular aging. Additionally, their studies identified DNA-dependent
protein kinase catalytic subunit (PRKDC; 600899) as a downstream target
of progerin. The absence of nuclear PRKDC holoenzyme correlated with
premature as well as physiologic aging. Because progerin also
accumulates during physiologic aging, Liu et al. (2011) argued that
their results provided an in vitro iPSC-based model to study the
pathogenesis of human premature and physiologic vascular aging.

ANIMAL MODEL

In progeria, the accumulation of farnesyl-prelamin A disrupts the
structural scaffolding for the cell nucleus, leading to misshapen
nuclei. Farnesyltransferase inhibitors (FTIs) can reverse this cellular
abnormality (e.g., Mallampalli et al., 2005). Fong et al. (2006) tested
the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse
model of progeria. The FTI-treated mice exhibited improved body weight,
grip strength, bone integrity, and percent survival at 20 weeks of age.
Fong et al. (2006) concluded that FTIs may have beneficial effects in
humans with progeria.

Yang et al. (2006) generated mice with a targeted HGPS mutation (Lmna
HG/+) and observed phenotypes similar to those in human HGPS patients,
including retarded growth, reduced amounts of adipose tissue,
micrognathia, osteoporosis, and osteolytic lesions in bone, which caused
spontaneous rib fractures in the mutant mice. Treatment with an FTI
increased adipose tissue mass, improved body weight curves, reduced the
number of rib fractures, and improved bone mineralization and bone
cortical thickness.

Varga et al. (2006) created a mouse model for progeria harboring the
common human G608G LMNA mutation (150330.0022). Mutant mice showed
striking arterial changes, including progressive loss of vascular smooth
muscle cells in the medial layer, elastic fiber breakage, and
proteoglycan and collagen deposition in a pattern very similar to that
seen in children with HGPS. Arterial calcification, adventitial
thickening, and severe loss of vascular smooth muscle cells was observed
in older mutant mice. Older mutant mice also showed impaired blood
pressure regulation.

In conditional transgenic mice with a human LMNA mutation, Sagelius et
al. (2008) observed external features of the syndrome, including hair
thinning and skin crusting, at postnatal week 4. After phenotype
development, transgenic expression was turned off, and there was a rapid
improvement of the phenotype within 4 weeks of transgenic suppression.
After 13 weeks, pathologic examination showed that skin from the mutant
mice was almost indistinguishable from wildtype skin, and there was also
improvement in teeth. Sagelius et al. (2008) concluded that, in these
tissues, expression of the progeria mutation did not cause irreversible
damage and that reversal of disease phenotype is possible.

HISTORY

Ayres and Mihan (1974) suggested that a fault in vitamin E metabolism
may be at the root of progeria and recommended vitamin E therapy for its
antioxidant effect.

*FIELD* SA
Brown and Darlington (1980); Goldstein and Moerman (1975); Harley
et al. (1981); Rautenstrauch et al. (1977); Viegas et al. (1974)
*FIELD* RF
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31. Jones, K. L.; Smith, D. W.; Harvey, M. A. S.; Hall, B. D.; Quan,
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33. Labeille, B.; Dupuy, P.; Frey-Follezou, I.; Larregue, M.; Maquart,
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iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472: 221-225,
2011.

36. Luengo, W. D.; Martinez, A. R.; Lopez, R. O.; Basalo, C. M.; Rojas-Atencio,
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L. P.; Canizalez-Tarazona, J.; Pena, J.; Luengo, J. D.; Hernandez,
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*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Postnatal onset growth retardation

HEAD AND NECK:
[Face];
Midface hypoplasia;
Micrognathia

CARDIOVASCULAR:
[Cardiac];
Premature atherosclerosis;
Premature coronary artery disease;
Angina pectoris;
Myocardial infarction;
Congestive heart failure

SKELETAL:
Generalized osteoporosis with pathologic fractures

SKIN, NAILS, HAIR:
[Skin];
Absence of subcutaneous fat;
[Hair];
Alopecia

MISCELLANEOUS:
Probably autosomal dominant with rare instances of affected sibs due
to germinal mosaicism;
Premature aging;
Median life expectancy, 13.4 years;
Paternal age effect

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0022)

*FIELD* CN
Ada Hamosh - updated: 04/23/2003
Michael J. Wright - revised: 6/23/1999
Ada Hamosh - revised: 6/23/1999

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/23/2003
alopez: 4/16/2003
joanna: 5/2/2002
joanna: 10/2/2001
root: 6/24/1999
kayiaros: 6/23/1999

*FIELD* CN
Ada Hamosh - updated: 10/11/2011
Ada Hamosh - updated: 6/7/2011
Marla J. F. O'Neill - updated: 10/19/2010
Cassandra L. Kniffin - updated: 1/11/2010
George E. Tiller - updated: 5/13/2009
Cassandra L. Kniffin - updated: 2/11/2009
Cassandra L. Kniffin - updated: 7/22/2008
Victor A. McKusick - updated: 3/10/2008
Cassandra L. Kniffin - updated: 12/17/2007
Marla J. F. O'Neill - updated: 3/8/2007
Victor A. McKusick - updated: 2/23/2007
Cassandra L. Kniffin - updated: 8/9/2006
Ada Hamosh - updated: 4/14/2006
Marla J. F. O'Neill - updated: 5/23/2005
Victor A. McKusick - updated: 3/8/2005
Victor A. McKusick - updated: 11/9/2004
Marla J. F. O'Neill - updated: 11/3/2004
Patricia A. Hartz - updated: 10/27/2004
Victor A. McKusick - updated: 10/20/2004
Victor A. McKusick - updated: 2/17/2004
Ada Hamosh - updated: 4/29/2003
Cassandra L. Kniffin - updated: 4/28/2003
Ada Hamosh - updated: 4/23/2003
Ada Hamosh - updated: 4/16/2003
Victor A. McKusick - updated: 1/10/2003
Victor A. McKusick - updated: 12/28/1999
Victor A. McKusick - updated: 2/26/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 08/31/2012
terry: 3/26/2012
carol: 2/29/2012
alopez: 10/11/2011
alopez: 6/9/2011
terry: 6/7/2011
carol: 5/25/2011
carol: 10/19/2010
terry: 10/13/2010
carol: 1/15/2010
ckniffin: 1/11/2010
wwang: 6/25/2009
terry: 6/3/2009
terry: 5/13/2009
wwang: 4/6/2009
ckniffin: 2/11/2009
wwang: 7/25/2008
ckniffin: 7/22/2008
alopez: 3/19/2008
terry: 3/10/2008
ckniffin: 12/17/2007
wwang: 4/2/2007
ckniffin: 3/16/2007
wwang: 3/12/2007
terry: 3/8/2007
wwang: 3/1/2007
terry: 2/23/2007
wwang: 8/11/2006
ckniffin: 8/9/2006
alopez: 4/18/2006
terry: 4/14/2006
wwang: 6/8/2005
wwang: 6/1/2005
terry: 5/23/2005
carol: 3/8/2005
terry: 2/21/2005
carol: 12/8/2004
alopez: 11/15/2004
terry: 11/9/2004
tkritzer: 11/4/2004
terry: 11/3/2004
mgross: 10/27/2004
terry: 10/20/2004
carol: 2/17/2004
alopez: 7/7/2003
alopez: 5/28/2003
alopez: 5/9/2003
alopez: 4/30/2003
terry: 4/29/2003
carol: 4/28/2003
ckniffin: 4/28/2003
alopez: 4/23/2003
joanna: 4/23/2003
carol: 4/17/2003
alopez: 4/16/2003
terry: 4/16/2003
tkritzer: 1/23/2003
tkritzer: 1/13/2003
terry: 1/10/2003
carol: 12/4/2002
tkritzer: 12/3/2002
terry: 11/27/2002
carol: 12/29/1999
terry: 12/28/1999
carol: 3/1/1999
terry: 2/26/1999
mimadm: 2/25/1995
supermim: 3/16/1992
carol: 4/11/1991
carol: 3/28/1991
carol: 12/5/1990
carol: 11/26/1990

MIM 181350
*RECORD*
*FIELD* NO
181350
*FIELD* TI
#181350 EMERY-DREIFUSS MUSCULAR DYSTROPHY 2, AUTOSOMAL DOMINANT; EDMD2
;;EMD2;;
EMERY-DREIFUSS MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT;;
read moreSCAPULOILIOPERONEAL ATROPHY WITH CARDIOPATHY;;
MUSCULAR DYSTROPHY WITH EARLY CONTRACTURES AND CARDIOMYOPATHY, AUTOSOMAL
DOMINANT;;
HAUPTMANN-THANNHAUSER MUSCULAR DYSTROPHY
EMERY-DREIFUSS MUSCULAR DYSTROPHY, ATYPICAL, AUTOSOMAL RECESSIVE,
INCLUDED;;
EMERY-DREIFUSS MUSCULAR DYSTROPHY 3, AUTOSOMAL RECESSIVE, INCLUDED;
EDMD3, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
Emery-Dreifuss muscular dystrophy (EDMD2) is caused by heterozygous
mutation in the gene encoding lamin A/C (LMNA; 150330).

See also limb-girdle muscular dystrophy type 1B (LGMD1B; 159001) and
LMNA-related congenital muscular dystrophy (613206), allelic disorders
with overlapping phenotypes.

DESCRIPTION

EDMD is characterized by myopathic changes in certain skeletal muscles
and early contractures at the neck, elbows, and Achilles tendons, as
well as cardiac conduction defects. 'Classic' Emery-Dreifuss muscular
dystrophy (310300) is an X-linked disorder caused by mutation in the
emerin gene (EMD; 300384) on Xq28 (Emery, 1989).

For a discussion of genetic heterogeneity of EDMD, see 310300.

CLINICAL FEATURES

Jennekens et al. (1975) reported 2 unrelated Dutch families in which 26
members had slowly progressive muscle weakness with
scapulo-ilio-peroneal distribution and late-onset cardiomyopathy.
Inheritance was autosomal dominant. Disease onset ranged from 17 to 42
years, and cardiomyopathy appeared late in the disease, always after
skeletal muscle involvement. Skeletal muscle biopsies showed neurogenic
and myopathic changes with inflammatory cell reaction and perivascular
cuffing. The disorder was intermediate between typical limb-girdle
muscular dystrophy (e.g., 159000), in which weakness appears first in
the pelvic girdle and thigh muscles, and from scapuloperoneal atrophy
(e.g., 181400), in which there is neurogenic weakness in the long
extensors of the feet and toes.

Chakravarti and Pearce (1981) reported 4 members of a family with
scapuloperoneal syndrome. Biopsies of skeletal muscle and spinal cord
confirmed a myopathic basis of the muscular atrophy. The authors noted
some unique features in this family, including early age at onset, rapid
progression, early muscle contractures, and a high incidence of severe
cardiomyopathy. Fenichel et al. (1982) reported autosomal dominant
humeropelvic muscular dystrophy and cardiomyopathy.

Miller et al. (1985) reported a woman with early-onset, slowly
progressive humeroperoneal muscle weakness and adult-onset
cardiomyopathy. There was some pelvic girdle involvement. She had marked
restriction of neck flexion beginning at age 11 years, with contractures
of the posterior cervical muscles, elbows, and ankles. EMG and biopsies
indicated a myopathy. At age 25 years, she was found to have atrial
fibrillation with slow ventricular rate, necessitating a cardiac
pacemaker. At age 30, she had difficulty climbing stairs or walking long
distances because of leg weakness. Cervical spine imaging showed
hypoplasia of vertebral bodies with partial fusion of apophyseal joints
and reduced flexion. The patient's father was seen at age 35 because of
limitation of neck flexion, noted weakness of leg muscles at age 38,
became aware of cardiac abnormalities at age 39, began use of a cane at
age 52, was chair-bound at age 60, and died at age 62 of progressive
heart failure. Miller et al. (1985) noted that the phenotype in this
family was consistent with Emery-Dreifuss muscular dystrophy, but that
the inheritance was autosomal dominant.

Becker (1986) suggested that the Hauptmann-Thannhauser eponym be
attached to autosomal dominant muscular dystrophy with early
contractures and cardiomyopathy because Hauptmann and Thannhauser
(1941), 2 German immigrants working in Boston, reported the disorder in
a family of French-Canadian descent in which 9 persons in 3 generations
were affected by a form of muscular dystrophy 'not heretofore described
in the literature.' The disorder was manifested by inability to flex the
neck and slight webbing due to shortened muscle as well as limitation on
spinal flexion and elbow extension from the same cause. The limb-girdle
muscles were underdeveloped and weak. The condition was apparently not
progressive. Witt et al. (1988) described a German family with an
autosomal dominant form of the Emery-Dreifuss syndrome. Several affected
members died in middle age of sudden cardiac death and at least 2 had a
pacemaker implanted. One patient had heart transplant. Four instances of
male-to-male transmission were observed in the family.

Orstavik et al. (1990) reported 4 females with EDMD, including a pair of
identical twins, in 3 successive generations. All patients developed
elbow contractures, scoliosis, and stiffness of the spine and neck from
the age of about 10 years, with little progression in later years. The
proband developed cardiomyopathy at age 45; her twin daughters had no
signs of cardiomyopathy at age 21 years. The affected individuals were
relatively short.

Bonne et al. (2000) reported phenotypic variability of EDMD2 among 53
patients, including 36 from 6 families and 17 sporadic cases. Twelve
patients showed only cardiac involvement, whereas the remaining 41 all
had muscle weakness and contractures. In addition, 12 patients had
normal electrocardiographic findings, most of whom also had normal
echocardiographic findings; these patients ranged in age from 4 to 25
years. Those with cardiac involvement had arrhythmias resulting in
ventricular dysfunction. Skeletal muscle involvement included
humeroperoneal wasting and weakness, scapular winging, rigidity of the
spine, and elbow and Achilles tendon contractures. The disease course
was generally slow, but there were 2 broad phenotypes: a milder one
characterized by late onset and a mild degree of weakness and
contractures, and a more severe phenotype with early presentation and a
rapidly progressive course.

Wessely et al. (2005) reported a 20-year-old woman with EDMD caused by
heterozygous mutation in the LMNA gene. She presented at age 20 years
with syncope and dyspnea on exertion and was found to have severely
decreased systolic function, first-degree heart block, left anterior
hemiblock, and low-amplitude P waves on EKG. Cardiac muscle biopsy
showed severe fibroadipose tissue replacement of the myocardium with
interstitial fibrosis. She underwent successful cardiac transplantation.

Benedetti et al. (2007) reported 27 individuals with mutations in the
LMNA gene resulting in a wide range of neuromuscular disorders.
Phenotypic analysis yielded 2 broad groups of patients. One group
included patients with childhood onset who had skeletal muscle
involvement with predominant scapuloperoneal and facial weakness,
consistent with EDMD or congenital muscular dystrophy (613205). The
second group included patients with later or adult onset who had cardiac
disorders or a limb-girdle myopathy, consistent with LGMD1B. Features
common to both groups included involvement of the neck or paravertebral
muscles and an age-dependent development of cardiomyopathy, most after
age 25 years. Both groups also had an increased frequency of sudden
death in the family. Genetic analysis showed that individuals in the
group with childhood onset tended to have missense mutations, whereas
those in the group with adult onset tended to have truncating mutations.
Benedetti et al. (2007) speculated that there may be 2 different
pathogenetic mechanisms associated with neuromuscular LMNA-related
disorders: late-onset phenotypes may arise through loss of LMNA function
secondary to haploinsufficiency, whereas dominant-negative or toxic
gain-of-function mechanisms may underly the more severe early
phenotypes.

Makri et al. (2009) reported 2 sisters with early-onset autosomal
dominant muscular dystrophy most consistent with EDMD. Because the girls
were born of consanguineous Algerian parents, they were at first thought
to have an autosomal recessive congenital muscular dystrophy. However,
genetic analysis identified a heterozygous mutation in the LMNA gene
(R527P; 150330.0003) in both patients that was not present in either
unaffected parent. The results were consistent with germline mosaicism
or a recurrent de novo event. The older sib had a difficult birth and
showed congenital hypotonia, diffuse weakness, and mild initial
respiratory and feeding difficulties. She sat unsupported at age 2 years
and walked independently from age 4 years with frequent falls and a
waddling gait. At 13 years she had a high-arched palate, moderate limb
hypotonia, and weakness of the pelvic muscles. There was proximal limb
wasting, moderate cervical, elbow, and ankle contractures, pes cavus,
spinal rigidity, and lordosis/scoliosis. Her sister had mild hypotonia
in early infancy, walked without support at 24 months, and showed
proximal muscle weakness. There were mild contractures of the elbow and
ankles. At age 9 years, she showed adiposity of the neck, trunk and
abdomen, consistent with lipodystrophy. Brain MRI and cognition were
normal in both sisters, and neither had cardiac involvement. Muscle
biopsies showed a dystrophic pattern.

INHERITANCE

Emery-Dreifuss muscular dystrophy-2 shows autosomal dominant inheritance
(Bonne et al., 2000).

Raffaele di Barletta et al. (2000) reported an unusual case of a
40-year-old man with what they termed a congenital muscular dystrophy or
a severe form of atypical Emery-Dreifuss muscular dystrophy. He was born
of first-cousin parents, suggesting recessive inheritance of the
disorder. The patient had experienced difficulties when he started
walking at age 14 months. At age 5 years, he could not stand because of
contractures. At age 40 years, he presented severe and diffuse muscle
wasting and was confined to a wheelchair. His intelligence was normal;
careful cardiologic examination showed that he did not have cardiac
problems. His parents were unaffected. Specialized cardiologic and
muscular examinations excluded abnormalities. Genetic analysis
identified a homozygous mutation in the LMNA gene (H222Y; 150330.0014).
Both unaffected parents were heterozygous for the mutation.

PATHOGENESIS

Manilal et al. (1999) noted that emerin, encoded by the gene mutant in
classic X-linked EDMD, is normal in the autosomal form of EDMD. They
found that the distribution of emerin most closely resembles that of
lamin A/C. A functional interaction between emerin and lamin A in nuclei
could explain the identical phenotype in the forms of EDMD.

Zhang et al. (2007) identified mutations in the SYNE1 (608441) and SYNE2
(608442) genes in patients with EDMD4 (612998) and EDMD5 (612999). Skin
fibroblasts from these patients showed similar defects in nuclear
morphology as those described in patients with EDMD due to mutations in
the LMNA and EMD genes. SYNE1 and SYNE2 mutant fibroblasts showed a
convoluted appearance with micronuclei, giant, and fragmented nuclei,
and chromatin reorganization. Patient fibroblasts and muscle cells
showed loss of nuclear envelope integrity with mislocalization of LMNA
and emerin. Immunofluorescent studies showed loss of SYNE1 or SYNE2
expression in the nuclear envelope and mitochondria of patient
fibroblasts. These same changes were also observed in fibroblasts from
patients with other genetic forms of EDMD, indicating that loss of
nesprin is a characteristic of all forms of EDMD. RNA interference of
SYNE1 or SYNE2 recapitulated the nuclear defects membrane defects and
changes in the organization of intranuclear heterochromatin observed in
patient cells. Overall, the findings showed the importance of the
nesprin/emerin/lamin complex in the maintenance of nuclear stability,
and suggested that changes in the binding stoichiometry of these
proteins is a common feature of EDMD. Zhang et al. (2007) concluded that
the disorder is caused in part by uncoupling of the nucleoskeleton and
cytoskeleton.

MAPPING

By genetic linkage analysis of a large affected French pedigree, Bonne
et al. (1999) mapped the locus for autosomal dominant Emery-Dreifuss
muscular dystrophy to an 8-cM interval on chromosome 1q11-q23. Results
from 4 other small affected families were suggestive of linkage to this
locus. The authors noted that this region contains the lamin A/C gene
(LMNA; 150330), a candidate gene encoding 2 proteins of the nuclear
lamina, lamins A and C, produced by alternative splicing. Bonne et al.
(1999) noted that limb-girdle muscular dystrophy with cardiac
involvement (LGMD1B) had been mapped to the same 1q11-q23 region by van
der Kooi et al. (1997), suggesting that the 2 disorders may be allelic.
The LGMD1B phenotype differs from autosomal dominant EMD by the absence
of significant contractures, the predominance of proximal limb weakness,
and the occasional presence of calf hypertrophy (van der Kooi et al.,
1996).

MOLECULAR GENETICS

In affected members of 5 families with autosomal dominant EDMD, Bonne et
al. (1999) identified 4 mutations in the LMNA gene that cosegregated
with the disease phenotype (150330.0001-150330.0004). These findings
represented the first identification of mutations in a component of the
nuclear lamina as a cause of an inherited muscle disorder.

Bonne et al. (2000) identified 18 different LMNA mutations among 53
patients with EDMD2. Mutations included 1 nonsense mutation, 2 deletions
of a codon, and 15 missense mutations. All mutations were distributed
between exons 1 and 9 in the region of LMNA common to both lamins A and
C. Most (76%) of the mutations were de novo events. There were no clear
genotype/phenotype correlations and there was marked inter- and
intrafamilial variability even in those with the same mutation.

Muchir et al. (2000) found mutations in the LMNA gene in affected
members of 3 families with LGMD1B linked to markers on chromosome
1q11-q21. Unique mutations were identified in each LGMD1B family: a
missense mutation (150330.0017), a deletion of a codon (150330.0018),
and a splice donor site mutation (150330.0019). Thus, Muchir et al.
(2000) demonstrated that LGMD1B and autosomal dominant Emery-Dreifuss
muscular dystrophy are allelic disorders.

*FIELD* SA
Gilchrist and Leshner (1986)
*FIELD* RF
1. Becker, P. E.: Dominant autosomal muscular dystrophy with early
contractures and cardiomyopathy (Hauptmann-Thannhauser). Hum. Genet. 74:
184 only, 1986.

2. Benedetti, S.; Menditto, I.; Degano, M.; Rodolico, C.; Merlini,
L.; D'Amico, A.; Palmucci, L.; Berardinelli, A.; Pegoraro, E.; Trevisan,
C. P.; Morandi, L.; Moroni, I.; and 15 others: Phenotypic clustering
of lamin A/C mutations in neuromuscular patients. Neurology 69:
1285-1292, 2007.

3. Bonne, G.; Di Barletta, M. R.; Varnous, S.; Becane, H. M.; Hammouda,
E. H.; Merlini, L.; Muntoni, F.; Greenberg, C. R.; Gary, F.; Urtizberea,
J.-A.; Duboc, D.; Fardeau, M.; Toniolo, D.; Schwartz, K.: Mutations
in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss
muscular dystrophy. Nature Genet. 21: 285-288, 1999.

4. Bonne, G.; Mercuri, E.; Muchir, A.; Urtizberea, A.; Becane, H.
M.; Recan, D.; Merlini, L.; Wehnert, M.; Boor, R.; Reuner, U.; Vorgerd,
M.; Wicklein, E. M.; and 13 others: Clinical and molecular spectrum
of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations
of the lamin A/C gene. Ann. Neurol. 48: 170-180, 2000.

5. Chakravarti, A.; Pearce, J. M. S.: Scapuloperoneal syndrome with
cardiomyopathy: report of a family with autosomal dominant inheritance
and unusual features. J. Neurol. Neurosurg. Psychiat. 44: 1146-1152,
1981.

6. Emery, A. E. H.: Emery-Dreifuss syndrome. J. Med. Genet. 26:
637-641, 1989.

7. Fenichel, G. M.; Sul, Y. C.; Kilroy, A. W.; Blouin, R.: An autosomal
dominant dystrophy with humeropelvic distribution and cardiomyopathy. Neurology 32:
1399-1401, 1982.

8. Gilchrist, J. M.; Leshner, R. T.: Autosomal dominant humeroperoneal
myopathy. Arch. Neurol. 43: 734-735, 1986.

9. Hauptmann, A.; Thannhauser, S. J.: Muscular shortening and dystrophy:
a heredofamilial disease. Arch. Neurol. Psychiat. 46: 654-664, 1941.

10. Jennekens, F. G. I.; Busch, H. F. M.; van Hemel, N. M.; Hoogland,
R. A.: Inflammatory myopathy in scapulo-ilio-peroneal atrophy with
cardiopathy: a study of two families. Brain 98: 709-722, 1975.

11. Makri, S.; Clarke, N. F.; Richard, P.; Maugenre, S.; Demay, L.;
Bonne, G.; Guicheney, P.: Germinal mosaicism for LMNA mimics autosomal
recessive congenital muscular dystrophy. Neuromusc. Disord. 19:
26-28, 2009.

12. Manilal, S.; Sewry, C. A.; Pereboev, A.; Man, N.; Gobbi, P.; Hawkes,
S.; Love, D. R.; Morris, G. E.: Distribution of emerin and lamins
in the heart and implications for Emery-Dreifuss muscular dystrophy. Hum.
Molec. Genet. 8: 353-359, 1999.

13. Miller, R. G.; Layzer, R. B.; Mellenthin, M. A.; Golabi, M.; Francoz,
R. A.; Mall, J. C.: Emery-Dreifuss muscular dystrophy with autosomal
dominant transmission. Neurology 35: 1230-1233, 1985.

14. Muchir, A.; Bonne, G.; van der Kooi, A. J.; van Meegen, M.; Baas,
F.; Bolhuis, P. A.; de Visser, M.; Schwartz, K.: Identification of
mutations in the gene encoding lamins A/C in autosomal dominant limb
girdle muscular dystrophy with atrioventricular conduction disturbances
(LGMD1B). Hum. Molec. Genet. 9: 1453-1459, 2000.

15. Orstavik, K. H.; Kloster, R.; Lippestad, C.; Rode, L.; Hovig,
T.; Fuglseth, K. N.: Emery-Dreifuss syndrome in three generations
of females, including identical twins. Clin. Genet. 38: 447-451,
1990.

16. Raffaele di Barletta, M.; Ricci, E.; Galluzzi, G.; Tonali, P.;
Mora, M.; Morandi, L.; Romorini, A.; Voit, T.; Orstavik, K. H.; Merlini,
L.; Trevisan, C.; Biancalana, V.; Housmanowa-Petrusewicz, I.; Bione,
S.; Ricotti, R.; Schwartz, K.; Bonne, G.; Toniolo, D.: Different
mutations in the LMNA gene cause autosomal dominant and autosomal
recessive Emery-Dreifuss muscular dystrophy. Am. J. Hum. Genet. 66:
1407-1412, 2000.

17. van der Kooi, A. J.; Ledderhof, T. M.; de Voogt, W. G.; Res, C.
J.; Bouwsma, G.; Troost, D.; Busch, H. F.; Becker, A. E.; de Visser,
M.: A newly recognized autosomal dominant limb girdle muscular dystrophy
with cardiac involvement. Ann. Neurol. 39: 636-642, 1996.

18. van der Kooi, A. J.; van Meegen, M.; Ledderhof, T. M.; McNally,
E. M.; de Visser, M.; Bolhuis, P. A.: Genetic localization of a newly
recognized autosomal dominant limb-girdle muscular dystrophy with
cardiac involvement (LGMD1B) to chromosome 1q11-21. Am. J. Hum. Genet. 60:
891-895, 1997.

19. Wessely, R.; Seidl, S.; Schomig, A.: Cardiac involvement in Emery-Dreifuss
muscular dystrophy. Clin. Genet. 67: 220-223, 2005.

20. Witt, T. N.; Garner, C. G.; Pongratz, D.; Baur, X.: Autosomal
dominant Emery-Dreifuss syndrome: evidence of a neurogenic variant
of the disease. Europ. Arch. Psychiat. Neurol. Sci. 237: 230-236,
1988.

21. Zhang, Q.; Bethmann, C.; Worth, N. F.; Davies, J. D.; Wasner,
C.; Feuer, A.; Ragnauth, C. D.; Yi, Q.; Mellad, J. A.; Warren, D.
T.; Wheeler, M. A.; Ellis, J. A.; Skepper, J. N.; Vorgerd, M.; Schlotter-Weigel,
B.; Weissberg, P. L.; Roberts, R. G.; Wehnert, M.; Shanahan, C. M.
: Nesprin-1 and -2 are involved in the pathogenesis of Emery-Dreifuss
muscular dystrophy and are critical for nuclear envelope integrity. Hum.
Molec. Genet. 16: 2816-2833, 2007.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Neck];
Restricted neck movement due to contractures

CARDIOVASCULAR:
[Heart];
Dilated cardiomyopathy;
Cardiac conduction defects;
Cardiac arrhythmias;
Increased risk of sudden cardiac death

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Scapular winging

SKELETAL:
[Spine];
Spinal rigidity;
Decreased cervical spine flexion due to contractures of posterior
cervical muscles;
[Limbs];
Elbow contractures;
[Feet];
Achilles tendon contractures

MUSCLE, SOFT TISSUE:
Humeroperoneal weakness and atrophy;
Distal lower limb muscle weakness and atrophy;
Limb-girdle muscle weakness, proximal, upper greater than lower;
Pelvic muscle involvement occurs later

LABORATORY ABNORMALITIES:
Moderately increased serum creatine kinase

MISCELLANEOUS:
Onset of muscle weakness in early childhood, usually before age 10
years;
Onset of cardiac involvement later, usually after age 20 years and
after skeletal muscle involvement;
Slowly progressive;
High frequency of de novo mutations;
Variable severity;
Some patients may have isolated cardiac involvement;
Limb-girdle muscular dystrophy 1B (LGMD1B, 159001) is an allelic
disorder with an overlapping phenotype;
See also X-linked EDMD (310300)

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2010
Cassandra L. Kniffin - revised: 4/14/2005

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/06/2010
ckniffin: 1/6/2010
joanna: 5/12/2005
ckniffin: 4/14/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 1/5/2010
Cassandra L. Kniffin - updated: 9/2/2009
Cassandra L. Kniffin - updated: 4/14/2005
Victor A. McKusick - updated: 10/20/2004
George E. Tiller - updated: 8/16/2000
Victor A. McKusick - updated: 2/23/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 03/21/2011
carol: 1/6/2010
ckniffin: 1/5/2010
wwang: 9/9/2009
ckniffin: 9/2/2009
tkritzer: 4/19/2005
ckniffin: 4/14/2005
terry: 10/20/2004
tkritzer: 2/18/2004
carol: 1/8/2003
carol: 4/2/2002
terry: 3/21/2001
alopez: 8/16/2000
carol: 7/11/2000
carol: 5/9/2000
carol: 4/28/1999
mgross: 3/10/1999
alopez: 3/1/1999
alopez: 2/26/1999
terry: 2/23/1999
terry: 6/5/1998
alopez: 7/23/1997
mimadm: 3/25/1995
supermim: 3/16/1992
carol: 1/8/1991
supermim: 3/20/1990
supermim: 1/20/1990
supermim: 1/3/1990

MIM 212112
*RECORD*
*FIELD* NO
212112
*FIELD* TI
#212112 CARDIOMYOPATHY, DILATED, WITH HYPERGONADOTROPIC HYPOGONADISM
;;MALOUF SYNDROME;;
read moreCARDIOMYOPATHY, CONGESTIVE, WITH HYPERGONADOTROPIC HYPOGONADISM;;
CARDIOMYOPATHY, DILATED, WITH PREMATURE OVARIAN FAILURE;;
CARDIOMYOPATHY WITH PRIMARY TESTICULAR FAILURE;;
NAJJAR SYNDROME;;
GENITAL ANOMALY WITH CARDIOMYOPATHY;;
CARDIOGENITAL SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
dilated cardiomyopathy and hypergonadotropic hypogonadism can be caused
by heterozygous mutation in the LMNA gene (150330).

CLINICAL FEATURES

Najjar et al. (1973) reported 3 sibs with genital anomaly, mental
retardation, and cardiomyopathy. Najjar et al. (1984) reported a second
unrelated family in which 2 brothers had severely hypoplastic genitalia
and cardiomyopathy. The parents were consanguineous in both instances.
The genital anomaly appeared to be due to primary testicular failure.
The testes were very small.

Sacks et al. (1980) described 3 brothers with cardiomyopathy and
hypergonadotropic hypogonadism. The proband was a 48-year-old man with
tricuspid regurgitation and, at autopsy, cardiomyopathy involving both
ventricles but with predominant involvement of the right ventricle. He
also had primary testicular failure and a distinctive type of cutaneous
collagenoma (see 115250) of the occipital scalp. The patient's 2
brothers were found to have testicular failure and signs of mild to
moderate cardiomyopathy, as well as similar scalp lesions. All 3
brothers had elevated serum levels of the gonadotropins follicle
stimulating hormone (FSH) and luteinizing hormone (LH). Their father had
died at 68 years of age with cardiomegaly, atrial fibrillation, and
chronic congestive heart failure. From birth he also had a posterior
occipital scalp lesion devoid of hair, similar to that of his 3 sons.

Malouf et al. (1985) reported 2 sisters, born of first-cousin Lebanese
Moslem Shiite parents, who had congestive cardiomyopathy associated with
ovarian dysgenesis and secondary hypergonadotropic hypogonadism. Other
features included bilateral ptosis and prominent nasal bones. They had 2
brothers who had died suddenly at the age of 18 years with normal
secondary sexual characteristics and no clinical evidence of heart
failure. Malouf et al. (1985) suggested that males with this syndrome
may have cardiomyopathy but not testicular dysgenesis.

Harbord et al. (1989) described cardiomyopathy in association with
Martsolf syndrome (212720), which has hypogonadism as a feature.

Narahara et al. (1992) described the sporadic case of an 18-year-old
girl with ovarian dysgenesis (resulting in hypergonadotropic
hypogonadism), dilated cardiomyopathy, mild mental retardation, broad
nasal base, bilateral blepharoptosis, and minor skeletal anomalies,
including arachnodactyly and mild thoracic scoliosis. She died at age 19
years due to intractable congestive heart failure. At autopsy,
histologic examination of the myocardium showed diffuse cellular
degeneration and interstitial fibrosis with no evidence of inflammation;
there was no degeneration of elastic fibers in the aortic media. Gonadal
tissue consisted only of stromal cells and mullerian tube remnants, with
virtually absent oocytes.

Thomas et al. (1993) described 2 brothers with cardiomyopathy and
genital anomalies. One brother was born with micropenis and bilateral
cryptorchidism but seemed otherwise well until age 5 weeks when he
developed congestive heart failure leading to death at age 7 months. The
other affected brother was the product of a pregnancy that ended in
miscarriage after 17 weeks. Autopsy showed hypoplastic penis and
markedly edematous myocardial interstitium with areas of myofiber
disarray.

Chen et al. (2003) studied a 23-year-old Iranian woman who presented in
her early teens with short stature and was referred for evaluation of
progeroid features. She had scleroderma-like skin, graying and thinning
of hair, increased urinary hyaluronic acid, osteoporosis,
osteosclerosis, hypogonadism, dilated cardiomyopathy, and sloping
shoulders.

Gursoy et al. (2006) reported 3 Turkish sibs with cardiomyopathy and
hypergonadotropic hypogonadism. The 19-year-old male proband, who had
hemiagenesis of the thyroid gland discovered during endocrine evaluation
for delayed puberty, also had cardiomyopathy diagnosed in childhood that
was complicated by ventricular tachycardia and recurrent cardiac
decompensation. He underwent orthotopic cardiac transplantation at age
15. His 2 older sisters had echocardiographically confirmed
cardiomyopathy, and 1 sister died as a result of cardiomyopathy at age
13. The affected living sister had hypergonadotropic hypogonadism with a
normal thyroid by ultrasound and was under consideration for cardiac
transplantation. The nonconsanguineous parents and a younger sister were
clinically and echocardiographically normal. None of the family members
had mental retardation or dysmorphic features.

Nguyen et al. (2007) described a 17-year-old Caucasian female of
northern European origin who developed recurrent shoulder dislocations
and joint contractures of her fifth digits at 5 years of age.
Osteoporosis was diagnosed at 8 years of age, along with abnormal skin
findings including telangiectases, sclerodactyly, and poikiloderma, and
she had a history of poor wound healing. Height and weight were both
below the second percentile. She had unusual facial features, including
small ears, narrow beaked nose, and very small chin. A soft tissue
calcification on the left elbow was noted. Echocardiogram showed mild to
moderate mitral valve regurgitation, and she was later diagnosed with
dilated cardiomyopathy. Nguyen et al. (2007) stated that the features of
this patient were consistent with atypical Werner syndrome (see 277700).

McPherson et al. (2009) restudied the patient originally described by
Nguyen et al. (2007) and reported additional features, including
premature ovarian failure with secondary amenorrhea at 15 years of age.
She had pubic hair but no breast development and elevated serum levels
of FSH and LH, and pelvic ultrasound showed infantile uterus and small
ovaries. McPherson et al. (2009) described a second patient with a
similar phenotype, a girl who underwent orthopedic evaluation at age 10
years and was found to have sloping shoulders, clavicular hypoplasia,
osteopenia, and acrogeric appearance of hands and feet, the skin of
which showed prominent vasculature and lack of subcutaneous tissue.
Mitral regurgitation was diagnosed at 10 years of age and she had
dilated cardiomyopathy by 12 years of age. Menarche occurred at age 12
years, followed by secondary amenorrhea at age 13; pubertal development
was incomplete with minimal breast development on the right side.
Hormone analysis showed low estradiol and elevated FSH and LH,
consistent with ovarian failure. Osteopenia was noted, as was
lipodystrophy, with disproportionately full cheeks and loss of fat in
the upper body. At age 15 years, her cardiac function deteriorated and
she died from an arrhythmia while awaiting cardiac transplantation.

MOLECULAR GENETICS

In a 23-year-old Iranian woman referred for evaluation of short stature
and progeroid features, who also had dilated cardiomyopathy,
hypogonadism, and sloping shoulders, Chen et al. (2003) identified a
heterozygous missense mutation in the LMNA gene (A57P; 150330.0030).
Although Chen et al. (2003) designated the patient as having 'atypical
Werner syndrome' (see 277700), Hegele (2003) suggested that the patient
more likely had late-onset Hutchinson-Gilford progeria syndrome (see
176670). However, McPherson et al. (2009) noted the phenotypic
similarity between this patient and 2 unrelated girls with
cardiomyopathy and hypergonadotropic hypogonadism, studied by Nguyen et
al. (2007) and McPherson et al. (2009), respectively, who were found to
be heterozygous for an adjacent L59R mutation in LMNA (150330.0052).

In a 17-year-old Caucasian female with premature ovarian failure and
dilated cardiomyopathy, who had features consistent with atypical Werner
syndrome (see 277700) but who was negative for mutation in the RECQL2
gene (604611), Nguyen et al. (2007) identified heterozygosity for a
missense mutation in the LMNA gene (L59R; 150330.0052). The authors
suggested the diagnosis of a laminopathy, most likely an atypical form
of mandibuloacral dysplasia (see 248370).

In a 15-year-old Caucasian girl with premature ovarian failure and
dilated cardiomyopathy, McPherson et al. (2009) identified
heterozygosity for the L59R mutation in the LMNA gene. McPherson et al.
(2009) noted phenotypic similarities between this patient and the
patient previously reported by Nguyen et al. (2007), who carried the
same mutation, as well as a patient originally described by Chen et al.
(2003) with an adjacent A57P mutation in LMNA (150330.0030). Features
common to these 3 patients included premature ovarian failure, dilated
cardiomyopathy, lipodystrophy, and progressive facial and skeletal
changes involving micrognathia and sloping shoulders, but not
acroosteolysis. Although the appearance of these patients was somewhat
progeroid, none had severe growth failure, alopecia, or rapidly
progressive atherosclerosis, and McPherson et al. (2009) suggested that
the phenotype represents a distinct laminopathy involving dilated
cardiomyopathy and hypergonadotropic hypogonadism.

*FIELD* RF
1. Chen, L.; Lee, L.; Kudlow, B. A.; Dos Santos, H. G.; Sletvold,
O.; Shafeghati, Y.; Botha, E. G.; Garg, E.; Hanson, N. B.; Martin,
G. M.; Mian, I. S.; Kennedy, B. K.; Oshima, J.: LMNA mutations in
atypical Werner's syndrome. Lancet 362: 440-445, 2003.

2. Gursoy, A.; Sahin, M.; Ertugrul, D. T.; Berberoglu, Z.; Sezgin,
A.; Tutuncu, N. B.; Demirag, N. G.: Familial dilated cardiomyopathy
hypergonadotrophic hypogonadism associated with thyroid hemiagenesis.
(Letter) Am. J. Med. Genet. 140A: 895-896, 2006.

3. Harbord, M. G.; Baraitser, M.; Wilson, J.: Microcephaly, mental
retardation, cataracts, and hypogonadism in sibs: Martsolf's syndrome. J.
Med. Genet. 26: 397-406, 1989.

4. Hegele, R. A.: Drawing the line in progeria syndromes. Lancet 362:
416-417, 2003.

5. Malouf, J.; Alam, S.; Kanj, H.; Mufarrij, A.; Der Kaloustian, V.
M.: Hypergonadotropic hypogonadism with congestive cardiomyopathy:
an autosomal-recessive disorder? Am. J. Med. Genet. 20: 483-489,
1985.

6. McPherson, E.; Turner, L.; Zador, I.; Reynolds, K.; Macgregor,
D.; Giampietro, P. F.: Ovarian failure and dilated cardiomyopathy
due to a novel lamin mutation. Am. J. Med. Genet. 149A: 567-572,
2009.

7. Najjar, S. S.; Der Kaloustian, V. M.; Ardati, K. O.: Genital anomaly
and cardiomyopathy: a new syndrome. Clin. Genet. 26: 371-373, 1984.

8. Najjar, S. S.; Der Kaloustian, V. M.; Nassif, S. I.: Genital anomaly,
mental retardation, and cardiomyopathy: a new syndrome? J. Pediat. 83:
286 only, 1973.

9. Narahara, K.; Kamada, M.; Takahashi, Y.; Tsuji, K.; Yokoyama, Y.;
Ninomiya, S.; Seino, Y.: Case of ovarian dysgenesis and dilated cardiomyopathy
supports existence of Malouf syndrome. Am. J. Med. Genet. 44: 369-373,
1992.

10. Nguyen, D.; Leistritz, D. F.; Turner, L.; MacGregor, D.; Ohson,
K.; Dancey, P.; Martin, G. M.; Oshima, J.: Collagen expression in
fibroblasts with a novel LMNA mutation. Biochem. Biophys. Res. Commun. 352:
603-608, 2007.

11. Sacks, H. N.; Crawley, I. S.; Ward, J. A.; Fine, R. M.: Familial
cardiomyopathy, hypogonadism, and collagenoma. Ann. Intern. Med. 93:
813-817, 1980.

12. Thomas, I. T.; Jewett, T.; Lantz, P.; Covitz, W.; Garber, P.;
Berry, M. N.: Najjar syndrome revisited. Am. J. Med. Genet. 47:
1151-1152, 1993.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Retrognathia;
[Eyes];
Ptosis, bilateral (in some patients);
[Nose];
Narrow, beaked nose

CARDIOVASCULAR:
[Heart];
Cardiomyopathy, dilated;
Mitral valve insufficiency;
Tricuspid valve insufficiency

CHEST:
[External features];
Sloping shoulders;
[Ribs, sternum, clavicles, and scapulae];
Clavicular hypoplasia

GENITOURINARY:
[Internal genitalia, male];
Testicular failure;
[Internal genitalia, female];
Ovarian failure, premature;
Ovarian dysgenesis

SKELETAL:
Osteopenia/osteoporosis;
[Hands];
Acrogeric appearance (prominent veins and lack of subcutaneous tissue);
[Feet];
Acrogeric appearance (prominent veins and lack of subcutaneous tissue)

MUSCLE, SOFT TISSUE:
Lipodystrophy

NEUROLOGIC:
[Central nervous system];
Mental retardation (in some patients)

ENDOCRINE FEATURES:
Hypergonadotropic hypogonadism

LABORATORY ABNORMALITIES:
Elevated serum levels of follicle stimulating hormone (FSH);
Elevated serum levels of luteinizing hormone (LH)

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0030)

*FIELD* CN
Marla J. F. O'Neill - updated: 01/29/2014
Marla J. F. O'Neill - revised: 12/28/2011

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 01/29/2014
joanna: 12/28/2011

*FIELD* CN
Marla J. F. O'Neill - updated: 10/19/2010
Marla J. F. O'Neill - updated: 8/11/2006

*FIELD* CD
Victor A. McKusick: 11/19/1991

*FIELD* ED
carol: 10/19/2010
carol: 10/11/2010
wwang: 8/18/2006
terry: 8/11/2006
terry: 6/11/1999
mimadm: 2/19/1994
carol: 11/4/1992
supermim: 3/16/1992
carol: 11/19/1991

MIM 248370
*RECORD*
*FIELD* NO
248370
*FIELD* TI
#248370 MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY; MADA
;;LIPODYSTROPHY, TYPE A, ASSOCIATED WITH MANDIBULOACRAL DYSPLASIA;;
read moreCRANIOMANDIBULAR DERMATODYSOSTOSIS
MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY, ATYPICAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because mandibuloacral
dysplasia type A (MADA) with partial lipodystrophy can be caused by
homozygous or compound heterozygous mutation in the gene encoding lamin
A/C (LMNA; 150330).

Atypical forms of MADA are also caused by mutation in the LMNA gene.

DESCRIPTION

Mandibuloacral dysplasia with type A lipodystrophy (MADA) is an
autosomal recessive disorder characterized by growth retardation,
craniofacial anomalies with mandibular hypoplasia, skeletal
abnormalities with progressive osteolysis of the distal phalanges and
clavicles, and pigmentary skin changes. The lipodystrophy is
characterized by a marked acral loss of fatty tissue with normal or
increased fatty tissue in the neck and trunk. Some patients may show
progeroid features. Metabolic complications can arise due to insulin
resistance and diabetes (Young et al., 1971; Simha and Garg, 2002;
summary by Garavelli et al., 2009).

See also MAD type B (MADB; 608612), which is caused by mutation in the
ZMPSTE24 gene (606480).

CLINICAL FEATURES

Young et al. (1971) described 2 teenaged males with a hypoplastic
mandible producing severe dental crowding, acroosteolysis, stiff joints,
atrophy of the skin over hands and feet, and hypoplastic clavicles. The
boys had an 'Andy Gump' appearance. Persistently wide cranial sutures
and multiple wormian bones were noted. Alopecia and short stature were
other features of this progeria-like syndrome.

Using the designation 'craniomandibular dermatodysostosis,' Danks et al.
(1974) described a patient with an abnormality similar to, but different
from cleidocranial dysplasia (119600) and pycnodysostosis (265800).
Changes in the skin and finger tips suggested diffuse involvement of
connective tissue and perhaps of blood vessels. Hematemesis occurred
repeatedly. Danks et al. (1974) suggested that the patient reported by
Cavallazzi et al. (1960) may have had this disorder. The authors also
suggested that the same disorder was present in the patient reported by
McKusick (1963) as cleidocranial dysostosis with acroosteolysis and
McKusick (1964) as pycnodysostosis. That patient died young. The
differential diagnosis also includes Hajdu-Cheney syndrome (102500) and
acrogeria (201200). Welsh (1975) reported a 'new progeroid syndrome' in
2 males and 2 females from a sibship of 14, suggesting autosomal
recessive inheritance; this disorder may have been mandibuloacral
dysplasia.

Pallotta and Morgese (1984) reported 2 Italian brothers with
mandibuloacral dysplasia. Hall and Mier (1985) described a 13-year-old
male with this disorder, and referred to 3 unpublished cases that
included a 37-year-old male and a brother and sister. Tenconi et al.
(1986) described an Italian family with 1 female and 2 males affected in
a sibship of 11. They noted that of 9 reported affected families, 5 were
Italian.

The 2 brothers reported by Parkash et al. (1990) as examples of
Hutchinson-Gilford progeria syndrome (HGPS; 176670) probably had MAD
(McKusick, 1991; Toriello, 1991; Cusano and Scarano, 1991). Parkash et
al. (1990) commented that the patients had 2 unusual findings, namely,
marked resorption of the mandible with loss of teeth in the elder sib
and prolonged survival. At the time of report, both sibs were alive and
active at ages 32 and 24 years. Both had hypoplastic clavicles with ease
of apposition of the shoulders. Acroosteolysis with progressive loss of
bone from the distal phalanges of the fingers and toes was found
bilaterally. The cranial bones were thin and the anterior fontanels and
sutures were still open. In the case of the youngest sib, wormian bones
were also present. Parkash (1991) defended the diagnosis of progeria.

Cutler et al. (1991) and Freidenberg et al. (1992) emphasized the
partial lipodystrophy present in the patients they observed. Cutler et
al. (1991) described 2 patients with extreme insulin resistance and
marked hypermetabolism. Freidenberg et al. (1992) studied the same 2
patients and a third patient, a 41-year-old male, who had been published
as an instance of Werner syndrome (277700) at age 24 years (Cohen et
al., 1973). Hearing loss was present in all 3 patients. In the patient
with MAD syndrome who had previously been misdiagnosed as having Werner
syndrome by Cohen et al. (1973), Ng and Stratakis (2000) found premature
adrenal cortical dysfunction of the zona reticularis, marked by a
decrease in 17,20-lyase activity (609300), consistent with that seen in
the elderly. They suggested that the prominence of the patient's eyes
was pseudo-proptosis, secondary to lack of subcutaneous periorbital fat.

Toriello (1995) reviewed published cases and examined the possibility of
heterogeneity.

Seftel et al. (1996) reported a male newborn from South Africa
(non-Italian descent) with confluent fontanels, sparse hair and
eyebrows, severe micrognathia, bulbar digits, and short clavicles. These
manifestations were consistent with mandibuloacral dysplasia. He also
had glanular hypospadias and died at 8 days of age. Seftel et al. (1996)
considered this case to represent a lethal neonatal form of the
disorder.

Prasad et al. (1998) reported 2 brothers and 2 unrelated girls with
typical features of MAD. Both girls presented with foot pain and had a
small infantile uterus and soft tissue calcinosis.

Tudisco et al. (2000) stated that only 11 families of mandibuloacral
dysplasia had been reported and that 5 of these were Italian. They
described an additional Italian patient born of consanguineous parents.
Consanguinity had previously been proved only in the family reported by
Zina et al. (1981). In the 33-year-old patient of Tudisco et al. (2000),
growth retardation, clavicular dysplasia, and delayed cranial suture
closure were first noted at the age of 5 years, when a diagnosis of
cleidocranial dysostosis was suggested. After the age of 18 years,
alopecia, marked micrognathia, distal phalangeal shortening, and joint
stiffness became apparent. His height was 161 cm, and he showed
premature loss of the lower teeth. X-rays showed marked osteolysis of
the distal finger phalanges, as well as delayed closure of cranial
sutures, and mandibular and clavicular hypoplasia.

Simha and Garg (2002) studied body fat distribution in 2 male and 2
female patients with MAD by anthropometry, dual energy x-ray
absorptiometry, and magnetic resonance imaging. Blood glucose and
insulin responses during an oral glucose tolerance test and fasting
serum lipoproteins were determined. Three of the 4 subjects had loss of
subcutaneous fat from the extremities with normal or slight excess in
the neck and truncal regions (termed type A pattern). In contrast, 1
patient had generalized loss of subcutaneous fat involving the face,
trunk, and extremities (type B pattern; 608612). All of the patients had
normal glucose tolerance but had fasting and postprandial
hyperinsulinemia suggestive of insulin resistance. Elevated serum
triglycerides with low high-density lipoprotein cholesterol levels were
noted in 3 subjects. The authors concluded that MAD presents with 2
types of body fat distribution patterns, both of which are associated
with insulin resistance and its metabolic complications.

Cogulu et al. (2003) described a 13-year-old girl with mandibuloacral
dysplasia who had absent breast development, although pubic and axillary
hair were normal. Menarche began at 10 years and she had regular
menstrual cycles. Hormone studies revealed no abnormalities.

Afifi and El-Bassyouni (2005) reported 2 unrelated Egyptian girls with
MAD, who were both born of consanguineous parents. Both patients had
micrognathia, prominent eyes, pointed nose, high-arched palate,
hypoplastic teeth, and sparse scalp hair. Other common features included
loss of subcutaneous fat from both upper and lower limbs and hypo- and
hyperpigmented spots over the trunk. Radiologic features showed delayed
closure of the cranial sutures, micrognathia, and hypoplastic clavicles.
The first patient also had acroosteolysis of the distal phalanges. Both
patients had laboratory findings consistent with insulin resistance.
Afifi and El-Bassyouni (2005) discussed the differential diagnosis of
MAD and noted the phenotypic overlap with several disorders, including
HGPS, Werner syndrome, Gottron type acrogeria, Hallermann-Streiff
syndrome (234100), and Hajdu-Cheney syndrome.

Lombardi et al. (2007) identified a patient with an apparent MADA
phenotype without clavicular hypoplasia, metabolic imbalances, and
resembling limb-girdle myopathy. Clinical features included a
hypoplastic mandible, acroosteolysis, pointed nose, partial loss of
subcutaneous fat, and a progeric appearance. Due to the absence of
clavicular dysplasia and normal metabolic profiles, generally associated
with muscle hyposthenia and generalized hypotonia, the authors
considered this phenotype an atypical laminopathy. The patient's cells
showed nuclear shape abnormalities, accumulation of prelamin A, and
irregular lamina thickness.

Kosho et al. (2007) reported a 56-year-old Japanese woman, born of
consanguineous parents, with MAD and type A lipodystrophy confirmed by
genetic analysis (150330.0046). The authors stated that she was the
oldest reported patient with the disorder. In addition to the MADA
phenotype, including progeroid appearance, acroosteolysis of the distal
phalanges, and loss of subcutaneous fat in the limbs, she had severe
progressive destructive skeletal and osteoporotic changes. Vertebral
collapse led to paralysis. However, Kosho et al. (2007) also noted that
other factors may have contributed to the severe osteoporosis observed
in this patient.

Garavelli et al. (2009) reported 2 unrelated patients with early
childhood onset of MADA features. The first child, a boy, presented at
age 5 years, 3 months with bulbous distal phalanges of fingers. He was
observed to have ocular proptosis, a thin nose, prominent cheeks, slight
micrognathia, malocclusion with overlapping teeth, thin skin with
prominent veins, skin spots, and lipodystrophy type A, with an acral
loss of fatty tissue also evident on the shoulders. He had wormian
bones, acroosteolysis, and decreased vertebral bone density. The second
child was a girl, born of consanguineous parents from Pakistan. She
presented at age 4 years, 2 months with a round face, chubby cheeks,
thin nose, short, broad distal phalanges, and lipodystrophy type A, with
subcutaneous fat more evident on the trunk than on limbs. Skeletal
survey showed wormian bones, thin clavicles, and short terminal
phalanges with acroosteolysis. Both patients were homozygous for the
common R527H mutation in LMNA (150330.0021). Garavelli et al. (2009)
emphasized that features of this disorder may become apparent as early
as preschool age and that bulbous fingertips may be a clue to the
diagnosis.

Guglielmi et al. (2010) provided follow-up on a 43-year-old man, whom
they stated was the second oldest reported MADA patient, who had
previously been studied by Novelli et al. (2002) and found to be
homozygous for an R527H mutation (150330.0021) in the LMNA gene. The
patient developed, over a period of nearly 2 years, deformation and
swelling of the right elbow, associated with pain and nearly total loss
of joint function, with elbow stiffness in slight flexion and severely
limited articular excursion in both active and passive pronation and
extension. Radiography of upper and lower limbs showed osteolysis and
destructive processes of the right elbow, as well as asymptomatic
resorption of both femoral greater trochanters that was more pronounced
on the left. In particular, the right elbow showed joint space narrowing
with loss of articular cartilage, dysplasia of the humeral condyles,
erosion of proximal ulna and radius bilaterally, and palmar angulation
of the ulnar olecranon with marked signs of hyperostosis and loss of
normal articular contacts. Guglielmi et al. (2010) noted that these
lesions were absent in radiographs from 7 years earlier, and only minor
alterations were detectable in radiographs at onset of symptoms 3 years
previously, including less extensive hyperostosis and condylar
dysplasia, with preserved articular contacts and no palmar angulation of
the ulna. In addition, progression of bone deformities of the hands were
evident, with progressive resorption of distal and middle phalanges
compared to earlier radiographs. Guglielmi et al. (2010) pointed out
that similar, but more extensive, skeletal changes had been described in
a 56-year-old Japanese woman who was the oldest MADA patient reported at
that time (Kosho et al., 2007), and concluded that in MAD, osteolysis is
not confined to the originally described sites (hands and clavicles),
but may affect other skeletal regions.

- Clinical Variability

Plasilova et al. (2004) reported 4 affected members of a consanguineous
family from north India with a phenotype that included features of both
MADA and Hutchinson-Gilford progeria syndrome (HGPS; 176670) associated
with a homozygous mutation in the LMNA gene (K542N; 150330.0033). The
patients showed uniform skeletal malformations such as acroosteolysis of
the digits, micrognathia, and clavicular aplasia/hypoplasia,
characteristic of MADA. They also showed hallmark features of progeria.
Plasilova et al. (2004) suggested that autosomal recessive MADA and HGPS
may represent a single disorder with varying degrees of severity.

Lombardi et al. (2007) identified a patient with an apparent MADA
phenotype without clavicular hypoplasia or metabolic imbalances, and
resembling limb-girdle myopathy. Clinical features included a
hypoplastic mandible, acroosteolysis, pointed nose, partial loss of
subcutaneous fat, and a progeric appearance. Due to the absence of
clavicular dysplasia and normal metabolic profiles, generally associated
with muscle hyposthenia and generalized hypotonia, the authors
considered this phenotype an atypical laminopathy. The patient's cells
showed nuclear shape abnormalities, accumulation and prelamin A, and
irregular lamina thickness.

Van Esch et al. (2006) described a 44-year-old man of European descent
who had a syndrome involving arthropathy, tendinous calcinosis, and
progeroid features. The arthropathy affected predominantly the distal
femora and proximal tibia in the knee with tendinous calcifications.
Progeroid features included a small pinched nose, small lips,
micrognathia with crowded teeth, cataract, and alopecia. He also had
generalized lipodystrophy, and sclerodermatous skin. However, he had
normal clavicles and no evidence of acroosteolysis. The authors
concluded that he had a novel phenotype. He died at 44 years of age from
Staphylococcus aureus sepsis resulting from infection of skin ulcers.
Genetic analysis identified a homozygous mutation in the LMNA gene
(S573L; 150330.0041). The patient's unaffected 15-year-old son and
70-year-old mother were both heterozygous carriers.

Zirn et al. (2008) reported a 7-year-old Turkish girl, born of
consanguineous parents, who was homozygous for a mutation (R471C;
150330.0026) in the LMNA gene. She had a phenotype most consistent with
an atypical form of MADA, including lipodystrophy, a progeroid
appearance, and congenital muscular dystrophy with rigid spine syndrome.
These latter features were reminiscent of Emery-Dreifuss muscular
dystrophy (181350), although there was no cardiac involvement. She
presented at age 10 months with proximal muscle weakness, contractures,
spinal rigidity, and a dystrophic skeletal muscle biopsy. Characteristic
progeroid features and features of lipodystrophy and mandibuloacral
dysplasia were noted at age 3 years and became more apparent with age.
Zirn et al. (2008) commented on the severity of the phenotype and
emphasized the phenotypic variability in patients with LMNA mutations.

MAPPING

By analysis of 5 consanguineous Italian families with MAD, Novelli et
al. (2002) demonstrated linkage of the disorder to chromosome 1q21.

MOLECULAR GENETICS

In 9 affected patients from 5 consanguineous Italian families with MAD,
Novelli et al. (2002) identified a homozygous mutation in the LMNA gene
(R527H; 150330.0021). The authors noted that LMNA also causes several
distinct disorders, including Dunnigan type familial partial
lipodystrophy (151660), a condition that is characterized by
subcutaneous fat loss and is invariably associated with insulin
resistance and diabetes. Simha et al. (2003) noted that the patients of
Novelli et al. (2002) had type A lipodystrophy.

In 2 of pedigrees with MAD and type A lipodystrophy, Simha et al. (2003)
identified the homozygous R527H LMNA mutation.

In a Mexican American boy with MAD born of related parents, Shen et al.
(2003) identified homozygosity for the R527H mutation. The authors noted
that all the patients reported by Novelli et al. (2002) shared a common
disease haplotype, but that the patients reported by Simha et al. (2003)
and their Mexican American patient had different haplotypes, indicating
independent origins of the mutation.

In 1 patient with an apparently typical HGPS phenotype who was 28 years
old at the time that DNA was obtained, Cao and Hegele (2003) identified
compound heterozygosity for 2 missense mutations in the LMNA gene
(150330.0025 and 150330.0026); this patient was later determined (Brown,
2004) to have mandibuloacral dysplasia.

In a patient with a MADA-like phenotype but without clavicular
hypoplasia or metabolic imbalances, Lombardi et al. (2007) found
compound heterozygosity for missense mutations in the LMNA gene
(150330.0021, 150330.0044).

PATHOGENESIS

Lombardi et al. (2008) detected significantly higher levels
(approximately 4.7-fold) of the active enzyme forms of MMP9 (120361) in
the serum of 5 patients with MADA compared to 16 controls. No
significant differences were found for several other metalloproteinases.
The findings suggested a pathogenic role for MMP9 in the skeletal
manifestations of the disorder.

*FIELD* RF
1. Afifi, H. H.; El-Bassyouni, H. T.: Mandibuloacral dysplasia: a
report of two Egyptian cases. Genet. Counsel. 16: 353-362, 2005.

2. Brown, W. T.: Personal Communication. Staten Island, N.Y. 1/12/2004.

3. Cao, H.; Hegele, R. A.: LMNA is mutated in Hutchinson-Gilford
progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid
syndrome (MIM 264090). J. Hum. Genet. 48: 271-274, 2003.

4. Cavallazzi, C.; Cremoncini, R.; Quadri, A.: Su di un caso di disostosi
cleido-cranica. [A case of cleidocranial dysostosis]. Riv. Clin.
Pediat. 65: 313-326, 1960.

5. Cogulu, O.; Gunduz, C.; Darcan, S.; Kadioglu, B.; Ozkinay, F.;
Ozkinay, C.; Arkun, R.: Mandibuloacral dysplasia with absent breast
development. (Letter) Am. J. Med. Genet. 119A: 391-392, 2003.

6. Cohen, L. K.; Thurmon, T. F.; Salvaggio, J.: Werner's syndrome. Cutis 12:
76-80, 1973.

7. Cusano, F.; Scarano, G.: Familial progeria or mandibulo-acral
dysplasia? (Letter) Am. J. Med. Genet. 41: 139 only, 1991.

8. Cutler, D. L.; Kaufmann, S.; Freidenberg, G. R.: Insulin-resistant
diabetes mellitus and hypermetabolism in mandibuloacral dysplasia:
a newly recognized form of partial lipodystrophy. J. Clin. Endocr.
Metab. 73: 1056-1061, 1991.

9. Danks, D. M.; Mayne, V.; Norman, H.; Wettenhall, B.; Hall, R. K.
: Craniomandibular dermatodysostosis. Birth Defects Orig. Art. Ser. X(12):
99-105, 1974.

10. Freidenberg, G. R.; Cutler, D. L.; Jones, M. C.; Hall, B.; Mier,
R. J.; Culler, F.; Jones, K. L.; Lozzio, C.; Kaufmann, S.: Severe
insulin resistance and diabetes mellitus in mandibuloacral dysplasia. Am.
J. Dis. Child. 146: 93-99, 1992.

11. Garavelli, L.; D'Apice, M. R.; Rivieri, F.; Bertoli, M.; Wischmeijer,
A.; Gelmini, C.; De Nigris, V.; Albertini, E.; Rosato, S.; Virdis,
R.; Bacchini, E.; Dal Zotto, R.; Banchini, G.; Iughetti, L.; Bernasconi,
S.; Superti-Furga, A.; Novelli, G.: Mandibuloacral dysplasia type
A in childhood. Am. J. Med. Genet. 149A: 2258-2264, 2009.

12. Guglielmi, V.; D'Adamo, M.; D'Apice, M. R.; Bellia, A.; Lauro,
D.; Federici, M.; Lauro, R.; Novelli, G.; Sbraccia, P.: Elbow deformities
in a patient with mandibuloacral dysplasia type A. Am. J. Med. Genet. 152A:
2711-2713, 2010.

13. Hall, B. D.; Mier, R. J.: Mandibuloacral dysplasia: a rare progressive
disorder with postnatal onset. (Abstract) Proc. Greenwood Genet.
Center 4: 125-126, 1985.

14. Kosho, T.; Takahashi, J.; Momose, T.; Nakamura, A.; Sakurai, A.;
Wada, T.; Yoshida, K.; Wakui, K.; Suzuki, T.; Kasuga, K.; Nishimura,
G.; Kato, H.; Fukushima, Y.: Mandibuloacral dysplasia and a novel
LMNA mutation in a woman with severe progressive skeletal changes. Am.
J. Med. Genet. 143A: 2598-2603, 2007.

15. Lombardi, F.; Fasciglione, G. F.; D'Apice, M. R.; Vielle, A.;
D'Adamo, M.; Sbraccia, P.; Marini, S.; Borgiani, P.; Coletta, M.;
Novelli, G.: Increased release and activity of matrix metalloproteinase-9
in patients with mandibuloacral dysplasia type A, a rare premature
ageing syndrome. Clin. Genet. 74: 374-383, 2008.

16. Lombardi, F.; Gullotta, F.; Columbaro, M.; Filareto, A.; D'Adamo,
M.; Vielle, A.; Guglielmi, V.; Nardone, A. M.; Azzolini, V.; Grosso,
E.; Lattanzi, G.; D'Apice, M. R.; Masala, S.; Maraldi, N. M.; Sbraccia,
P.; Novelli, G.: Compound heterozygosity for mutations in LMNA in
a patient with a myopathic and lipodystrophic mandibuloacral dysplasia
type A phenotype. J. Clin. Endocr. Metab. 92: 4467-4471, 2007.

17. McKusick, V. A.: Medical genetics 1962. J. Chronic Dis. 16:
457-634, 1963.

18. McKusick, V. A.: Medical genetics 1963. J. Chronic Dis. 17:
1077-1215, 1964.

19. McKusick, V. A.: Review of Dr. Parkash's report. (Letter) Am.
J. Med. Genet. 41: 137 only, 1991.

20. Ng, D.; Stratakis, C. A.: Premature adrenal cortical dysfunction
in mandibuloacral dysplasia: a progeroid-like syndrome. (Letter) Am.
J. Med. Genet. 95: 293-295, 2000.

21. Novelli, G.; Muchir, A.; Sangiuolo, F.; Helbling-Leclerc, A.;
D'Apice, M. R.; Massart, C.; Capon, F.; Sbraccia, P.; Federici, M.;
Lauro, R.; Tudisco, C.; Pallotta, R.; Scarano, G.; Dallapiccola, B.;
Merlini, L.; Bonne, G.: Mandibuloacral dysplasia is caused by a mutation
in LMNA-encoding lamin A/C. Am. J. Hum. Genet. 71: 426-431, 2002.

22. Pallotta, R.; Morgese, G.: Mandibuloacral dysplasia: a rare progeroid
syndrome: two brothers confirm autosomal recessive inheritance. Clin.
Genet. 26: 133-138, 1984.

23. Parkash, H.: Reply to Dr. Toriello. (Letter) Am. J. Med. Genet. 41:
140 only, 1991.

24. Parkash, H.; Sidhu, S. S.; Raghavan, R.; Deshmukh, R. N.: Hutchinson-Gilford
progeria: familial occurrence. Am. J. Med. Genet. 36: 431-433, 1990.

25. Plasilova, M.; Chattopadhyay, C.; Pal, P.; Schaub, N. A.; Buechner,
S. A.; Mueller, H.; Miny, P.; Ghosh, A.; Heinimann, K.: Homozygous
missense mutation in the lamin A/C gene causes autosomal recessive
Hutchinson-Gilford progeria syndrome. J. Med. Genet. 41: 609-614,
2004.

26. Prasad, P. V. S.; Padmavathy, L.; Sethurajan, S.: Familial mandibuloacral
dysplasia--a report of four cases. Int. J. Derm. 37: 600-616, 1998.

27. Seftel, M. D.; Wright, C. A.; Li Wan Po, P.; de Ravel, T. J. L.
: Lethal neonatal mandibuloacral dysplasia. Am. J. Med. Genet. 66:
52-54, 1996.

28. Shen, J. J.; Brown, C. A.; Lupski, J. R.; Potocki, L.: Mandibuloacral
dysplasia caused by homozygosity for the R527H mutation in lamin A/C. J.
Med. Genet. 40: 854-857, 2003.

29. Simha, V.; Agarwal, A. K.; Oral, E. A.; Fryns, J.-P.; Garg, A.
: Genetic and phenotypic heterogeneity in patients with mandibuloacral
dysplasia-associated lipodystrophy. J. Clin. Endocr. Metab. 88:
2821-2824, 2003.

30. Simha, V.; Garg, A.: Body fat distribution and metabolic derangements
in patients with familial partial lipodystrophy associated with mandibuloacral
dysplasia. J. Clin. Endocr. Metab. 87: 776-785, 2002.

31. Tenconi, R.; Miotti, F.; Miotti, A.; Audino, G.; Ferro, R.; Clementi,
M.: Another Italian family with mandibuloacral dysplasia: why does
it seem more frequent in Italy? Am. J. Med. Genet. 24: 357-364,
1986.

32. Toriello, H. V.: Mandibuloacral 'dysplasia'. (Letter) Am. J.
Med. Genet. 41: 138 only, 1991.

33. Toriello, H. V.: Mandibulo-acral dysplasia: heterogeneity versus
variability. Clin. Dysmorph. 4: 12-24, 1995.

34. Tudisco, C.; Canepa, G.; Novelli, G.; Dallapiccola, B.: Familial
mandibuloacral dysplasia: report of an additional Italian patient. Am.
J. Med. Genet. 94: 237-241, 2000.

35. Van Esch, H.; Agarwal, A. K.; Debeer, P.; Fryns, J.-P.; Garg,
A.: A homozygous mutation in the lamin A/C gene associated with a
novel syndrome of arthropathy, tendinous calcinosis, and progeroid
features. J. Clin. Endocr. Metab. 91: 517-521, 2006.

36. Welsh, O.: Study of a family with a new progeroid syndrome. Birth
Defects Orig. Art. Ser. XI(5): 25-38, 1975.

37. Young, L. W.; Radebaugh, J. F.; Rubin, P.; Sensenbrenner, J. A.;
Fiorelli, G.: New syndrome manifested by mandibular hypoplasia, acroosteolysis,
stiff joints and cutaneous atrophy (mandibuloacral dysplasia) in two
unrelated boys. Birth Defects Orig. Art. Ser. VII(7): 291-297, 1971.

38. Zina, A. M.; Cravario, A.; Bundino, S.: Familial mandibuloacral
dysplasia. Brit. J. Derm. 105: 719-723, 1981.

39. Zirn, B.; Kress, W.; Grimm, T.; Berthold, L. D.; Neubauer, B.;
Kuchelmeister, K.; Muller, U.; Hahn, A.: Association of homozygous
LMNA mutation R471C with new phenotype: mandibuloacral dysplasia,
progeria, and rigid spine muscular dystrophy. Am. J. Med. Genet. 146A:
1049-1054, 2008.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Growth retardation, postnatal

HEAD AND NECK:
[Face];
Mandibular hypoplasia;
Bird-like facies;
Normal or increased facial adipose tissue;
Full cheeks;
[Eyes];
Prominent eyes;
[Nose];
Pinched nose;
Pointed nose;
Beak nose;
[Mouth];
High-arched palate;
Absence of tongue papillae;
[Teeth];
Dental overcrowding;
Loss of teeth;
Hypoplastic teeth;
[Neck];
Normal or increased adipose tissue around the neck

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Clavicular hypoplasia;
Progressive acroosteolysis of the clavicle

SKELETAL:
Joint contractures;
Joint stiffness;
[Skull];
Delayed closure of cranial sutures;
Wormian bones;
[Hands];
Acroosteolysis of distal phalanges;
Fingertip rounding;
[Feet];
Acroosteolysis of distal phalanges

SKIN, NAILS, HAIR:
[Skin];
Mottled pigmentation;
Skin atrophy (especially over hands and feet);
Soft tissue calcinosis;
[Hair];
Alopecia, partial;
Sparse, lusterless scalp hair

MUSCLE, SOFT TISSUE:
Partial lipodystrophy (abnormal distribution of adipose tissue);
Loss of subcutaneous adipose tissue from extremities;
Normal or increased truncal adipose tissue;
Normal or increased adipose tissue around the neck;
Normal or increased facial adipose tissue;
Soft tissue or tendinous calcinosis may occur

ENDOCRINE FEATURES:
Insulin-resistant diabetes mellitus;
Impaired glucose tolerance

LABORATORY ABNORMALITIES:
Hyperglycemia;
Hyperlipidemia;
Hyperinsulinemia

MISCELLANEOUS:
Onset in childhood;
Genetic heterogeneity (see MADB, 608612);
Allelic disorder to Dunnigan-type familial partial lipodystrophy (151660)

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0021)

*FIELD* CN
Cassandra L. Kniffin - updated: 2/7/2006
Cassandra L. Kniffin - revised: 5/5/2004

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/06/2010
ckniffin: 2/24/2010
ckniffin: 2/7/2006
joanna: 5/5/2004
ckniffin: 4/27/2004

*FIELD* CN
Marla J. F. O'Neill - updated: 2/21/2012
Cassandra L. Kniffin - updated: 10/13/2010
Cassandra L. Kniffin - updated: 4/7/2010
Cassandra L. Kniffin - updated: 3/5/2009
Cassandra L. Kniffin - updated: 2/13/2009
John A. Phillips, III - updated: 9/23/2008
Cassandra L. Kniffin - updated: 2/7/2006
George E. Tiller - updated: 4/14/2004
Victor A. McKusick - updated: 2/17/2004
Cassandra L. Kniffin - updated: 1/6/2004
John A. Phillips, III - updated: 8/25/2003
Victor A. McKusick - updated: 6/26/2003
Victor A. McKusick - updated: 8/16/2002
John A. Phillips, III - updated: 7/25/2002
Victor A. McKusick - updated: 11/29/2000
Victor A. McKusick - updated: 11/10/2000
Victor A. McKusick - updated: 10/4/2000
Iosif W. Lurie - updated: 8/5/1997
Iosif W. Lurie - updated: 9/17/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 02/22/2012
terry: 2/21/2012
wwang: 10/19/2010
ckniffin: 10/13/2010
terry: 9/21/2010
wwang: 4/13/2010
ckniffin: 4/7/2010
carol: 1/15/2010
ckniffin: 1/11/2010
wwang: 3/11/2009
ckniffin: 3/5/2009
wwang: 2/19/2009
ckniffin: 2/13/2009
alopez: 12/29/2008
alopez: 9/23/2008
wwang: 9/7/2006
wwang: 6/22/2006
wwang: 2/10/2006
ckniffin: 2/7/2006
terry: 2/21/2005
tkritzer: 1/20/2005
carol: 12/8/2004
carol: 5/3/2004
ckniffin: 4/29/2004
alopez: 4/14/2004
carol: 2/17/2004
tkritzer: 1/13/2004
ckniffin: 1/6/2004
alopez: 8/25/2003
tkritzer: 7/21/2003
terry: 6/26/2003
tkritzer: 8/23/2002
tkritzer: 8/22/2002
terry: 8/16/2002
tkritzer: 7/25/2002
mcapotos: 1/26/2001
mcapotos: 12/13/2000
terry: 11/29/2000
carol: 11/13/2000
terry: 11/10/2000
carol: 10/4/2000
terry: 10/4/2000
jenny: 8/5/1997
joanna: 7/7/1997
jamie: 2/4/1997
mark: 1/29/1997
carol: 9/17/1996
terry: 5/7/1994
mimadm: 2/19/1994
carol: 8/24/1992
supermim: 3/17/1992
carol: 3/7/1992
carol: 10/29/1991

MIM 275210
*RECORD*
*FIELD* NO
275210
*FIELD* TI
#275210 RESTRICTIVE DERMOPATHY, LETHAL
;;TIGHT SKIN CONTRACTURE SYNDROME, LETHAL;;
read moreHYPERKERATOSIS-CONTRACTURE SYNDROME;;
FETAL HYPOKINESIA SEQUENCE DUE TO RESTRICTIVE DERMOPATHY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
lethal restrictive dermopathy can be caused by heterozygous mutation in
the LMNA gene (150330) on chromosome 1q22 or by homozygous or compound
heterozygous mutation in the ZMPSTE24 gene (606480) on chromosome 1p34.

DESCRIPTION

Restrictive dermopathy is a rare, lethal genodermatosis with
characteristic manifestations that are easily recognizable at birth:
thin, tightly adherent translucent skin with erosions at flexure sites,
superficial vessels, typical facial dysmorphism, and generalized joint
ankylosis. Prenatal signs can include intrauterine growth retardation,
reduced fetal movements, polyhydramnios, and premature rupture of the
membranes. Most infants die within the first week of life (summary by
Smigiel et al., 2010).

CLINICAL FEATURES

In 2 Hutterite sibships from different endogamous subdivisions ('leut,'
or deme) and in a Mennonite kindred, Lowry et al. (1985) described a
unique fatal disorder. The major manifestations were severe intrauterine
growth retardation, congenital contractures, and tense skin that was
easily eroded. The skin was drawn tightly over the face causing a
narrow, pinched nose, small mouth, limited jaw mobility, and ectropion
(in 1). No organ malformations were found. Histologically, the skin
showed hyperkeratosis. Lowry et al. (1985) postulated that the primary
defect represents a skin dysplasia and presented a 'pedigree of causes'
(term of Hans Gruneberg) or 'pathogenesis chart' (term of Lowry et al.)
relating all features of the disorder back to a mutant gene through that
basic defect.

Witt et al. (1986) reported a similar condition in brother and sister
born from consecutive pregnancies. Both had rigid and tightly adherent
skin in association with generalized contractures, unusual facies,
pulmonary hypoplasia, abnormal placenta, and short umbilical cord. Both
died soon after birth.

Holbrook et al. (1987) were apparently of the opinion that this is the
same disorder as that described in entry 226730: aplasia cutis congenita
with pyloric stenosis. Although gastrointestinal atresia was not present
in these cases, this feature is not always present; it was found in 1
patient reported by Carmi et al. (1982) and was absent in the sib.
Holbrook et al. (1987) indicated that a third affected baby had been
born in the family originally reported by Witt et al. (1986).

Mok et al. (1990) reported 3 cases; 1 was in a child of consanguineous
Pakistani parents. Van Hoestenberghe et al. (1990) described an affected
infant with neonatal teeth and survival to the age of 4 months. Verloes
et al. (1992) described 3 unrelated affected stillborn infants, each
with consanguineous parents. Two of them were of Algerian ancestry and
one Turkish. Clinical findings included a tight, thin, translucent skin
which tore spontaneously in flexion creases, arthrogryposis multiplex
congenita (which included the temporomandibular joint), enlarged
fontanels, typical face, and dysplasia of clavicles and long bones. Lenz
and Meschede (1993) found in the German literature 2 cases with typical
manifestations of this disorder. Antoine (1929) called this condition
'generalized congenital skin atrophy,' and Wepler (1938) described it as
a 'generalized skin hypoplasia.'

Happle et al. (1992) observed restrictive dermopathy in 2 brothers. The
first-born brother died 4 days after birth. He showed generalized
desquamation, marked joint contractures, and facial hypoplasia.
Prominent light microscopic findings were hyperorthokeratosis
intermingled with parakeratosis and absence of elastic fibers in a
thinned dermis. Electron microscopic examination of the epidermis showed
lack of keratin filaments and an abnormal globular shape of the
keratohyalin granules. The following pregnancy resulted in the birth of
a preterm boy who died within 2 hours. At the twentieth week of
gestational age, fetal biopsy specimens failed to reveal any
abnormalities by light or electron microscopy. Thus, feasibility of
prenatal diagnosis must be regarded with great caution.

Hoffmann et al. (1993) reported 2 unrelated cases. One died at 5 days of
age, the second at 2 months of age. Hamel et al. (1992) reported 2
successively born male infants with this disorder. After the birth of
the first affected child, who died after 4 days, a prenatal diagnosis
was performed in the second pregnancy; at 19.5 weeks, 5 fetal skin
biopsies from various parts of the body were obtained and investigated
by light and electron microscopy. No morphologic abnormalities could be
detected. The pregnancy was monitored by ultrasound and continued
uneventfully until, at 29 weeks, polyhydramnios developed and the fetal
movements disappeared abruptly. The infant was born in breech position
at 29.5 weeks and had typical restrictive dermopathy. He died after 1
hour. Thus, skin biopsy is not a reliable means of prenatal diagnosis.

Paige et al. (1992) found many dead and degenerating fibroblasts in the
dermis on ultrastructural examination, and demonstrated their poor
growth in vitro. Studies of collagen from a skin sample showed a marked
increase in mature cross-links, indicating a decrease in skin collagen
turnover. Paige et al. (1992) suggested that the findings indicate a
primary disorder of fibroblasts.

Dean et al. (1993) reported the clinical features and histologic
findings in 2 sibs who died from restrictive dermopathy in the neonatal
period. Fibroblasts displayed increased expression of the alpha-1
(192968) and alpha-2 (192974) subunits of integrin, which are
responsible for collagen binding. Since integrins may play an important
role in tissue differentiation, the findings were thought to support the
hypothesis that restrictive dermopathy is a disorder of skin
differentiation.

Mau et al. (1997) described an affected boy of consanguineous parents
and reviewed 30 previous cases. Sillevis Smitt et al. (1998) reported on
12 cases of restrictive dermopathy seen during a period of 8 years by
the Dutch Task Force on Genodermatology. In most of these children the
features were prematurity, fixed facial expression, micrognathia, mouth
in the 'O' position, rigid and tense skin with erosions and denudations,
and multiple joint contractures. A wide ascending aorta and dextrocardia
were present in single patients.

MOLECULAR GENETICS

In 2 of 9 fetuses with restrictive dermopathy, Navarro et al. (2004)
identified heterozygous splicing mutations in the LMNA gene, resulting
in the complete or partial loss of exon 11 (150330.0036 and 150330.0022,
respectively). In the other 7 patients, they identified a heterozygous
1-bp insertion resulting in a premature stop codon in the ZMPSTE24 gene
(606480.0001). This metalloproteinase is specifically involved in the
posttranslational processing of lamin A precursor. In all patients
carrying a ZMPSTE24 mutation, loss of expression of lamin A as well as
abnormal patterns of nuclear sizes and shapes and mislocalization of
lamin-associated proteins was seen. Navarro et al. (2004) concluded that
a common pathogenetic pathway, involving defects of the nuclear lamina
and matrix, is involved in restrictive dermopathy.

Navarro et al. (2005) described 7 previously reported patients and 3 new
patients with restrictive dermopathy who were homozygous or compound
heterozygous for ZMPSTE24 mutations. In all cases there was complete
absence of both ZMPSTE24 and mature lamin A, associated with prelamin A
accumulation. The authors concluded that restrictive dermopathy is
either a primary or a secondary laminopathy, caused by dominant de novo
LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations.
The accumulation of truncated or normal length prelamin A is, therefore,
a shared pathophysiologic feature in recessive and dominant restrictive
dermopathy.

Moulson et al. (2003) suggested that the gene encoding fatty acid
transport protein-4 (SLC27A4; 604194) is a candidate gene for
restrictive dermopathy because of the findings in a phenotypically
identical mutation in the mouse called 'wrinkle-free' (wrfr). Moulson et
al. (2005) ruled out SLC27A4 as a candidate, and subsequently, they
identified homozygous or compound heterozygous mutations in the ZMPSTE24
gene (606480.0001; 606480.0007; 606480.0008) in patients with lethal
restrictive dermopathy. All the mutations resulted in premature
termination and lack of a functional protein. Cultured cells and tissue
from affected individuals showed accumulation of unprocessed toxic lamin
A and aggregates of lamin A in nuclei, suggesting that the disorder
results from defective processing of lamin A.

In a female infant with lethal restrictive dermopathy, born to
aboriginal Taiwanese parents from the same tribe but not known to be
consanguineous, Chen et al. (2009) identified homozygosity for a
nonsense mutation in the ZMPSTE24 gene (606480.0006). The infant, who
died at 3 hours of life due to respiratory insufficiency, had no
mutation in the LMNA gene. The unaffected parents and both grandmothers
were heterozygous for the ZMPSTE24 mutation; an unaffected older sister
did not inherit the mutation. An uncommon prenatal finding observed in
the affected infant was spontaneous complete chorioamniotic membrane
separation at 31 weeks' gestation.

Smigiel et al. (2010) reported 2 Polish brothers with restrictive
dermopathy who died at 7 days and 12 days of age. In the second brother,
they identified compound heterozygosity for 2 inactivating mutations in
the ZMPSTE24 gene (606480.0010 and 606480.0011). No DNA was available
from the first brother; the unaffected parents were each heterozygous
for one of the mutations.

POPULATION GENETICS

Li (2010) identified a homozygous mutation in the ZMPSTE24 gene
(1085dupT; 606480.0001) in an infant girl with restrictive dermopathy.
She was born of Mexican Mennonite parents who had immigrated to Canada.
The mother reported several neonatal deaths in her family. Li (2010)
postulated that since this family was of Mennonite descent, it may
represent a founder mutation in this group. However, Miner (2010) noted
that Moulson et al. (2005) had previously identified a different
truncating mutation in the ZMPSTE24 gene (54dupT; 606480.0007) as
causing restrictive dermopathy in 2 related Mennonite families from
Pennsylvania, suggesting allelic heterogeneity even within this isolated
population.

In 2 unrelated Old Colony Mennonite infants, 1 from Alberta and 1 from
Ontario, who died shortly after birth from restrictive dermopathy,
Loucks et al. (2012) identified homozygosity for the common 1085dupT
mutation in the ZMPSTE24 gene. In addition, the mutation was found in
heterozygosity in the obligate-carrier parents of 2 unrelated deceased
Schmiedeleut Hutterite infants with restrictive dermopathy, 1 from South
Dakota and 1 from Manitoba (the latter patient was originally reported
by Reed et al., 1993). Haplotype analysis suggested a small 1.36-Mb
shared haplotype distal to the mutation. In a cohort of approximately
1,200 Schmiedeleut Hutterites from South Dakota, Loucks et al. (2012)
determined a high carrier frequency of the 1085dupT mutation
(approximately 1/21), making it likely that the mutation predates the
1874 separation of the Hutterites into the 3 current essentially
endogamous leuts and lending support to the hypothesis (Lowry et al.,
1985) that the mutation was introduced into the Hutterites in 1783 when
some Mennonites joined the Hutterite brethren. Noting that the 1085dupT
mutation accounts for nearly 75% of the reported causative ZMPSTE24
mutations in restrictive dermopathy, Loucks et al. (2012) suggested that
1085dupT may represent a recurrent mutation due to a mutational hotspot.

In a carrier screening of autosomal recessive mutations involving 1,644
Schmiedeleut (S-leut) Hutterites in the United States, Chong et al.
(2012) identified the restrictive dermopathy mutation 1085dupT (dbSNP
rs137854889, 606480.0007) in heterozygous state in 87 individuals among
1,361 screened and in homozygous state in none, for a carrier frequency
of 0.064 (1 in 15.5). The carrier frequency in other populations was
unknown, and Chong et al. (2012) noted that less than 60 cases had been
reported worldwide.

*FIELD* SA
Toriello (1986)
*FIELD* RF
1. Antoine, T.: Ein Fall von allgemeiner, angeborener Haut-atrophie. Monatsschr.
Geburtsh. Gynaekol. 81: 276-283, 1929.

2. Carmi, R.; Sofer, S.; Karplus, M.; Ben-Yakar, Y.; Mahler, D.; Zirkin,
H.; Bar-Ziv, J.: Aplasia cutis congenita in two sibs discordant for
pyloric atresia. Am. J. Med. Genet. 11: 319-328, 1982.

3. Chen, M.; Kuo, H.-H.; Huang, Y.-C.; Ke, Y.-Y.; Chang, S.-P.; Chen,
C.-P.; Lee, D.-J.; Lee, M.-L.; Lee, M.-H.; Chen, T.-H.; Chen, C.-H.;
Lin, H.-M.; Liu, C.-S.; Ma, G.-C.: A case of restrictive dermopathy
with complete chorioamniotic membrane separation caused by a novel
homozygous nonsense mutation in the ZMPSTE24 gene. (Letter) Am. J.
Med. Genet. 149A: 1550-1554, 2009.

4. Chong, J. X.; Ouwenga, R.; Anderson, R. L.; Waggoner, D. J.; Ober,
C.: A population-based study of autosomal-recessive disease-causing
mutations in a founder population. Am. J. Hum. Genet. 91: 608-620,
2012.

5. Dean, J. C. S.; Gray, E. S.; Stewart, K. N.; Brown, T.; Lloyd,
D. J.; Smith, N. C.; Pope, F. M.: Restrictive dermopathy: a disorder
of skin differentiation with abnormal integrin expression. Clin.
Genet. 44: 287-291, 1993.

6. Hamel, B. C. J.; Happle, R.; Steylen, P. M.; Kollee, L. A. A.;
Schuurmans Stekhoven, J. H.; Nijhuis, J. G.; Rauskolb, R.; Anton-Lamprecht,
I.: False-negative prenatal diagnosis of restrictive dermopathy. Am.
J. Med. Genet. 44: 824-826, 1992.

7. Happle, R.; Schuurmans Stekhoven, J. H.; Hamel, B. C. J.; Kollee,
L. A. A.; Nijhuis, J. G.; Anton-Lamprecht, I.; Steijlen, P. M.: Restrictive
dermopathy in two brothers. Arch. Derm. 128: 232-235, 1992.

8. Hoffmann, R.; Lohner, M.; Bohm, N.; Leititis, J.; Helwig, H.:
Restrictive dermopathy: a lethal congenital skin disorder. Europ.
J. Pediat. 152: 95-98, 1993.

9. Holbrook, K. A.; Dale, B. A.; Witt, D. R.; Hayden, M. R.; Toriello,
H. V.: Arrested epidermal morphogenesis in three newborn infants
with a fatal genetic disorder (restrictive dermopathy). J. Invest.
Derm. 88: 330-339, 1987.

10. Lenz, W.; Meschede, D.: Historical note on restrictive dermopathy
and report of two new cases. (Letter) Am. J. Med. Genet. 47: 1235-1237,
1993.

11. Li, C.: Homozygosity for the common mutation c.1085dupT in the
ZMPSTE24 gene in a Mennonite baby with restrictive dermopathy and
placenta abruption. (Letter) Am. J. Med. Genet. 152A: 262-263, 2010.

12. Loucks, C.; Parboosingh, J. S.; Chong, J. X.; Ober, C.; Siu, V.
M.; Hegele, R. A.; Rupar, C. A.; McLeod, D. R.; Pinto, A.; Chudley,
A. E.; Innes, A. M.: A shared founder mutation underlies restrictive
dermopathy in Old Colony (Dutch-German) Mennonite and Hutterite patients
in North America. (Letter) Am. J. Med. Genet. 158A: 1229-1232, 2012.

13. Lowry, R. B.; Machin, G. A.; Morgan, K.; Mayock, D.; Marx, L.
: Congenital contractures, edema, hyperkeratosis, and intrauterine
growth retardation: a fatal syndrome in Hutterite and Mennonite kindreds. Am.
J. Med. Genet. 22: 531-543, 1985.

14. Mau, U.; Kendziorra, H.; Kaiser, P.; Enders, H.: Restrictive
dermopathy: report and review. Am. J. Med. Genet. 71: 179-185, 1997.

15. Miner, J. H.: Restrictive dermopathy and ZMPSTE24 mutations in
Mennonites: evidence for allelic heterogeneity. (Letter) Am. J. Med.
Genet. 152A: 2140-2141, 2010.

16. Mok, Q.; Curley, R.; Tolmie, J. L.; Marsden, R. A.; Patton, M.
A.; Davies, E. G.: Restrictive dermopathy: a report of 3 cases. J.
Med. Genet. 27: 315-319, 1990.

17. Moulson, C. L.; Go, G.; Gardner, J. M.; van der Wal, A. C.; Smitt,
J. H. S.; van Hagen, J. M.; Miner, J. H.: Homozygous and compound
heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive
dermopathy. J. Invest. Derm. 125: 913-919, 2005.

18. Moulson, C. L.; Martin, D. R.; Lugus, J. J.; Schaffer, J. E.;
Lind, A. C.; Miner, J. H.: Cloning of wrinkle-free, a previously
uncharacterized mouse mutation, reveals crucial roles for fatty acid
transport protein 4 in skin and hair development. Proc. Nat. Acad.
Sci. 100: 5274-5279, 2003.

19. Navarro, C. L.; Cadinanos, J.; De Sandre-Giovannoli, A.; Bernard,
R.; Courrier, S.; Boccaccio, I.; Boyer, A.; Kleijer, W. J.; Wagner,
A.; Giuliano, F.; Beemer, F. A.; Freije, J. M.; Cau, P.; Hennekam,
R. C. M.; Lopez-Otin, C.; Badens, C.; Levy, N.: Loss of ZMPSTE24
(FACE-1) causes autosomal recessive restrictive dermopathy and accumulation
of lamin A precursors. Hum. Molec. Genet. 14: 1503-1513, 2005.

20. Navarro, C. L.; De Sandre-Giovannoli, A.; Bernard, R.; Boccaccio,
I.; Boyer, A.; Genevieve, D.; Hadj-Rabia, S.; Gaudy-Marqueste, C.;
Smitt, H. S.; Vabres, P.; Faivre, L.; Verloes, A.; Van Essen, T.;
Flori, E.; Hennekam, R.; Beemer, F. A.; Laurent, N.; Le Merrer, M.;
Cau, P.; Levy, N.: Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear
disorganization and identity restrictive dermopathy as a lethal neonatal
laminopathy. Hum. Molec. Genet. 13: 2493-2503, 2004.

21. Paige, D. G.; Lake, B. D.; Bailey, A. J.; Ramani, P.; Harper,
J. I.: Restrictive dermopathy: a disorder of fibroblasts. Brit.
J. Derm. 127: 630-634, 1992.

22. Reed, M. H.; Chudley, A. E.; Kroeker, M.; Wilmot, D. M.: Restrictive
dermopathy. Pediat. Radiol. 23: 617-619, 1993.

23. Sillevis Smitt, J. H.; van Asperen, C. J.; Niessen, C. M.; Beemer,
F. A.; van Essen, A. J.; Hulsmans, R. F. H. J.; Oranje, A. P.; Steijlen,
P. M.; Wesby-van Swaay, E.; Tamminga, P.; Breslau-Siderius, E. J.;
Dutch Task Force on Genodermatology: Restrictive dermopathy: report
of 12 cases. Arch. Derm. 134: 577-579, 1998.

24. Smigiel, R.; Jakubiak, A.; Esteves-Viera, V.; Szela, K.; Halon,
A.; Jurek, T.; Levy, N.; De Sandre-Giovannoli, A.: Novel frameshifting
mutations of the ZMPSTE24 gene in two siblings affected with restrictive
dermopathy and review of the mutations described in the literature. Am.
J. Med. Genet. 152A: 447-452, 2010.

25. Toriello, H. V.: Restrictive dermopathy and report of another
case. (Editorial) Am. J. Med. Genet. 24: 625-629, 1986.

26. Van Hoestenberghe, M.; Legius, E.; Vandevoorde, W.; Eykens, A.;
Jaeken, J.; Eggermont, E.; Devos, R.; De Wolf-Peeters, C.; Fryns,
J.-P.: Restrictive dermopathy with distinct morphological abnormalities. Am.
J. Med. Genet. 36: 297-300, 1990.

27. Verloes, A.; Mulliez, N.; Gonzales, M.; Laloux, F.; Hermanns-Le,
T.; Pierard, G. E.; Koulischer, L.: Restrictive dermopathy, a lethal
form of arthrogryposis multiplex with skin and bone dysplasias: three
new cases and review of the literature. Am. J. Med. Genet. 43: 539-547,
1992.

28. Wepler, W.: Zur Frage allgemeiner Hypoplasie der Haut. Beitr.
Path. Anat. 101: 457-469, 1938.

29. Witt, D. R.; Hayden, M. R.; Holbrook, K. A.; Dale, B. A.; Baldwin,
V. J.; Taylor, G. P.: Restrictive dermopathy: a newly recognized
autosomal recessive skin dysplasia. Am. J. Med. Genet. 24: 631-648,
1986.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Intrauterine growth retardation

HEAD AND NECK:
[Head];
Large fontanel;
[Face];
Micrognathia;
Expressionless facies;
[Ears];
Dysplastic ears;
Low-set ears;
[Eyes];
Hypertelorism;
Entropion;
Short palpebral fissures;
Sparse/absent eyelashes;
Sparse/absent eyebrows;
[Nose];
Small, pinched nose;
Choanal atresia;
[Mouth];
Small mouth;
Submucous cleft palate;
Cleft palate;
Ankylosis of temporomandibular joint;
[Teeth];
Natal teeth

CARDIOVASCULAR:
[Heart];
Atrial septal defect;
[Vascular];
Patent ductus arteriosus

RESPIRATORY:
[Lung];
Pulmonary hypoplasia

CHEST:
[External features];
Increased anterioposterior diameter of chest;
[Ribs, sternum, clavicles, and scapulae];
Thin, dysplastic bipartite clavicles;
Ribbon-like ribs

GENITOURINARY:
[External genitalia, male];
Hypospadias;
[Ureters];
Ureteral duplication

SKELETAL:
[Skull];
Poorly mineralized skull;
Widened suture;
Large fontanelles;
[Spine];
Kyphoscoliosis;
[Limbs];
Joint contractures;
Overtubulated long bones;
[Feet];
Rocker-bottom feet

SKIN, NAILS, HAIR:
[Skin];
Tight, rigid skin;
Skin erosions;
Prominent superficial vasculature;
Skin fissures (groin, axilla, neck);
Epidermal hyperkeratosis;
Dermis thinning;
Abnormal alignment of collagen bundles;
Absence of normal rete ridge pattern;
[Nails];
Short nails;
Long nails;
[Hair];
Sparse/absent eyelashes;
Sparse/absent eyebrows;
Sparse/absent lanugo;
Normal scalp hair

ENDOCRINE FEATURES:
Adrenal hypoplasia

PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal activity;
[Amniotic fluid];
Polyhydramnios;
[Placenta and umbilical cord];
Short umbilical cord;
Hydropic placenta;
[Delivery];
Premature rupture of membranes;
Stillbirth;
Premature birth

MISCELLANEOUS:
Liveborn often die within first week of life;
Genetic heterogeneity

MOLECULAR BASIS:
Caused by mutation in the zinc metalloproteinase STE24 gene (ZMPSTE24,
606480.0003);
Caused by mutation in the lamin A/C gene (LMNA, 150330.0022)

*FIELD* CN
Joanna S. Amberger - updated: 6/23/2005
Kelly A. Przylepa - revised: 12/3/2001

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/19/2011
ckniffin: 5/22/2007
joanna: 6/23/2005
joanna: 3/14/2005
joanna: 12/3/2001

*FIELD* CN
Marla J. F. O'Neill - updated: 3/21/2013
Ada Hamosh - updated: 2/7/2013
Marla J. F. O'Neill - updated: 10/23/2012
Cassandra L. Kniffin - updated: 1/6/2011
Marla J. F. O'Neill - updated: 12/4/2009
George E. Tiller - updated: 6/11/2008
George E. Tiller - updated: 5/19/2005
Victor A. McKusick - updated: 6/13/2003
Victor A. McKusick - updated: 7/13/1998
Victor A. McKusick - updated: 8/18/1997
Iosif W. Lurie - updated: 8/13/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 09/06/2013
carol: 3/26/2013
terry: 3/21/2013
alopez: 2/11/2013
terry: 2/7/2013
carol: 10/23/2012
terry: 10/23/2012
wwang: 1/24/2011
ckniffin: 1/6/2011
carol: 1/6/2010
carol: 12/23/2009
terry: 12/4/2009
wwang: 7/29/2009
wwang: 6/11/2008
wwang: 3/1/2007
tkritzer: 5/25/2005
terry: 5/19/2005
tkritzer: 1/20/2005
mgross: 3/17/2004
alopez: 6/23/2003
terry: 6/13/2003
terry: 7/13/1998
terry: 8/18/1997
carol: 8/13/1996
terry: 7/27/1994
warfield: 3/31/1994
mimadm: 3/13/1994
carol: 3/12/1994
carol: 3/10/1993
carol: 1/28/1993

MIM 605588
*RECORD*
*FIELD* NO
605588
*FIELD* TI
#605588 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B1; CMT2B1
;;CHARCOT-MARIE-TOOTH DISEASE, NEURONAL, TYPE 2B1;;
read moreCHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, 2B1;;
CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2B1
*FIELD* TX
A number sign (#) is used with this entry because this form of autosomal
recessive axonal CMT can be caused by homozygous mutation in the lamin
A/C gene (LMNA; 150330) on chromosome 1q22. Mutations in the LMNA gene
have been found to cause several other disorders.

DESCRIPTION

Charcot-Marie-Tooth disease constitutes a clinically and genetically
heterogeneous group of hereditary motor and sensory neuropathies. On the
basis of electrophysiologic criteria, CMT is divided into 2 major types:
type 1, the demyelinating form, characterized by a motor median nerve
conduction velocity less than 38 m/s (see CMT1B; 118200); and type 2,
the axonal form, with a normal or slightly reduced nerve conduction
velocity.

For a phenotypic description and a discussion of genetic heterogeneity
of axonal CMT type 2, see CMT2A1 (118210).

CLINICAL FEATURES

Bouhouche et al. (1999) studied a large consanguineous Moroccan
autosomal recessive CMT2 family with 9 affected sibs. Onset of CMT was
in the second decade in all affected individuals, who had weakness and
wasting of the distal lower limb muscles and lower limb areflexia. Pes
cavus was present in 7 patients, and there was proximal muscle
involvement in 6. Motor nerve conduction velocities were normal or
slightly reduced in all patients, reflecting an axonal process.

MAPPING

In the large Moroccan family with CMT2, Bouhouche et al. (1999) excluded
linkage to known CMT loci. A genomewide search showed linkage of the
disorder in this family to markers on 1q, specifically 1q21.2-q21.3.

MOLECULAR GENETICS

Bouhouche et al. (1999) excluded the myelin protein zero gene (MPZ;
159440) as a candidate for mutation in this disorder by physical mapping
and direct sequencing.

In 3 consanguineous Algerian families with autosomal recessive CMT2
linked to chromosome 1q21, De Sandre-Giovannoli et al. (2002) identified
a homozygous mutation in the LMNA gene (R298C; 150330.0020).

ANIMAL MODEL

De Sandre-Giovannoli et al. (2002) reported that Lmna null mice
presented with an axonal clinical and pathologic phenotype that is
highly similar to patients with autosomal recessive CMT2.

*FIELD* RF
1. Bouhouche, A.; Benomar, A.; Birouk, N.; Mularoni, A.; Meggouh,
F.; Tassin, J.; Grid, D.; Vandenberghe, A.; Yahyaoui, M.; Chkili,
T.; Brice, A.; LeGuern, E.: A locus for an axonal form of autosomal
recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3. Am.
J. Hum. Genet. 65: 722-727, 1999.

2. De Sandre-Giovannoli, A.; Chaouch, M.; Kozlov, S.; Vallat, J.-M.;
Tazir, M.; Kassouri, N.; Szepetowski, P.; Hammadouche, T.; Vandenberghe,
A.; Stewart, C. L.; Grid, D.; Levy, N.: Homozygous defects in LMNA,
encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive
axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and
mouse. Am. J. Hum. Genet. 70: 726-736, 2002. Note: Erratum: Am.
J. Hum. Genet. 70: 1075 only, 2002.

*FIELD* CS
INHERITANCE:
Autosomal recessive

SKELETAL:
[Spine];
Kyphoscoliosis may be present;
[Feet];
Pes cavus;
Foot deformities

NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Proximal muscle involvement may occur;
'Steppage' gait;
Foot drop;
Distal sensory impairment;
Hyporeflexia;
Areflexia;
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s);
Axonal atrophy on nerve biopsy;
Axonal degeneration/regeneration on nerve biopsy;
Small 'onion bulbs' may be present;
Decreased number of myelinated fibers may be found

MISCELLANEOUS:
Onset in second decade;
Usually begins in feet and legs (peroneal distribution);
Upper limb involvement may occur later;
Severe course;
Genetic heterogeneity (see CMT2B2, 605589);
For autosomal dominant forms of axonal neuropathy, see CMT2A (118210)

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0020)

*FIELD* CD
Cassandra L. Kniffin: 4/22/2003

*FIELD* ED
ckniffin: 05/02/2003

*FIELD* CN
Cassandra L. Kniffin - reorganized: 4/29/2003
Victor A. McKusick - updated: 3/21/2002

*FIELD* CD
Victor A. McKusick: 1/25/2001

*FIELD* ED
joanna: 02/11/2014
carol: 3/23/2012
carol: 1/26/2012
terry: 3/3/2010
mgross: 3/15/2005
ckniffin: 5/8/2003
carol: 4/29/2003
ckniffin: 4/24/2003
ckniffin: 4/23/2003
alopez: 4/19/2002
alopez: 3/27/2002
terry: 3/21/2002
carol: 1/25/2001

MIM 610140
*RECORD*
*FIELD* NO
610140
*FIELD* TI
#610140 HEART-HAND SYNDROME, SLOVENIAN TYPE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreSlovenian type heart-hand syndrome is caused by heterozygous mutation in
the LMNA gene (150330) on chromosome 1q22.

CLINICAL FEATURES

Sinkovec et al. (2005) reported a Slovenian family with 10 affected
members in 4 generations who had adult-onset progressive sinoatrial and
atrioventricular conduction disease, sudden death due to ventricular
tachyarrhythmia, dilated cardiomyopathy, and a unique type of
brachydactyly with mild hand involvement and more severe foot
involvement. Hand changes included short distal, middle, and proximal
phalanges and clinodactyly; foot changes included short distal and
proximal phalanges and metatarsal bones, short or absent middle
phalanges, terminal symphalangism, duplication of the bases of the
second metatarsals, extra ossicles, and syndactyly.

Renou et al. (2008) reexamined 5 affected and 3 unaffected members of
the Slovenian family with heart-hand syndrome originally reported by
Sinkovec et al. (2005) and observed overt myopathy in a 62-year-old
affected female, who had proximal upper limb muscle weakness without
joint contractures, myopathic EMG pattern, and slightly elevated
creatine phosphokinase (CPK). Her 45-year-old niece also had myopathic
pattern on EMG, but normal CPK and no overt muscle weakness; no other
family members had muscle weakness or joint contractures.

MAPPING

Using microsatellite markers for known disease loci in a Slovenian
family with a form of heart-hand syndrome, Sinkovec et al. (2005)
excluded linkage to SCN5A (600163), ROR2 (602337), TBX5 (601620), and
TBX3 (601621).

MOLECULAR GENETICS

Renou et al. (2008) analyzed the LMNA gene in 12 members of the family
with heart-hand syndrome originally reported by Sinkovec et al. (2005)
and identified a heterozygous splice site mutation (150330.0045) that
cosegregated with disease in 6 affected members and was not found in 100
healthy controls. A 32-year-old female mutation carrier showed only
slight cardiac involvement, which led Renou et al. (2008) to consider
that disease severity may be related to age as in other LNMA-related
cardiac diseases.

*FIELD* RF
1. Renou, L.; Stora, S.; Yaou, R. B.; Volk, M.; Sinkovec, M.; Demay,
L.; Richard, P.; Peterlin, B.; Bonne, G.: Heart-hand syndrome of
Slovenian type: a new kind of laminopathy. (Letter) J. Med. Genet. 45:
666-671, 2008.

2. Sinkovec, M.; Petrovic, D.; Volk, M.; Peterlin, B.: Familial progressive
sinoatrial and atrioventricular conduction disease of adult onset
with sudden death, dilated cardiomyopathy, and brachydactyly: a new
type of heart-hand syndrome? Clin. Genet. 68: 155-160, 2005.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Heart];
Cardiomyopathy, dilated;
Conduction disease, sinoatrial and atrioventricular, progressive;
Ventricular tachyarrhythmia (can result in sudden death)

SKELETAL:
[Hands];
Brachydactyly;
Clinodactyly;
[Feet];
Brachydactyly (more severe than in hands);
Short or absent middle phalanges;
Symphalangism, terminal;
Duplication of bases of second metatarsals;
Extra ossicles;
Syndactyly

MUSCLE, SOFT TISSUE:
Myopathy (rare)

NEUROLOGIC:
[Peripheral nervous system];
Proximal weakness, upper extremities (1 patient)

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0045)

*FIELD* CD
Marla J. F. O'Neill: 1/5/2010

*FIELD* ED
joanna: 01/06/2010
joanna: 1/5/2010

*FIELD* CN
Marla J. F. O'Neill - updated: 2/19/2009

*FIELD* CD
Marla J. F. O'Neill: 5/23/2006

*FIELD* ED
terry: 03/27/2012
joanna: 3/2/2010
wwang: 2/23/2009
terry: 2/19/2009
carol: 5/23/2006

MIM 613205
*RECORD*
*FIELD* NO
613205
*FIELD* TI
#613205 MUSCULAR DYSTROPHY, CONGENITAL, LMNA-RELATED
;;MDCL
*FIELD* TX
A number sign (#) is used with this entry because this form of
read morecongenital muscular dystrophy (MDC) is caused by heterozygous mutation
in the gene encoding lamin A/C (LMNA; 150330) on chromosome 1q22.

See also limb-girdle muscular dystrophy type 1B (LGMD1B; 159001) and
Emery-Dreifuss muscular dystrophy-2 (EDMD2; 181350), allelic disorders
with overlapping phenotypes.

CLINICAL FEATURES

Mercuri et al. (2004) reported a patient with LMNA-related congenital
muscular dystrophy. The infant lost the ability to roll over at age 5
months, and later showed difficulties in lifting her arms and head.
Other features included feeding difficulties, requiring a nasogastric
tube, marked axial and limb weakness, talipes foot deformities, and
increased serum creatine kinase. She also had a narrow chest and a
predominantly diaphragmatic pattern of breathing.

D'Amico et al. (2005) reported an 18-month-old boy with so-called
'dropped head syndrome,' characterized by prominent neck extension
weakness. His primary motor milestones were within the normal range, but
he had difficulty holding up his head and problems walking at age 12
months. Neurological examination at 15 months confirmed significant neck
extensor weakness with mild axial and limb girdle weakness. However, the
boy could walk alone, walk up stairs, and rise from a chair, and there
was no significant decrease in distal muscle strength. Cardiac
examination was normal. Genetic analysis identified a de novo
heterozygous 3-bp deletion in the LMNA gene (150330.0050).

Quijano-Roy et al. (2008) described a form of congenital muscular
dystrophy with onset in the first year of life in 15 unrelated children.
Three patients had severe early-onset disease, with decreased fetal
movements in utero, no motor development, severe hypotonia, diffuse limb
and axial muscle weakness and atrophy, and talipes foot deformities.
There were contractures in the distal limb joints, stiff and
hyperextensible spine, and neck weakness. All 3 infants required
mechanical ventilation at some point, and 2 of the patients had evidence
of cardiac arrhythmia. The remaining 12 children initially acquired head
and trunk control and independent ambulation, but most lost head control
due to neck extensor weakness, a phenotype consistent with 'dropped head
syndrome.' Despite variable severity, there was a consistent clinical
pattern overall among the 15 patients. They typically presented with
selective axial weakness and wasting of the cervicoaxial muscles. Limb
involvement was predominantly proximal in upper extremities and distal
in lower extremities. Talipes feet and a rigid spine with thoracic
lordosis developed early. Proximal contractures appeared later, most
often in lower limbs, sparing the elbows. Ten children required
ventilatory support. Cardiac arrhythmias were observed in 4 of the
oldest patients, but were symptomatic only in 1. Creatine kinase levels
were mild to moderately increased. Muscle biopsies showed dystrophic
changes in 9 children and nonspecific myopathic changes in the
remaining. Quijano-Roy et al. (2008) concluded that the LMNA mutations
identified appeared to correlate with a relatively severe phenotype,
broadening the spectrum of laminopathies. The authors suggested that
this group of patients may define a new disease entity, which they
designated LMNA-related congenital muscular dystrophy.

- Early-Onset Myopathy with Progeroid Features

Kirschner et al. (2005) described a young girl with a phenotype
combining early-onset myopathy with progeroid features who was found to
have a de novo heterozygous mutation in the LMNA gene (S143F;
150330.0034). The child presented during the first year of life with
myopathy with marked axial weakness; progeroid features, including
growth failure, sclerodermatous skin changes, and osteolytic lesions,
developed later. Routine examination at the age of 8 years revealed a
mediolateral myocardial infarction. Although LMNA mutations are known to
cause Hutchinson-Gilford progeria (HGPS; 176670) and muscular dystrophy,
this was the first report of a patient combining features of these 2
phenotypes resulting from a single mutation in LMNA.

MOLECULAR GENETICS

In a patient with LMNA-related congenital muscular dystrophy, Mercuri et
al. (2004) identified a de novo heterozygous mutation in the LMNA gene
(E3358K; 150330.0049). Four additional unrelated patients with less
severe muscular dystrophy, including EDMD2 (181350) and LGMD1B (159001)
carried the same mutation.

In 15 children with congenital muscular dystrophy, Quijano-Roy et al.
(2008) identified 11 different de novo heterozygous mutations in the
LMNA gene (see, e.g., 150330.0047-150330.0049).

*FIELD* RF
1. D'Amico, A.; Haliloglu, G.; Richard, P.; Talim, B.; Maugenre, S.;
Ferreiro, A.; Guicheney, P.; Menditto, I.; Benedetti, S.; Bertini,
E.; Bonne, G.; Topaloglu, H.: Two patients with 'dropped head syndrome'
due to mutations in LMNA or SEPN1 genes. Neuromusc. Disord. 15:
521-524, 2005.

2. Kirschner, J.; Brune, T.; Wehnert, M.; Denecke, J.; Wasner, C.;
Feuer, A.; Marquardt, T.; Ketelsen, U.-P.; Wieacker, P.; Bonnemann,
C. G.; Korinthenberg, R.: p.S143F mutation in lamin A/C: a new phenotype
combining myopathy and progeria. Ann. Neurol. 57: 148-151, 2005.

3. Mercuri, E.; Poppe, M.; Quinlivan, R.; Messina, S.; Kinali, M.;
Demay, L.; Bourke, J.; Richard, P.; Sewry, C.; Pike, M.; Bonne, G.;
Muntoni, F.; Bushby, K.: Extreme variability of phenotype in patients
with an identical missense mutation in the lamin A/C Gene: from congenital
onset with severe phenotype to milder classic Emery-Dreifuss variant. Arch.
Neurol. 61: 690-694, 2004.

4. Quijano-Roy, S.; Mbieleu, B.; Bonnemann, C. G.; Jeannet, P.-Y.;
Colomer, J.; Clarke, N. F.; Cuisset, J.-M.; Roper, H.; De Meirleir,
L.; D'Amico, A.; Yaou, R. B.; Nascimento, A.; and 12 others: De
novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann.
Neurol. 64: 177-186, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Failure to thrive

HEAD AND NECK:
[Neck];
Neck muscle weakness;
Floppy neck;
Loss of head control

CARDIOVASCULAR:
[Heart];
Conduction abnormalities (less common)

RESPIRATORY:
Respiratory insufficiency due to muscle weakness

SKELETAL:
Joint contractures;
[Spine];
Rigid spine;
Stiff spine;
[Limbs];
Elbow laxity;
[Feet];
Talipes foot deformities

MUSCLE, SOFT TISSUE:
Muscle weakness, severe, proximal and distal;
Generalized amyotrophy;
Hypotonia, severe;
Axial weakness;
Head drop due to neck muscle weakness;
Dystrophic features and atrophic fibers seen on muscle biopsy;
Variability in fiber size

NEUROLOGIC:
[Central nervous system];
Delayed motor development

PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements

LABORATORY ABNORMALITIES:
Increased serum creatine kinase

MISCELLANEOUS:
Prenatal onset or onset in infancy;
Variable severity;
Progressive disorder;
Patients who acquire ability to walk may lose it

MOLECULAR BASIS:
Caused by mutation in the lamin A/C gene (LMNA, 150330.0047)

*FIELD* CD
Cassandra L. Kniffin: 1/4/2010

*FIELD* ED
joanna: 04/26/2013
ckniffin: 1/5/2010

*FIELD* CD
Cassandra L. Kniffin: 12/31/2009

*FIELD* ED
carol: 04/30/2012
terry: 3/27/2012
ckniffin: 1/11/2010
carol: 1/6/2010
ckniffin: 1/5/2010

RBCC Red Blood Cell Collection

Full text data of LMNA