RBCC Red Blood Cell Collection

LBR [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Lamin-B receptor (Integral nuclear envelope inner membrane protein; LMN2R)

UniProt Q14739
ID LBR_HUMAN Reviewed; 615 AA.
AC Q14739; B2R5P3; Q14740; Q53GU7; Q59FE6;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 31-JAN-2002, sequence version 2.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Lamin-B receptor;
DE AltName: Full=Integral nuclear envelope inner membrane protein;
DE AltName: Full=LMN2R;
GN Name=LBR;
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], AND INTERACTION WITH DNA; LMNB1 AND LMNB2.
RX PubMed=8157662;
RA Ye Q., Worman H.J.;
RT "Primary structure analysis and lamin B and DNA binding of human LBR,
RT an integral protein of the nuclear envelope inner membrane.";
RL J. Biol. Chem. 269:11306-11311(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASN-154.
RX PubMed=8157663;
RA Schuler E., Lin F., Worman H.J.;
RT "Characterization of the human gene encoding LBR, an integral protein
RT of the nuclear envelope inner membrane.";
RL J. Biol. Chem. 269:11312-11317(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-154.
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-154.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASN-154.
RC TISSUE=Liver;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ASN-154.
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=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 [8]
RP SUBUNIT, AND INTERACTION WITH CBX5.
RX PubMed=9169472; DOI=10.1074/jbc.272.23.14983;
RA Ye Q., Callebaut I., Pezhman A., Courvalin J.-C., Worman H.J.;
RT "Domain-specific interactions of human HP1-type chromodomain proteins
RT and inner nuclear membrane protein LBR.";
RL J. Biol. Chem. 272:14983-14989(1997).
RN [9]
RP PHOSPHORYLATION BY SRPK1.
RX PubMed=10049757; DOI=10.1006/bbrc.1999.0249;
RA Papoutsopoulou S., Nikolakaki E., Giannakouros T.;
RT "SRPK1 and LBR protein kinases show identical substrate
RT specificities.";
RL Biochem. Biophys. Res. Commun. 255:602-607(1999).
RN [10]
RP FUNCTION.
RX PubMed=10828963; DOI=10.1021/bi992908b;
RA Duband-Goulet I., Courvalin J.-C.;
RT "Inner nuclear membrane protein LBR preferentially interacts with DNA
RT secondary structures and nucleosomal linker.";
RL Biochemistry 39:6483-6488(2000).
RN [11]
RP DISEASE.
RX PubMed=12118250; DOI=10.1038/ng925;
RA Hoffmann K., Dreger C.K., Olins A.L., Olins D.E., Shultz L.D.,
RA Lucke B., Karl H., Kaps R., Mueller D., Vaya A., Aznar J., Ware R.E.,
RA Sotelo Cruz N., Lindner T.H., Herrmann H., Reis A., Sperling K.;
RT "Mutations in the gene encoding the lamin B receptor produce an
RT altered nuclear morphology in granulocytes (Pelger-Huet anomaly).";
RL Nat. Genet. 31:410-414(2002).
RN [12]
RP DISEASE.
RX PubMed=12618959; DOI=10.1086/373938;
RA Waterham H.R., Koster J., Mooyer P., van Noort G., Kelley R.I.,
RA Wilcox W.R., Wanders R.J., Hennekam R.C.M., Oosterwijk J.C.;
RT "Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3
RT beta-hydroxysterol delta 14-reductase deficiency due to mutations in
RT the lamin B receptor gene.";
RL Am. J. Hum. Genet. 72:1013-1017(2003).
RN [13]
RP SUBUNIT, AND INTERACTION WITH CBX5.
RX PubMed=15882967; DOI=10.1016/j.bbrc.2005.04.016;
RA Lechner M.S., Schultz D.C., Negorev D., Maul G.G., Rauscher F.J. III;
RT "The mammalian heterochromatin protein 1 binds diverse nuclear
RT proteins through a common motif that targets the chromoshadow
RT domain.";
RL Biochem. Biophys. Res. Commun. 331:929-937(2005).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-118, AND MASS
RP 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 [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-55; LYS-594 AND LYS-601, AND
RP 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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-97 AND THR-118, AND MASS
RP 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 [18]
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 [19]
RP PHOSPHORYLATION AT SER-71 AND SER-86 BY CDK1.
RX PubMed=21795390; DOI=10.1091/mbc.E11-03-0199;
RA Tseng L.C., Chen R.H.;
RT "Temporal control of nuclear envelope assembly by phosphorylation of
RT lamin B receptor.";
RL Mol. Biol. Cell 22:3306-3317(2011).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-99, AND MASS
RP 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 [21]
RP STRUCTURE BY NMR OF 1-55.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the Tudor domain of human lamin-B receptor.";
RL Submitted (SEP-2006) to the PDB data bank.
RN [22]
RP STRUCTURE BY NMR OF 1-55.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the Tudor domain of human lamin-B receptor.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [23]
RP VARIANTS PHA LEU-119 AND ARG-569.
RX PubMed=14617022; DOI=10.1046/j.1365-2141.2003.04621.x;
RA Best S., Salvati F., Kallo J., Garner C., Height S., Thein S.L.,
RA Rees D.C.;
RT "Lamin B-receptor mutations in Pelger-Huet anomaly.";
RL Br. J. Haematol. 123:542-544(2003).
RN [24]
RP VARIANT REYNS CYS-372.
RX PubMed=20522425; DOI=10.1136/jmg.2009.071696;
RA Gaudy-Marqueste C., Roll P., Esteves-Vieira V., Weiller P.J.,
RA Grob J.J., Cau P., Levy N., De Sandre-Giovannoli A.;
RT "LBR mutation and nuclear envelope defects in a patient affected with
RT Reynolds syndrome.";
RL J. Med. Genet. 47:361-370(2010).
CC -!- FUNCTION: Anchors the lamina and the heterochromatin to the inner
CC nuclear membrane.
CC -!- SUBUNIT: Interacts directly with CBX5. Can interact with
CC chromodomain proteins. Interacts directly with DNA. Interaction
CC with DNA is sequence independent with higher affinity for
CC supercoiled and relaxed circular DNA than linear DNA.
CC -!- INTERACTION:
CC Q13185:CBX3; NbExp=4; IntAct=EBI-1055147, EBI-78176;
CC P45973:CBX5; NbExp=4; IntAct=EBI-1055147, EBI-78219;
CC -!- SUBCELLULAR LOCATION: Nucleus inner membrane; Multi-pass membrane
CC protein.
CC -!- DOMAIN: The Tudor domain may not recognize methylation marks, but
CC rather bind unassembled free histone H3 (By similarity).
CC -!- PTM: Phosphorylated by CDK1 in mitosis when the inner nuclear
CC membrane breaks down into vesicles that dissociate from the lamina
CC and the chromatin. It is phosphorylated by different protein
CC kinases in interphase when the membrane is associated with these
CC structures. Phosphorylation of LBR and HP1 proteins may be
CC responsible for some of the alterations in chromatin organization
CC and nuclear structure which occur at various times during the cell
CC cycle. Phosphorylated by SRPK1. In late anaphase LBR is
CC dephosphorylated, probably by PP1 and/or PP2A, allowing
CC reassociation with chromatin.
CC -!- DISEASE: Pelger-Huet anomaly (PHA) [MIM:169400]: An autosomal
CC dominant inherited abnormality of granulocytes, characterized by
CC abnormal ovoid shape, reduced nuclear segmentation and an
CC apparently looser chromatin structure. Some individuals
CC occasionally have skeletal anomalies, developmental delay, and
CC seizures. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Hydrops-ectopic calcification-moth-eaten skeletal
CC dysplasia (HEM) [MIM:215140]: Rare autosomal recessive
CC chondrodystrophy characterized by early in utero lethality and,
CC therefore, considered to be nonviable. Affected fetuses typically
CC present with fetal hydrops, short-limbed dwarfism, and a marked
CC disorganization of chondro-osseous calcification and may present
CC with polydactyly and additional nonskeletal malformations.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Reynolds syndrome (REYNS) [MIM:613471]: A syndrome
CC specifically associating limited cutaneous systemic sclerosis and
CC primary biliary cirrhosis. It is characterized by liver disease,
CC telangiectasia, abrupt onset of digital paleness or cyanosis in
CC response to cold exposure or stress (Raynaud phenomenon), and
CC variable features of scleroderma. The liver disease is
CC characterized by pruritis, jaundice, hepatomegaly, increased serum
CC alkaline phosphatase and positive serum mitochondrial
CC autoantibodies, all consistent with primary biliary cirrhosis.
CC Note=The disease may be caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the ERG4/ERG24 family.
CC -!- SIMILARITY: Contains 1 Tudor domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD92751.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/LBR";
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DR EMBL; L25931; AAA59494.1; -; mRNA.
DR EMBL; L25941; AAA59495.1; -; Genomic_DNA.
DR EMBL; L25932; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25933; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25934; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25935; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25936; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25937; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25938; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25939; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; L25940; AAA59495.1; JOINED; Genomic_DNA.
DR EMBL; AB209514; BAD92751.1; ALT_INIT; mRNA.
DR EMBL; AK222834; BAD96554.1; -; mRNA.
DR EMBL; AK312258; BAG35190.1; -; mRNA.
DR EMBL; CH471098; EAW69741.1; -; Genomic_DNA.
DR EMBL; BC020079; AAH20079.1; -; mRNA.
DR PIR; A53616; A53616.
DR RefSeq; NP_002287.2; NM_002296.3.
DR RefSeq; NP_919424.1; NM_194442.2.
DR UniGene; Hs.435166; -.
DR UniGene; Hs.735694; -.
DR PDB; 2DIG; NMR; -; A=1-55.
DR PDBsum; 2DIG; -.
DR ProteinModelPortal; Q14739; -.
DR SMR; Q14739; 1-55.
DR DIP; DIP-5987N; -.
DR IntAct; Q14739; 8.
DR MINT; MINT-1631069; -.
DR STRING; 9606.ENSP00000272163; -.
DR PhosphoSite; Q14739; -.
DR DMDM; 20141468; -.
DR PaxDb; Q14739; -.
DR PeptideAtlas; Q14739; -.
DR PRIDE; Q14739; -.
DR DNASU; 3930; -.
DR Ensembl; ENST00000272163; ENSP00000272163; ENSG00000143815.
DR Ensembl; ENST00000338179; ENSP00000339883; ENSG00000143815.
DR GeneID; 3930; -.
DR KEGG; hsa:3930; -.
DR UCSC; uc001hoy.3; human.
DR CTD; 3930; -.
DR GeneCards; GC01M225589; -.
DR HGNC; HGNC:6518; LBR.
DR HPA; HPA049840; -.
DR MIM; 169400; phenotype.
DR MIM; 215140; phenotype.
DR MIM; 600024; gene.
DR MIM; 613471; phenotype.
DR neXtProt; NX_Q14739; -.
DR Orphanet; 1426; Greenberg dysplasia.
DR Orphanet; 779; Reynolds syndrome.
DR PharmGKB; PA30304; -.
DR eggNOG; NOG72042; -.
DR HOGENOM; HOG000193296; -.
DR HOVERGEN; HBG007825; -.
DR InParanoid; Q14739; -.
DR OMA; VINLVML; -.
DR OrthoDB; EOG75B85C; -.
DR PhylomeDB; Q14739; -.
DR BioCyc; MetaCyc:HS07110-MONOMER; -.
DR BRENDA; 1.3.1.70; 2681.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; LBR; human.
DR EvolutionaryTrace; Q14739; -.
DR GeneWiki; Lamin_B_receptor; -.
DR GenomeRNAi; 3930; -.
DR NextBio; 15431; -.
DR PRO; PR:Q14739; -.
DR ArrayExpress; Q14739; -.
DR Bgee; Q14739; -.
DR CleanEx; HS_LBR; -.
DR Genevestigator; Q14739; -.
DR GO; GO:0005639; C:integral to nuclear inner membrane; TAS:ProtInc.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0003677; F:DNA binding; TAS:ProtInc.
DR GO; GO:0005521; F:lamin binding; TAS:ProtInc.
DR GO; GO:0016628; F:oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor; IEA:InterPro.
DR GO; GO:0006695; P:cholesterol biosynthetic process; TAS:Reactome.
DR InterPro; IPR001171; Ergosterol_biosynth_ERG4_ERG24.
DR InterPro; IPR019023; Lamin-B_rcpt_of_tudor.
DR InterPro; IPR018083; Sterol_reductase_CS.
DR InterPro; IPR002999; Tudor.
DR Pfam; PF01222; ERG4_ERG24; 1.
DR Pfam; PF09465; LBR_tudor; 1.
DR SMART; SM00333; TUDOR; 1.
DR PROSITE; PS01017; STEROL_REDUCT_1; 1.
DR PROSITE; PS01018; STEROL_REDUCT_2; 1.
DR PROSITE; PS50304; TUDOR; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Disease mutation;
KW DNA-binding; Membrane; Nucleus; Phosphoprotein; Polymorphism;
KW Receptor; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1 615 Lamin-B receptor.
FT /FTId=PRO_0000207510.
FT TOPO_DOM 1 211 Nuclear (Potential).
FT TRANSMEM 212 232 Helical; (Potential).
FT TRANSMEM 258 278 Helical; (Potential).
FT TRANSMEM 299 319 Helical; (Potential).
FT TRANSMEM 326 346 Helical; (Potential).
FT TRANSMEM 386 406 Helical; (Potential).
FT TRANSMEM 447 467 Helical; (Potential).
FT TRANSMEM 481 501 Helical; (Potential).
FT TRANSMEM 561 581 Helical; (Potential).
FT DOMAIN 1 62 Tudor.
FT MOD_RES 55 55 N6-acetyllysine.
FT MOD_RES 67 67 Phosphoserine (By similarity).
FT MOD_RES 71 71 Phosphoserine; by CDK1.
FT MOD_RES 86 86 Phosphoserine; by CDK1.
FT MOD_RES 97 97 Phosphoserine.
FT MOD_RES 99 99 Phosphoserine.
FT MOD_RES 118 118 Phosphothreonine.
FT MOD_RES 594 594 N6-acetyllysine.
FT MOD_RES 601 601 N6-acetyllysine.
FT VARIANT 119 119 P -> L (in PHA).
FT /FTId=VAR_017841.
FT VARIANT 154 154 S -> N (in dbSNP:rs2230419).
FT /FTId=VAR_024318.
FT VARIANT 169 169 R -> C (in dbSNP:rs2230420).
FT /FTId=VAR_052155.
FT VARIANT 311 311 T -> A (in dbSNP:rs2275601).
FT /FTId=VAR_020209.
FT VARIANT 372 372 R -> C (in REYNS).
FT /FTId=VAR_063811.
FT VARIANT 569 569 P -> R (in PHA).
FT /FTId=VAR_017842.
FT CONFLICT 301 301 A -> P (in Ref. 1; AAA59494).
FT CONFLICT 452 452 F -> L (in Ref. 5; BAD96554).
FT CONFLICT 530 530 T -> S (in Ref. 1; AAA59494).
FT STRAND 11 15
FT TURN 17 19
FT STRAND 22 31
FT TURN 32 35
FT STRAND 36 40
FT STRAND 46 50
FT TURN 51 53
SQ SEQUENCE 615 AA; 70703 MW; 5A7388776F43C66D CRC64;
MPSRKFADGE VVRGRWPGSS LYYEVEILSH DSTSQLYTVK YKDGTELELK ENDIKPLTSF
RQRKGGSTSS SPSRRRGSRS RSRSRSPGRP PKSARRSASA SHQADIKEAR REVEVKLTPL
ILKPFGNSIS RYNGEPEHIE RNDAPHKNTQ EKFSLSQESS YIATQYSLRP RREEVKLKEI
DSKEEKYVAK ELAVRTFEVT PIRAKDLEFG GVPGVFLIMF GLPVFLFLLL LMCKQKDPSL
LNFPPPLPAL YELWETRVFG VYLLWFLIQV LFYLLPIGKV VEGTPLIDGR RLKYRLNGFY
AFILTSAVIG TSLFQGVEFH YVYSHFLQFA LAATVFCVVL SVYLYMRSLK APRNDLSPAS
SGNAVYDFFI GRELNPRIGT FDLKYFCELR PGLIGWVVIN LVMLLAEMKI QDRAVPSLAM
ILVNSFQLLY VVDALWNEEA LLTTMDIIHD GFGFMLAFGD LVWVPFIYSF QAFYLVSHPN
EVSWPMASLI IVLKLCGYVI FRGANSQKNA FRKNPSDPKL AHLKTIHTST GKNLLVSGWW
GFVRHPNYLG DLIMALAWSL PCGFNHILPY FYIIYFTMLL VHREARDEYH CKKKYGVAWE
KYCQRVPYRI FPYIY
//

MIM 169400
*RECORD*
*FIELD* NO
169400
*FIELD* TI
#169400 PELGER-HUET ANOMALY; PHA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morePelger-Huet anomaly can be caused by heterozygous mutation in the gene
encoding the lamin B receptor (LBR; 600024) on chromosome 1q42.

CLINICAL FEATURES

Pelger-Huet anomaly is an autosomal dominant disorder characterized by
abnormal nuclear shape and chromatin organization in blood granulocytes.
(Hoffmann et al., 2002). Heterozygotes show hypolobulated neutrophil
nuclei with coarse chromatin. Presumed homozygous individuals have ovoid
neutrophil nuclei, as well as varying degrees of developmental delay,
epilepsy, and skeletal abnormalities.

The nucleus of the granulocytes is hyposegmented, being rodlike,
dumbbell- or peanut-shaped, or spectaclelike. This anomaly is also found
in the rabbit. The homozygote in the rabbit has chondrodystrophy
(Nachtsheim, 1950). Stobbe and Jorke (1965) posited that skeletal
abnormality apparently does not occur in the human homozygote. However,
Aznar and Vaya (1981) described a presumed homozygote in whom postaxial
polydactyly of all 4 limbs was also present. See also Haverkamp Begemann
and van Lookeren Campagne (1952). Hoffmann et al. (2002) identified a
man homozygous for Pelger-Huet anomaly who had 2 parents who were
heterozygotes and himself showed not the typical bilobed nucleus but a
round nucleus in neutrophils; he also showed short metacarpals in some
fingers.

Rioux et al. (1968) reported an extensively affected French-Canadian
kindred. The nuclei of leukocytes had a pince-nez appearance. Oneson et
al. (1987) described a child with familial Pelger-Huet anomaly who
developed acute lymphoblastic leukemia. The disorder is effectively
detected by the average lobe index (ALI) of the neutrophils. The ALI is
the total number of nuclear lobes in 100 neutrophils divided by 100. The
normal range for ALI is 2.5 to 3.1 (mean, 2.8). ALI in the affected
nonleukemic members of this family varied from 1.12 to 1.60, with the
lowest values in children and the highest values in adults. That folate
deficiency increases segmentation was indicated by the fact that the ALI
of the proband increased during 6-mercaptopurine and methotrexate
therapy. Elevation of temperature to 42 degrees C resulted in an
increase in the ALI of both normal cells and cells with the Pelger-Huet
anomaly.

Fishbein and Falletta (1991) described a newborn with Pelger-Huet
anomaly associated with multiple congenital anomalies (diaphragmatic
hernia, coarse facies, and distal limb anomalies) suggestive of Fryns
syndrome. The parents did not have the blood anomaly.

POPULATION GENETICS

In Spokane, Washington, Ludden and Harvey (1962) found 4 cases among
43,000 persons. Affected persons were of German or Dutch descent. In
Cleveland, Skendzel and Hoffman (1962) found a frequency of 1 in 4,785
routine smears. All figures in this country and also that of Davidson in
England (1 in 6,000) are lower than that of Nachtsheim (1 in 1,020).

The frequency of PHA is estimated to be approximately 0.01-0.1%
(Skendzel and Hoffman, 1962), but the frequency is much higher in
Vasterbotten County in northern Sweden (0.6%) and in the mountain
village of Gelenau in southeastern Germany (1.01%), according to
Hoffmann et al. (2002), who did positional cloning studies in families
from the latter region.

MAPPING

By genomewide linkage scan, Hoffmann et al. (2002) mapped the PHA locus
to 1q41-q43, the region that contains the lamin B receptor gene (LBR;
600024).

MOLECULAR GENETICS

To identify the genetic cause of PHA, Hoffmann et al. (2002) studied 11
families from Gelenau with 18 unaffected and 29 affected members,
including a presumed homozygous individual. In contrast to the
neutrophils of healthy subjects, all neutrophils of individuals of PHA
had bilobed or rod-like nuclei. The presumed homozygous individuals had
neutrophils with round, nonsegmented nuclei and presented with mental
retardation, disproportionate body habitus, macrocephalus with prominent
forehead, ventricular septal defect, and short metacarpals in several
fingers. Hoffmann et al. (2002) identified a founder haplotype in 10 of
the 11 families. The affected members of these 10 families carried the
same mutation, a 5-bp deletion in the 3-prime splice site region of
intron 12 of the LBR gene (600024.0001). In the affected individual in
the eleventh family, a different splice acceptor site mutation was
found, in intron 2 of LBR (600024.0002). Six further mutations in LBR
were found in individuals from Spain, the United States, and Mexico.
Only splice site, frameshift, and nonsense mutations were found.

The lethal autosomal recessive fetal chondrodystrophy hydrops-ectopic
calcification-'moth-eaten' (HEM), or Greenberg, skeletal dysplasia
(215140) is caused by lack of the 3-beta-hydroxysterol
delta(14)-reductase activity of the LBR gene resulting from homozygous
mutations in the gene. Waterham et al. (2003) suggested that Pelger-Huet
anomaly represents the heterozygous state of this deficiency. Oosterwijk
et al. (2003), however, identified 11 reported patients with Pelger-Huet
anomaly and homozygosity for mutations in the LBR gene and found that
none had skeletal dysplasia, early lethality, congenital abnormalities,
or skin abnormalities. They suggested that homozygous LBR mutations
result in distinct mild (PHA homozygosity) or severe (Greenberg skeletal
dysplasia) phenotypes based on allelic heterogeneity.

BIOCHEMICAL FEATURES

Hoffmann et al. (2002) found that the expression of the lamin B receptor
affected neutrophil nuclear shape and chromatin distribution in a
dose-dependent manner. Hoffmann et al. (2002) stated that their findings
have implications for understanding the interactions between the nuclear
envelope and heterochromatin, the pathogenesis of Pelger-like conditions
in leukemia (Sainty et al., 2000), infection (Shenkenberg et al., 1982),
and toxic drug reactions (Juneja et al., 1996), as well as the evolution
of neutrophil nuclear shape.

ANIMAL MODEL

In 2 independent mouse strains with the blood phenotype associated with
homozygosity for Pelger-Huet anomaly (Green et al., 1975), Hoffmann et
al. (2002) found 1 frameshift and 1 nonsense mutation in Lbr.

Mice with the 'ichthyosis' (ic) phenotype display marked abnormalities
in nuclear heterochromatin, similar to those observed in PHA. Shultz et
al. (2003) observed that mice homozygous for deleterious mutations at
the ic locus present with a blood phenotype similar to PHA and develop
other phenotypic abnormalities, including alopecia, variable expression
of syndactyly, and hydrocephalus. The ic locus on mouse chromosome 1
shares conserved synteny with the chromosomal location of the human LBR
locus on human chromosome 1. Shultz et al. (2003) identified 1 nonsense
and 2 frameshift mutations within the Lbr gene of mice homozygous for 1
of 3 independent mutations (ic, icJ, or ic4J, respectively) at the
ichthyosis locus. These allelic mutations resulted in a truncated or
severely impaired protein. Tissues from mice homozygous for the icJ
mutation revealed a complete loss of Lbr protein, as shown by
immunofluorescence microscopy and immunoblotting.

*FIELD* SA
Jensson et al. (1977); Latimer et al. (1985); Rosse and Gurney (1959);
Ware et al. (1988)
*FIELD* RF
1. Aznar, J.; Vaya, A.: Homozygous form of the Pelger-Huet leukocyte
anomaly in man. Acta Haemat. 66: 59-62, 1981.

2. Fishbein, J. D.; Falletta, J. M.: Pelger-Huet anomaly in an infant
with multiple congenital anomalies. Am. J. Hemat. 38: 240-242, 1991.

3. Green, M. C.; Shultz, L. D.; Nedzi, L. A.: Abnormal nuclear morphology
of leukocytes in the mouse mutant ichthyosis. Transplantation 20:
172-175, 1975.

4. Haverkamp Begemann, N.; van Lookeren Campagne, A.: Homozygous
form of Pelger-Huet's nuclear anomaly in man. Acta Haemat. 7: 295-302,
1952.

5. Hoffmann, K.; Dreger, C. K.; Olins, A. L.; Olins, D. E.; Shultz,
L. D.; Lucke, B.; Karl, H.; Kaps, R.; Muller, D.; Vaya, A.; Aznar,
J.; Ware, R. E.; Cruz, N. S.; Lindner, T. H.; Herrmann, H.; Reis,
A.; Sperling, K.: Mutations in the gene encoding the lamin B receptor
produce an altered nuclear morphology in granulocytes (Pelger-Huet
anomaly). Nature Genet. 31: 410-414, 2002.

6. Jensson, O.; Arnason, K.; Johannesson, G. M.; Ulfarsson, J.: Studies
on the Pelger anomaly in Iceland. Acta Med. Scand. 201: 183-185,
1977.

7. Juneja, S. K.; Matthews, J. P.; Luzinat, R.; Fan, Y.; Michael,
M.; Rischin, D.; Millward, M. J.; Toner, G. C.: Association of acquired
Pelger-Huet anomaly with taxoid therapy. Brit. J. Haemat. 93: 139-141,
1996.

8. Latimer, K. S.; Rakich, P. M.; Thompson, D. F.: Pelger-Huet anomaly
in cats. Vet. Path. 22: 370-374, 1985.

9. Ludden, T. E.; Harvey, M.: Pelger-Huet anomaly of leukocytes:
report of a case and survey of incidence. Am. J. Clin. Path. 37:
302-304, 1962.

10. Nachtsheim, H.: The Pelger-anomaly in man and rabbit: mendelian
character of the nuclei of the leucocytes. J. Hered. 41: 131-137,
1950.

11. Oneson, R.; Sabio, H.; Innes, D. J., Jr.: Acute lymphoblastic
leukaemia in a child with familial Pelger-Huet anomaly. Brit. J.
Haemat. 66: 193-197, 1987.

12. Oosterwijk, J. C.; Mansour, S.; van Noort, G.; Waterham, H. R.;
Hall, C. M.; Hennekam, R. C. M.: Congenital abnormalities reported
in Pelger-Huet homozygosity as compared to Greenberg/HEM dysplasia:
highly variable expression of allelic phenotypes. J. Med. Genet. 40:
937-941, 2003.

13. Rioux, E.; St. Arneault, G.; Brosseau, C.: The Pelger-Huet anomaly
of leukocytes: description of a Quebec kindred. Canad. Med. Assoc.
J. 99: 621-624, 1968.

14. Rosse, W. F.; Gurney, C. W.: The Pelger-Huet anomaly in three
families and its uses in determining the disappearance of transfused
neutrophils from the peripheral blood. Blood 14: 170-186, 1959.

15. Sainty, D.; Liso, V.; Cantu-Rajnoldi, A.; Head, D.; Mozziconacci,
M.-J.; Arnoulet, C.; Benattar, L.; Fenu, S.; Mancini, M.; Duchayne,
E.; Mahon, F.-X.; Gutierrez, N.; Birg, F.; Biondi, A.; Grimwade, D.;
Lafage-Pochitaloff, M.; Hagemeijer, A.; Flandrin, G.: A new morphologic
classification system for acute promyelocytic leukemia distinguishes
cases with underlying PLZF/RARA gene rearrangements. Blood 96: 1287-1296,
2000.

16. Shenkenberg, T. D.; Rice, L.; Waddell, C. C.: Acquired Pelger-Huet
nuclear anomaly with tuberculosis. Arch. Intern. Med. 142: 153-154,
1982.

17. Shultz, L. D.; Lyons, B. L.; Burzenski, L. M.; Gott, B.; Samuels,
R.; Schweitzer, P. A.; Dreger, C.; Herrmann, H.; Kalscheuer, V.; Olins,
A. L.; Olins, D. E.; Sperling, K.; Hoffmann, K.: Mutations at the
mouse ichthyosis locus are within the lamin B receptor gene: a single
gene model for human Pelger-Huet anomaly. Hum. Molec. Genet. 12:
61-69, 2003.

18. Skendzel, L. P.; Hoffman, G. C.: The Pelger anomaly of leukocytes:
forty-one cases in seven families. Am. J. Clin. Path. 37: 294-301,
1962.

19. Stobbe, V. H.; Jorke, D.: Befunde an homozygoten Pelger-merkmalstragern. Schweiz.
Med. Wschr. 95: 1524-1529, 1965.

20. Ware, R.; Kurtzberg, J.; Brazy, J.; Falletta, J. M.: Congenital
Pelger-Huet anomaly in triplets. Am. J. Hemat. 27: 226-227, 1988.

21. Waterham, H. R.; Koster, J.; Mooyer, P.; van Noort, G.; Kelley,
R. I.; Wilcox, W. R.; Wanders, R. J. A.; Hennekam, R. C. M.; Oosterwijk,
J. C.: Autosomal recessive HEM/Greenberg skeletal dysplasia is caused
by 3-beta-hydroxysterol delta(14)-reductase deficiency due to mutations
in the lamin B receptor gene. Am. J. Hum. Genet. 72: 1013-1017,
2003.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Head];
Macrocephaly (homozygote);
[Face];
Prominent forehead (homozygote)

CARDIOVASCULAR:
[Heart];
Ventricular septal defect (homozygote)

SKELETAL:
[Hands];
Polydactyly (homozygote);
Short metacarpals (homozygote)

NEUROLOGIC:
[Central nervous system];
Developmental delay (homozygote);
Seizure disorder (homozygote)

HEMATOLOGY:
Hypolobulated (bilobed or rod-like) granulocyte nuclei (heterozygote);
Ovoid granulocyte nuclei (homozygote);
Coarse granulocyte chromatin

MISCELLANEOUS:
Allelic to hydropic and prenatally lethal chondrodystrophy (215140);
Increased frequency in Vastebotten County in Northern Sweden and Gelenau
in southeastern Germany

MOLECULAR BASIS:
Caused by mutations in the lamin B receptor gene (LBR, 600024.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 6/12/2003

*FIELD* ED
terry: 02/12/2009
joanna: 6/12/2003
alopez: 9/4/2002

*FIELD* CN
George E. Tiller - updated: 10/26/2004
Natalie E. Krasikov - updated: 3/30/2004
Victor A. McKusick - updated: 4/11/2003
Victor A. McKusick - updated: 7/16/2002

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

*FIELD* ED
carol: 03/23/2012
carol: 5/21/2008
terry: 9/14/2007
tkritzer: 10/26/2004
carol: 4/7/2004
terry: 3/30/2004
tkritzer: 4/23/2003
tkritzer: 4/21/2003
terry: 4/11/2003
alopez: 9/4/2002
cwells: 7/16/2002
mimadm: 1/14/1995
pfoster: 5/9/1994
supermim: 3/16/1992
carol: 12/12/1991
supermim: 3/20/1990
ddp: 10/27/1989

MIM 215140
*RECORD*
*FIELD* NO
215140
*FIELD* TI
#215140 HYDROPS-ECTOPIC CALCIFICATION-MOTH-EATEN SKELETAL DYSPLASIA
;;HEM SKELETAL DYSPLASIA;;
read moreGREENBERG DYSPLASIA;;
CHONDRODYSTROPHY, HYDROPIC AND PRENATALLY LETHAL TYPE;;
MOTH-EATEN SKELETAL DYSPLASIA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of autosomal recessive skeletal dysplasia is caused by mutation in
the gene encoding lamin B receptor (LBR; 600024).

CLINICAL FEATURES

Greenberg et al. (1988) described 2 sibs, the offspring of
consanguineous parents, who presented with an apparently 'new' severe
form of short-limb dwarfism. The chondroosseus radiologic and histologic
features were distinctive. The first sib presented at 30 weeks of
gestation with severe hydrops following fetal death; the second was
detected by ultrasonography at 20 weeks. Radiologic abnormalities
included an unusual 'moth-eaten' appearance of the markedly short long
bones, bizarre ectopic ossification centers, and marked platyspondyly
with unusual ossification centers. Extensive extramedullary
erythropoiesis was found in both fetuses. Chondroosseous histology was
characterized by marked disorganization with interspersed masses of
cartilage, bone, and mesenchymal tissue. The first fetus was male, the
second female. The parents were third cousins of Greek extraction.

Spranger and Maroteaux (1990) reported a third case of the association
of hydrops fetalis with ectopic calcifications and 'moth-eaten' skeletal
dysplasia.

Chitayat et al. (1993) reported a fourth case in an offspring of
consanguineous parents of East-Indian origin. They referred to the
disorder as Greenberg hydrops-ectopic calcification-moth-eaten skeletal
dysplasia, or HEM dysplasia. The radiologic changes included
platyspondyly with multiple extra ossification centers, extraneous
calcification in the ribs, sternum, pelvis, and epiphyses, and
moth-eaten long bones. The histopathologic changes included chondrocytes
with dilated rough endoplasmic reticulum and inclusion bodies with
homogeneous material of intermediate electron density.

Horn et al. (2000) described several nonskeletal malformations in a case
of Greenberg dysplasia: omphalocele, intestinal malformation, abnormal
fingernails, and hypolobated lungs.

Trajkovski et al. (2002) reported the prenatal ultrasound diagnosis of a
case of Greenberg dysplasia in the male fetus of a nonconsanguineous
Macedonian couple. Polyhydramnios, hydrops fetalis, severely short
limbs, and cystic hygroma were noted on ultrasound. After the pregnancy
was terminated, radiologic examination showed typical features of
Greenberg dysplasia. The fetus had a large head with depressed nasal
bridge, midface hypoplasia, and prominent orbital arches. Light
microscopic examination of ribs and long bones showed severe
disorganization, absent cartilage column formation, and abrupt
transition from cartilage to normal bone.

MOLECULAR GENETICS

Waterham et al. (2003) conducted chemical and molecular investigations
in cells from a fetus with HEM skeletal dysplasia, the product of
healthy consanguineous Turkish parents, who presented with intrauterine
growth retardation at 17 weeks' gestation on fetal ultrasound performed
on the 24-year-old mother. The fetus showed severe hydrops and
short-limb skeletal dysplasia. Amniotic fluid examination showed a 46,XY
karyotype. Intrauterine death occurred at 18 weeks and delivery was
induced. Postmortem examination showed severe hydrops, extremely short
edematous limbs, and postaxial polydactyly on both hands. Radiographic
examination showed severe platyspondyly, short irregular ribs, a
'moth-eaten' aspect of scapular and pelvic bones, and very short tubular
bones with angulated diaphyses. Waterham et al. (2003) found elevated
levels of cholesta-8,14-dien-3-beta-ol in cultured skin fibroblasts,
compatible with a deficiency of the cholesterol biosynthetic enzyme
3-beta-hydroxysterol delta(14)-reductase. Sequence analysis of 2
candidate genes encoding putative human sterol delta(14)-reductases,
TM7SF2 (603414) and LBR, identified homozygosity for a 7-bp substitution
in exon 13 of the LBR gene (600024.0003), which resulted in a truncated
protein. Functional complementation of the HEM cells by transfection
with control LBR cDNA confirmed that LBR encoded the defective sterol
delta(14)-reductase. The healthy mother showed hypolobulated nuclei in
60% of her granulocytes. Waterham et al. (2003) suggested that classic
Pelger-Huet anomaly (PHA; 169400), which is also caused by mutation in
the LBR gene, represents a heterozygous state of 3-beta-hydroxysterol
delta(14)-reductase deficiency.

Oosterwijk et al. (2003), however, identified 11 reported patients with
Pelger-Huet anomaly and homozygosity for mutations in the LBR gene and
found that none had skeletal dysplasia, early lethality, congenital
abnormalities, or skin abnormalities. They suggested that homozygous LBR
mutations result in distinct mild (PHA homozygosity) or severe
(Greenberg skeletal dysplasia) phenotypes based on allelic
heterogeneity.

Herman (2003) reviewed the cholesterol biosynthetic pathway and the 6
disorders involving enzyme defects in post-squalene cholesterol
biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis
(602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960),
CHILD syndrome (308050), lathosterolosis (607330), and HEM skeletal
dysplasia.

ANIMAL MODEL

Wassif et al. (2007) studied mice with deficits of Lbr and/or Tm7sf2,
another sterol delta(14)-reductase, and demonstrated that these proteins
provide substantial enzymatic redundancy with respect to cholesterol
synthesis; they concluded, therefore, that HEM dysplasia is a
laminopathy rather than an inborn error of cholesterol synthesis.

*FIELD* RF
1. Chitayat, D.; Gruber, H.; Mullen, B. J.; Pauzner, D.; Costa, T.;
Lachman, R.; Rimoin, D. L.: Hydrops-ectopic calcification-moth-eaten
skeletal dysplasia (Greenberg dysplasia): prenatal diagnosis and further
delineation of a rare genetic disorder. Am. J. Med. Genet. 47: 272-277,
1993.

2. Greenberg, C. R.; Rimoin, D. L.; Gruber, H. E.; DeSa, D. J. B.;
Reed, M.; Lachman, R. S.: A new autosomal recessive lethal chondrodystrophy
with congenital hydrops. Am. J. Med. Genet. 29: 623-632, 1988.

3. Herman, G. E.: Disorders of cholesterol biosynthesis: prototypic
metabolic malformation syndromes. Hum. Molec. Genet. 12(R1): R75-R88,
2003.

4. Horn, L.-C.; Faber, R.; Meiner, A.; Piskazeck, U.; Spranger, J.
: Greenberg dysplasia: first reported case with additional non-skeletal
malformations and without consanguinity. Prenatal Diag. 20: 1008-1011,
2000. Note: Erratum: Prenat. Diag. 21: 425 only, 2001.

5. Oosterwijk, J. C.; Mansour, S.; van Noort, G.; Waterham, H. R.;
Hall, C. M.; Hennekam, R. C. M.: Congenital abnormalities reported
in Pelger-Huet homozygosity as compared to Greenberg/HEM dysplasia:
highly variable expression of allelic phenotypes. J. Med. Genet. 40:
937-941, 2003.

6. Spranger, J.; Maroteaux, P.: The lethal osteochondrodysplasias. Adv.
Hum. Genet. 19: 11-12, 1990.

7. Trajkovski, Z.; Vrcakovski, M.; Saveski, J.; Gucev, Z. S.: Greenberg
dysplasia (hydrops-ectopic calcification-moth-eaten skeletal dysplasia):
prenatal ultrasound diagnosis and review of literature. Am. J. Med.
Genet. 111: 415-419, 2002.

8. Wassif, C. A.; Brownson, K. E.; Sterner, A. L.; Forlino, A.; Zerfas,
P. M.; Wilson, W. K.; Starost, M. F.; Porter, F. D.: HEM dysplasia
and ichthyosis are likely laminopathies and not due to 3-beta-hydroxysterol
delta-14-reductase deficiency. Hum. Molec. Genet. 16: 1176-1187,
2007.

9. Waterham, H. R.; Koster, J.; Mooyer, P.; van Noort, G.; Kelley,
R. I.; Wilcox, W. R.; Wanders, R. J. A.; Hennekam, R. C. M.; Oosterwijk,
J. C.: Autosomal recessive HEM/Greenberg skeletal dysplasia is caused
by 3-beta-hydroxysterol delta(14)-reductase deficiency due to mutations
in the lamin B receptor gene. Am. J. Hum. Genet. 72: 1013-1017,
2003.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Head];
Large head;
[Face];
Micrognathia;
Small maxilla

RESPIRATORY:
[Larynx];
Laryngeal calcifications;
[Airways];
Tracheal calcifications

CHEST:
[External features];
Narrow thorax;
[Ribs, sternum, clavicles, and scapulae];
Anterior rib punctate calcifications;
Sternal punctate calcifications;
11 ribs

SKELETAL:
[Skull];
Deficient skull ossification;
[Spine];
Platyspondyly with multiple extra ossification centers;
[Pelvis];
Iliac apophysis, pubis and ischial punctate calcifications;
[Limbs];
Rhizomelia;
Epiphyseal punctate calcifications;
Moth-eaten (fragmented) long bones;
[Hands];
Polydactyly

HEMATOLOGY:
Extramedullary erythropoiesis

PRENATAL MANIFESTATIONS:
Severe hydrops

LABORATORY ABNORMALITIES:
Elevated cholesta-8,14-dien-3-beta-ol

MISCELLANEOUS:
Allelic to Pelger-Huet anomaly (169400);
Heterozygotes show hypolobulated nuclei (Pelger-Huet anomaly, 169400)

MOLECULAR BASIS:
Caused by mutation in the lamin B receptor (LBR, 600024.0003)

*FIELD* CN
Kelly A. Przylepa - updated: 10/7/2003
Joanna S. Amberger - updated: 4/23/2003
Kelly A. Przylepa - revised: 1/10/2002

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

*FIELD* ED
terry: 02/12/2009
joanna: 3/14/2005
joanna: 10/7/2003
joanna: 4/23/2003
joanna: 1/10/2002

*FIELD* CN
Marla J. F. O'Neill - updated: 1/20/2011
George E. Tiller - updated: 3/3/2005
Natalie E. Krasikov - updated: 3/30/2004
Victor A. McKusick - updated: 4/11/2003
Deborah L. Stone - updated: 3/5/2003

*FIELD* CD
Victor A. McKusick: 12/20/1988

*FIELD* ED
carol: 09/19/2013
wwang: 2/2/2011
terry: 1/20/2011
alopez: 3/3/2005
carol: 4/7/2004
terry: 3/30/2004
tkritzer: 4/23/2003
tkritzer: 4/21/2003
terry: 4/11/2003
carol: 3/5/2003
mimadm: 2/19/1994
carol: 10/7/1993
carol: 10/5/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989

MIM 600024
*RECORD*
*FIELD* NO
600024
*FIELD* TI
*600024 LAMIN B RECEPTOR; LBR
;;LMN2R
*FIELD* TX

DESCRIPTION

The LBR gene encodes the lamin B receptor, an inner nuclear membrane
read moreprotein that binds lamin B (LMNB1; 150340 and LMNB2; 150341). The
nuclear envelope is composed of the nuclear lamina, the nuclear pore
complexes, and the nuclear membranes. The nuclear membranes can be
divided into 3 morphologically distinct but interconnected domains: the
outer nuclear membrane, the inner nuclear membrane, and the nuclear pore
membrane. The inner nuclear membrane is adjacent to the nuclear lamina,
a meshwork of intermediate filament proteins termed lamins. The nuclear
lamina is a discontinuous structure that occupies only a fraction of the
nuclear periphery, and at some points, the inner nuclear membrane may
interact directly with the chromatin. Several integral proteins of the
nuclear envelope inner membrane that may be associated with the lamina
and the chromatin have been identified. (summary by Ye and Worman,
1994).

CLONING

Ye and Worman (1994) isolated clones corresponding to the LBR gene from
a HeLa cell cDNA library. The deduced 615-residue protein showed 68%
amino acid identity with the chicken lamin B receptor. The LBR protein
has a basic nucleoplasmic N-terminal domain of 208 amino acids followed
by a hydrophobic domain with 8 putative transmembrane segments.
Phosphorylation sites were also identified. The LBR N-terminal domain
precipitated lamin B from nuclear extracts and associated with DNA. The
stretch between amino acids 71 and 100, which contains a ser/arg-rich
stretch, was necessary for DNA binding. The findings suggested that LBR
can potentially mediate the interaction of both the nuclear lamina and
the chromatin with the inner nuclear membrane.

Worman et al. (1988) cloned avian lamin B receptor (LBR) that binds in
vitro to lamin B. Subsequently, Courvalin et al. (1990) identified a
mammalian homolog of avian LBR was identified by cross-reactive
autoantibodies from patients with primary biliary cirrhosis.

GENE STRUCTURE

Schuler et al. (1994) showed by restriction mapping that the human LBR
transcription unit spans approximately 35 kb. A transcription start site
is located approximately 4 kb 5-prime to the translation initiation
codon. The LBR gene contains 13 protein-coding exons. The nucleoplasmic
domain is encoded by exons 1 to 4, and the hydrophobic domain, with 8
putative transmembrane segments, is encoded by exons 5 to 13. The
hydrophobic domain is homologous to 3 yeast polypeptides, suggesting
that this higher eukaryotic gene may have evolved through recombination
between a gene that encoded a soluble nuclear protein and a membrane
protein gene similar to those in yeast.

MAPPING

Wydner et al. (1996) mapped the LBR gene to chromosome 1q42.1 by
fluorescence in situ hybridization.

GENE FUNCTION

Differentiation of olfactory sensory neurons is characterized by
expression of a single olfactory receptor. Clowney et al. (2012) found
that silenced olfactory receptor genes from different chromosomes
converged into approximately 5 distinct foci within nuclei of mouse
olfactory sensory neurons. The active olfactory receptor gene was absent
from these foci. Clowney et al. (2012) found that loss of Lbr expression
was critical for chromatin compaction and silencing of olfactory
receptor genes. Expression of Lbr in mouse olfactory sensory neurons
caused redistribution of olfactory receptor gene foci to the nuclear
envelope, concomitant with loss of specific olfactory receptor gene
expression by individual neurons. Lbr expression did not alter
expression of nonolfactory receptor genes and did not alter the
distribution of primary heterochromatin marks. Clowney et al. (2012)
concluded that the primary epigenetic signature silencing olfactory
receptor genes is reinforced by secondary and tertiary repressive
organization and that absence of LBR is required for formation of the
necessary higher-order repressive heterochromatin.

MOLECULAR GENETICS

- Pelger-Huet Anomaly

Pelger-Huet anomaly (169400) is an autosomal dominant disorder
characterized by abnormal nuclear shape and chromatin organization in
blood granulocytes. Affected individuals show hypolobulated neutrophil
nuclei with coarse chromatin. Presumed homozygous individuals have ovoid
neutrophil nuclei, as well as varying degrees of developmental delay,
epilepsy, and skeletal abnormalities. Homozygous offspring in an extinct
rabbit lineage showed severe chondrodystrophy, developmental anomalies,
and increased pre- and postnatal mortality in association with
Pelger-Huet anomaly (Nachtsheim, 1950). By genomewide linkage scan,
Hoffmann et al. (2002) showed that Pelger-Huet anomaly is linked to
1q41-q43. In the LBR gene, which resides in this region, they identified
4 splice site, 2 frameshift, and 2 nonsense mutations. The lamin B
receptor, a member of the sterol reductase family, is evolutionarily
conserved and integral to the inner nuclear membrane; it targets
heterochromatin and lamins to the nuclear membrane. Hoffmann et al.
(2002) found that lymphoblastoid cells from heterozygous individuals
affected with Pelger-Huet anomaly showed reduced expression of the lamin
B receptor, and cells homozygous with respect to Pelger-Huet anomaly
contain only trace amounts of it. They found that expression of the
lamin B receptor affected neutrophil nuclear shape and chromatin
distribution in a dose-dependent manner. Since the lamin B receptor may
be a sterol reductase, loss of most LBR expression might lead to changes
in sterol metabolism that cause developmental abnormalities, as has been
shown for the highly homologous delta-7 sterol reductase (DHCR7;
602858), which is mutant in Smith-Lemli-Opitz syndrome (270400).

Following linkage studies in 2 families with Pelger-Huet anomaly, Best
et al. (2003) sequenced the LBR gene and identified 2 mutations present
in heterozygous state (600024.0004-600024.0005). In addition, the LBR
gene was sequenced in a single English man with Pelger-Huet anomaly and
a third mutation was identified (600024.0006).

- Hydrops-Ectopic Calcification-Moth-Eaten Skeletal Dysplasia

Hydrops-ectopic calcification-'moth-eaten' (HEM), or Greenberg, skeletal
dysplasia (215140) is an autosomal recessive chondrodystrophy with a
lethal course, characterized by fetal hydrops, short limbs, and abnormal
chondroosseous calcification. Waterham et al. (2003) found elevated
levels of cholesta-8,14-dien-3-beta-ol in cultured skin fibroblasts of
an 18-week-old fetus with HEM skeletal dysplasia, compatible with a
deficiency of the cholesterol biosynthetic enzyme 3-beta-hydroxysterol
delta(14)-reductase. Sequence analysis of 2 candidate genes encoding
putative human 3-beta-hydroxysterol delta(14)-reductases, TM7SF2
(603414) and LBR, identified a mutation in the LBR gene that resulted in
a truncated protein (600024.0003). The healthy mother showed
hypolobulated nuclei in 60% of her granulocytes. Waterham et al. (2003)
thus suggested that classic Pelger-Huet anomaly represents the
heterozygous state of 3-beta-hydroxysterol delta(14)-reductase
deficiency. Waterham et al. (2003) stated that HEM skeletal dysplasia
was the sixth inherited disorder of cholesterol biosynthesis for which
the molecular basis was resolved. An abnormal granulocyte chromatin
structure occurs in heterozygous and homozygous individuals with
Pelger-Huet anomaly and severe skeletal abnormalities occur in
individuals with homozygous HEM skeletal dysplasia, which indicates that
the lamin B receptor has 2 different physiologic functions: preserving
chromatin structure by promoting heterochromatin binding to the inner
nuclear membrane (Ye and Worman, 1994) and functioning as the primary
sterol delta(14)-reductase in human cholesterol biosynthesis. Waterham
et al. (2003) stated that the latter function was somewhat unexpected,
as all enzymes involved in the post-squalene cholesterol biosynthesis
pathway had been localized to the ER membrane, whereas the lamin B
receptor is present (at least predominantly) in the inner nuclear
membrane. In this respect, the gene product of TM7SF2 seemed a priori a
better candidate, since it is localized in the ER membrane and also
exhibits sterol delta(14)-reductase activity.

Wassif et al. (2007) studied mice with deficits of Lbr and/or Tm7sf2,
another sterol delta(14)-reductase, and demonstrated that these proteins
provide substantial enzymatic redundancy with respect to cholesterol
synthesis; they concluded, therefore, that HEM dysplasia is a
laminopathy rather than an inborn error of cholesterol synthesis.

- Reynolds Syndrome

In a 76-year-old Caucasian woman with Reynolds syndrome (613471),
comprising primary biliary sclerosis, scleroderma, Raynaud phenomenon,
and telangiectasia, Gaudy-Marqueste et al. (2010) identified a
heterozygous mutation in the LBR gene (R372C; 600024.0007). Blood smear
did not show Pelget-Huet anomaly. Studies of patient lymphoblastoid
cells did not show abnormalities, but patient fibroblasts showed
decreased LBR and decreased levels of lamin proteins, as well as
dysmorphic nuclei with mottled chromatin. These findings suggested that
the R372C mutation exerted a dominant-negative effect on LBR-interacting
proteins, perhaps resulting from decreased stabilization of the mutant
protein and increased proteosome-mediated degradation.

ANIMAL MODEL

In 2 independent mouse strains with an associated Pelger-Huet anomaly
blood phenotype (Green et al., 1975), Hoffmann et al. (2002) found 1
frameshift and 1 nonsense mutation in the Lbr gene.

Mice with the 'ichthyosis' (ic) phenotype display marked abnormalities
in nuclear heterochromatin, similar to those observed in Pelger-Huet
anomaly (PHA). Shultz et al. (2003) observed that mice homozygous for
deleterious mutations at the ic locus present with a blood phenotype
similar to PHA and develop other phenotypic abnormalities, including
alopecia, variable expression of syndactyly, and hydrocephalus. The ic
locus on mouse chromosome 1 shares conserved synteny with the
chromosomal location of the human LBR locus on human chromosome 1.
Shultz et al. (2003) identified 1 nonsense and 2 frameshift mutations
within the Lbr gene of mice homozygous for 1 of 3 independent mutations
(ic, icJ, or ic4J, respectively) at the ichthyosis locus. These allelic
mutations resulted in a truncated or severely impaired protein. Tissues
from mice homozygous for the icJ mutation revealed a complete loss of
Lbr protein, as shown by immunofluorescence microscopy and
immunoblotting.

Using a gene-trap (GT) method, Cohen et al. (2008) created mice
homozygous for an insertion into exon 9 of the Lbr gene (Lbr GT/GT
mice), resulting in a C-terminally truncated protein. Lbr GT/GT mice
exhibited embryonic lethality with incomplete penetrance, shortened
postnatal life span, hydrocephaly, and syndactyly, as well as chromatin
atypia in neutrophils. Lbr GT/GT fibroblasts had wrinkled nuclei or
smooth nuclei associated with micronuclei, as well as mislocalized
nuclear proteins. Granulocyte number was enhanced in Lbr GT/GT mice, and
mutant granulocytes lacked mature segmented nuclei, with a block in late
maturation. However, mutant granulocytes showed normal ability to kill
bacteria.

*FIELD* AV
.0001
PELGER-HUET ANOMALY
LBR, 6-BP DEL, IVS12AS, -5-10

Pelger-Huet anomaly (169400) is unusually frequent in the mountain
village of Gelenau in southeastern Germany (Karl, 1967). To identify the
genetic cause of Pelger-Huet anomaly, Hoffmann et al. (2002) studied 11
families from Gelenau with 18 unaffected and 29 affected members,
including a presumed homozygous individual in one family. All
neutrophils of these individuals had bilobed or rod-like nuclei. The
presumed homozygous individual had neutrophils with round, nonsegmented
nuclei and presented with mental retardation, disproportionate body
habitus, macrocephalus with prominent forehead, ventricular septal
defect, and short metacarpals. In 10 of the 11 families the same
haplotype was identified. Although ancestral recombination events had
eroded this founder haplotype, the families shared a crucial region
defined by 2 particular markers. The eleventh family had a different
haplotype, and genealogic analysis showed that the family had ancestors
who were not born in Gelenau. All families sharing the founder haplotype
were found by Hoffmann et al. (2002) to have a deletion of 6 bp in the
acceptor splice site region of intron 12 of the LBR gene. The deletion
involved nucleotides -5 to -10 at the 3-prime end of intron 12. Although
the mutation did not directly affect the consensus splice acceptor site,
cDNA analysis showed that exon 13 was missing in the processed
transcript sequence, which confirmed the functional disruption of this
splice site.

Hoffmann et al. (2002) pictured the hands of an individual found to be
homozygous, with 2 heterozygous parents. Shortened third and fifth
metacarpals were present in the left hand, and shortened third, fourth,
and fifth metacarpals in the right hand; the neutrophils had rounded
nuclei.

.0002
PELGER-HUET ANOMALY
LBR, IVS2AS, A-G, -2

In 1 of 11 families with Pelger-Huet anomaly (169400) residing in
Gelenau, Hoffmann et al. (2002) found a splice acceptor site mutation in
intron 2 of the LBR gene. The family showed a different haplotype from
that of other families in the same region who shared a founder
haplotype, and was found to have ancestry outside the region of Gelenau.

.0003
HYDROPS-ECTOPIC CALCIFICATION-MOTH-EATEN SKELETAL DYSPLASIA
LBR, 7-BP SUB, NT1599

Waterham et al. (2003) described a fetus, the product of a
consanguineous Turkish marriage, who presented with intrauterine growth
retardation at 17 weeks' gestation and was found to have severe hydrops
and short-limb skeletal dysplasia consistent with thanatophoric
dysplasia. Intrauterine death occurred at 18 weeks, and delivery was
induced. Fetal examination showed severe hydrops, extremely shortened
edematous limbs, and postaxial polydactyly on both hands. Radiographic
examination showed severe platyspondyly, short irregular ribs, a
'moth-eaten' aspect of scapular and pelvic bones, and very short tubular
bones with angular diaphyses. Histopathology showed almost complete
absence of ossification, severe disorganization of cartilage (with
nodular calcification deposits), and defective or absent joint
formation. On the basis of these findings, the diagnosis of HEM skeletal
dysplasia (215140), also known as Greenberg dysplasia, was made.
Elevated levels of cholesta-8,14-dien-3-beta-ol in cultured skin
fibroblasts were consistent with deficiency of 3-beta-hydroxysterol
delta(14)-reductase. Sequence analysis of the LBR gene identified a
homozygous 7-bp substitution at nucleotide 1599 in exon 13,
TCTTCTA-CTAGAAG, which resulted in a truncated protein. The mother
showed classic Pelger-Huet anomaly (169400), which represents the
heterozygous state of 3-beta-hydroxysterol delta(14)-reductase
deficiency.

.0004
PELGER-HUET ANOMALY
LBR, PRO119LEU

In a family from Slovakia, Best et al. (2003) found that Pelger-Huet
anomaly (169400) was associated with a C-to-T transition in exon 3 of
the LBR gene, changing codon 119 from CCG (pro) to CTG (leu) (P119L).

.0005
PELGER-HUET ANOMALY
LBR, IVS11AS, A-G, -9

In a family from southern Italy, Best et al. (2003) identified
association of Pelger-Huet anomaly (169400) with a splice acceptor site
mutation in the LBR gene: IVS11-9A-G.

.0006
PELGER-HUET ANOMALY
LBR, PRO569ARG

In an English man with Pelger-Huet anomaly (169400), Best et al. (2003)
identified a heterozygous C-to-G transversion in exon 14 of the LBR
gene, resulting in a pro569-to-arg (P569R) substitution.

.0007
REYNOLDS SYNDROME
LBR, ARG372CYS

In a 76-year-old Caucasian woman with Reynolds syndrome (613471),
Gaudy-Marqueste et al. (2010) identified a heterozygous 1114C-T
transition in exon 9 of the LBR gene, resulting in an arg372-to-cys
(R372C) substitution in a highly conserved residue between the fourth
and fifth transmembrane domains in the C terminus. The mutation was not
found in 400 control chromosomes. The patient had a long history of
Raynaud phenomenon, telangiectasia, mild cholestasis associated with
mitochondrial autoantibodies consistent with primary biliary cirrhosis,
and limited cutaneous scleroderma. Blood smear did not show Pelget-Huet
anomaly. Studies of patient lymphoblastoid cells did not show
abnormalities, but patient fibroblasts showed decreased LBR and
decreased levels of lamin proteins, as well as dysmorphic nuclei with
mottled chromatin. These findings suggested that the R372C mutation
exerted a dominant-negative effect on LBR-interacting proteins, perhaps
resulting from decreased stabilization of the mutant protein and
increased proteosome-mediated degradation. Gaudy-Marqueste et al. (2010)
hypothesized that the mutation caused a global perturbation of the
nuclear envelope protein network.

*FIELD* RF
1. Best, S.; Salvati, F.; Kallo, J.; Garner, C.; Height, S.; Thein,
S. L.; Rees, D. C.: Lamin B-receptor mutations in Pelger-Huet anomaly. Brit.
J. Haemat. 123: 542-544, 2003.

2. Clowney, E. J.; LeGros, M. A.; Mosley, C. P.; Clowney, F. G.; Markenskoff-Papadimitriou,
E. C.; Myllys, M.; Barnea, G.; Larabell, C. A.; Lomvardas, S.: Nuclear
aggregation of olfactory receptor genes governs their monogenic expression. Cell 151:
724-737, 2012.

3. Cohen, T. V.; Klarmann, K. D.; Sakchaisri, K.; Cooper, J. P.; Kuhns,
D.; Anver, M.; Johnson, P. F.; Williams, S. C.; Keller, J. R.; Stewart,
C. L.: The lamin B receptor under transcriptional control of C/EBP-epsilon
is required for morphological but not functional maturation of neutrophils. Hum.
Molec. Genet. 17: 2921-2933, 2008.

4. Courvalin, J.-C.; Lassoued, K.; Worman, H. J.; Blobel, G.: Identification
and characterization of autoantibodies against the nuclear envelope
lamin B receptor from patients with primary biliary cirrhosis. J.
Exp. Med. 172: 961-967, 1990.

5. Gaudy-Marqueste, C.; Roll, P.; Esteves-Vieira, V.; Weiller, P.-J.;
Grob, J. J.; Cau, P.; Levy, N.; De Sandre-Giovannoli, A.: LBR mutation
and nuclear envelope defects in a patient affected with Reynolds syndrome. J.
Med. Genet. 47: 361-370, 2010.

6. Green, M. C.; Shultz, L. D.; Nedzi, L. A.: Abnormal nuclear morphology
of leukocytes in the mouse mutant ichthyosis: a possible transplantation
marker. Transplantation 20: 172-175, 1975.

7. Hoffmann, K.; Dreger, C. K.; Olins, A. L.; Olins, D. E.; Shultz,
L. D.; Lucke, B.; Karl, H.; Kaps, R.; Muller, D.; Vaya, A.; Aznar,
J.; Ware, R. E.; Cruz, N. S.; Lindner, T. H.; Herrmann, H.; Reis,
A.; Sperling, K.: Mutations in the gene encoding the lamin B receptor
produce an altered nuclear morphology in granulocytes (Pelger-Huet
anomaly). Nature Genet. 31: 410-414, 2002.

8. Karl, H.: Die besondere Haufund von Merkmalstragern der Pelger-Huet-Kernanomalie
der Leukozyten in Gelenau im Erzgebirge.: Thesis Humboldt Univ.:Berlin,
Germany , 1967.

9. Nachtsheim, H.: The Pelger-anomaly in man and rabbit. J. Hered. 41:
131-137, 1950.

10. Schuler, E.; Lin, F.; Worman, H. J.: Characterization of the
human gene encoding LBR, an integral protein of the nuclear envelope
inner membrane. J. Biol. Chem. 269: 11312-11317, 1994.

11. Shultz, L. D.; Lyons, B. L.; Burzenski, L. M.; Gott, B.; Samuels,
R.; Schweitzer, P. A.; Dreger, C.; Herrmann, H.; Kalscheuer, V.; Olins,
A. L.; Olins, D. E.; Sperling, K.; Hoffmann, K.: Mutations at the
mouse ichthyosis locus are within the lamin B receptor gene: a single
gene model for human Pelger-Huet anomaly. Hum. Molec. Genet. 12:
61-69, 2003.

12. Wassif, C. A.; Brownson, K. E.; Sterner, A. L.; Forlino, A.; Zerfas,
P. M.; Wilson, W. K.; Starost, M. F.; Porter, F. D.: HEM dysplasia
and ichthyosis are likely laminopathies and not due to 3-beta-hydroxysterol
delta-14-reductase deficiency. Hum. Molec. Genet. 16: 1176-1187,
2007.

13. Waterham, H. R.; Koster, J.; Mooyer, P.; van Noort, G.; Kelley,
R. I.; Wilcox, W. R.; Wanders, R. J. A.; Hennekam, R. C. M.; Oosterwijk,
J. C.: Autosomal recessive HEM/Greenberg skeletal dysplasia is caused
by 3-beta-hydroxysterol delta(14)-reductase deficiency due to mutations
in the lamin B receptor gene. Am. J. Hum. Genet. 72: 1013-1017,
2003.

14. Worman, H. J.; Yuan, J.; Blobel, G.; Georgatos, S. D.: A lamin
B receptor in the nuclear envelope. Proc. Nat. Acad. Sci. 85: 8531-8534,
1988.

15. 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.

16. Ye, Q.; Worman, H. J.: Primary structure analysis and lamin B
and DNA binding of human LBR, an integral protein of the nuclear envelope
inner membrane. J. Biol. Chem. 269: 11306-11311, 1994.

*FIELD* CN
Patricia A. Hartz - updated: 01/08/2014
Patricia A. Hartz - updated: 11/23/2011
Marla J. F. O'Neill - updated: 1/20/2011
Cassandra L. Kniffin - updated: 7/7/2010
George E. Tiller - updated: 10/26/2004
Victor A. McKusick - updated: 1/23/2004
Victor A. McKusick - updated: 4/11/2003
Victor A. McKusick - updated: 8/29/2002
Victor A. McKusick - updated: 7/16/2002
Alan F. Scott- updated: 4/22/1996

*FIELD* CD
Victor A. McKusick: 7/12/1994

*FIELD* ED
mgross: 01/08/2014
mcolton: 12/18/2013
alopez: 10/3/2012
mgross: 12/9/2011
terry: 11/23/2011
wwang: 2/2/2011
terry: 1/20/2011
wwang: 7/12/2010
ckniffin: 7/7/2010
terry: 12/17/2009
tkritzer: 10/26/2004
carol: 4/7/2004
tkritzer: 1/29/2004
terry: 1/23/2004
tkritzer: 4/23/2003
tkritzer: 4/21/2003
terry: 4/11/2003
tkritzer: 11/19/2002
alopez: 9/4/2002
terry: 8/29/2002
alopez: 8/1/2002
alopez: 7/22/2002
cwells: 7/16/2002
terry: 4/22/1996
mark: 4/22/1996
mark: 5/9/1995
mimadm: 7/30/1994
jason: 7/12/1994

MIM 613471
*RECORD*
*FIELD* NO
613471
*FIELD* TI
#613471 REYNOLDS SYNDROME
;;PRIMARY BILIARY CIRRHOSIS, SCLERODERMA, RAYNAUD DISEASE, AND TELANGIECTASIA
read more*FIELD* TX
A number sign (#) is used with this entry because a heterozygous
mutation in the LBR gene (600024) on chromosome 1q42.1 has been
identified in 1 patient with this disorder.

CLINICAL FEATURES

Reynolds et al. (1971) reported 6 unrelated women, ranging in age from
38 to 51 years, with a constellation of clinical features, including
liver disease, telangiectasia, Raynaud phenomenon, and variable features
of scleroderma (181750). The liver disease was characterized by
pruritus, jaundice, hepatomegaly, increased serum alkaline phosphatase,
and positive serum mitochondrial autoantibodies, all consistent with
primary biliary cirrhosis (PBC; 109720). Liver biopsies showed variable
subtle features of PBC, including absence of cholangioles and
inflammatory cells, in most patients. Telangiectases were present on the
fingerpads of all patients, on the lips in 5, and in the
gastrointestinal tract in at least 2. Most patients described pain and
blanching of the hands upon cold exposure, and all except 1 patient had
sclerodactyly of the hands and forearms. Two had decreased esophageal
motility, and 3 had areas of calcinosis cutis. These findings were
reminiscent of CREST syndrome (see 181750). Three patients had upper
gastrointestinal bleeding, which was related to telangiectasia or
esophageal varices. Nonspecific symptoms included fatigue and
generalized increase in skin pigmentation. None had a family history of
the disorder. The association of PBC with a form of scleroderma
suggested to Reynolds et al. (1971) an immunologic etiology for the
liver disease.

Murray-Lyon et al. (1970) reported 2 unrelated women in their sixties
with scleroderma affecting the hands and esophagus associated with PBC,
telangiectasia, and Raynaud disease. One also had areas of calcinosis of
the skin. Both had mitochondrial autoantibodies.

Gaudy-Marqueste et al. (2010) reported a 76-year-old Caucasian woman
with Reynolds syndrome. She had a long history of Raynaud phenomenon,
telangiectasia, and mild cholestasis. Laboratory studies showed
autoimmune markers, such as increased erythrocyte sedimentation rate,
antimitochondrial autoantibodies, and antinuclear antibodies. She had
limited cutaneous scleroderma, and was diagnosed with PBC.

MOLECULAR GENETICS

In a 76-year-old Caucasian woman with Reynolds syndrome, Gaudy-Marqueste
et al. (2010) identified a heterozygous mutation in the LBR gene (R372C;
600024.0007). Studies of patient lymphoblastoid cells did not show
abnormalities, but patient fibroblasts showed decreased LBR and
decreased levels of lamin proteins, as well as dysmorphic nuclei with
mottled chromatin. These findings suggested that the R372C mutation
exerted a dominant-negative effect on LBR-interacting proteins, perhaps
resulting from decreased stabilization of the mutant protein and
increased proteasome-mediated degradation.

*FIELD* RF
1. Gaudy-Marqueste, C.; Roll, P.; Esteves-Vieira, V.; Weiller, P.-J.;
Grob, J. J.; Cau, P.; Levy, N.; De Sandre-Giovannoli, A.: LBR mutation
and nuclear envelope defects in a patient affected with Reynolds syndrome. J.
Med. Genet. 47: 361-370, 2010.

2. Murray-Lyon, I. M.; Thompson, R. P. H.; Ansell, I. D.; Williams,
R.: Scleroderma and primary biliary cirrhosis. Brit. Med. J. 3:
258-259, 1970.

3. Reynolds, T. B.; Denison, E. K.; Frankl, H. D.; Lieberman, F. L.;
Peters, R. L.: Primary biliary cirrhosis with scleroderma, Raynaud's
phenomenon and telangiectasia. Am. J. Med. 50: 302-312, 1971.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Mouth];
Telangiectasia of the lips

ABDOMEN:
[Liver];
Hepatomegaly;
Primary biliary cirrhosis;
Absence of cholangioles;
Inflammatory cell infiltrate;
Destruction of the limiting plate;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Decreased esophageal peristalsis;
Upper gastrointestinal bleeding;
Steatorrhea, mild

SKIN, NAILS, HAIR:
[Skin];
Jaundice;
Pruritis;
Telangiectasia, particularly of the fingerpads and lips;
Sclerodactyly;
Calcinosis cutis;
Raynaud phenomenon;
Blanching of the fingers in response to cold;
Numbness, pain, and tingling of the fingers in response to cold;
Generalized darkening of the skin;
Tight, shiny skin over the forearms and hands

LABORATORY ABNORMALITIES:
Increased serum alkaline phosphatase;
Hyperbilirubinemia;
Increased serum cholesterol;
Abnormal liver function tests;
Serum mitochondrial autoantibodies

MISCELLANEOUS:
More common in women;
A mutation in the LBR gene has been identified in 1 patient (as of
July 2010)

MOLECULAR BASIS:
Caused by mutation in the lamin B receptor gene (LBR, 600024.0007)

*FIELD* CD
Cassandra L. Kniffin: 7/7/2010

*FIELD* ED
joanna: 10/21/2011
ckniffin: 7/7/2010

*FIELD* CD
Cassandra L. Kniffin: 7/7/2010

*FIELD* ED
carol: 11/02/2012
carol: 7/12/2010
wwang: 7/12/2010
ckniffin: 7/7/2010