RBCC

Full text data of FLNA

FLNA (FLN, FLN1) [Confidence: high (present in two of the MS resources)]
Filamin-A; FLN-A (Actin-binding protein 280; ABP-280; Alpha-filamin; Endothelial actin-binding protein; Filamin-1; Non-muscle filamin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

Comments
Isoform P21333-2 was detected.

UniProt P21333
ID FLNA_HUMAN Reviewed; 2647 AA.
AC P21333; E9KL45; Q5HY53; Q5HY55; Q8NF52;
DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 182.
DE RecName: Full=Filamin-A;
DE Short=FLN-A;
DE AltName: Full=Actin-binding protein 280;
DE Short=ABP-280;
DE AltName: Full=Alpha-filamin;
DE AltName: Full=Endothelial actin-binding protein;
DE AltName: Full=Filamin-1;
DE AltName: Full=Non-muscle filamin;
GN Name=FLNA; Synonyms=FLN, FLN1;
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] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2391361; DOI=10.1083/jcb.111.3.1089;
RA Gorlin J.B., Yamin R., Egan S., Stewart M., Stossel T.P.,
RA Kwiatkowski D.J., Hartwig J.H.;
RT "Human endothelial actin-binding protein (ABP-280, nonmuscle filamin):
RT a molecular leaf spring.";
RL J. Cell Biol. 111:1089-1105(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8088819; DOI=10.1006/geno.1994.1226;
RA Patrosso M.C., Repetto M., Villa A., Milanesi L., Frattini A.,
RA Faranda S., Mancini M., Maestrini E., Toniolo D., Vezzoni P.;
RT "The exon-intron organization of the human X-linked gene (FLN1)
RT encoding actin-binding protein 280.";
RL Genomics 21:71-76(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8733135; DOI=10.1093/hmg/5.5.659;
RA Chen E.Y., Zollo M., Mazzarella R.A., Ciccodicola A., Chen C.-N.,
RA Zuo L., Heiner C., Burough F.W., Ripetto M., Schlessinger D.,
RA D'Urso M.;
RT "Long-range sequence analysis in Xq28: thirteen known and six
RT candidate genes in 219.4 kb of high GC DNA between the RCP/GCP and
RT G6PD loci.";
RL Hum. Mol. Genet. 5:659-668(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=20736409; DOI=10.1074/mcp.M110.001719;
RA Li J., Liu F., Wang H., Liu X., Liu J., Li N., Wan F., Wang W.,
RA Zhang C., Jin S., Liu J., Zhu P., Liu Y.;
RT "Systematic mapping and functional analysis of a family of human
RT epididymal secretory sperm-located proteins.";
RL Mol. Cell. Proteomics 9:2517-2528(2010).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Spleen;
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 MRNA] (ISOFORM 1).
RX PubMed=21697133; DOI=10.1167/iovs.11-7479;
RA Oshikawa M., Tsutsui C., Ikegami T., Fuchida Y., Matsubara M.,
RA Toyama S., Usami R., Ohtoko K., Kato S.;
RT "Full-length transcriptome analysis of human retina-derived cell lines
RT ARPE-19 and Y79 using the vector-capping method.";
RL Invest. Ophthalmol. Vis. Sci. 52:6662-6670(2011).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [8]
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 [9]
RP PROTEIN SEQUENCE OF 2-24; 44-51; 64-87; 101-127; 172-190; 300-376;
RP 384-400; 428-437; 497-504; 581-593; 656-664; 685-700; 761-771;
RP 774-781; 829-837; 842-900; 907-916; 959-973; 983-994; 1020-1032;
RP 1165-1172; 1235-1294; 1297-1312; 1360-1399; 1440-1450; 1465-1486;
RP 1492-1532; 1539-1547; 1550-1592; 1622-1633; 1636-1644; 1726-1753;
RP 1801-1809; 1815-1831; 1892-1907; 1965-1993; 2015-2024; 2026-2049;
RP 2202-2215; 2243-2250; 2265-2289; 2311-2333; 2335-2361; 2396-2405;
RP 2521-2540; 2585-2598 AND 2613-2631, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT SER-2, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (NOV-2005) to UniProtKB.
RN [10]
RP PROTEIN SEQUENCE OF 25-54; 917-940; 1037-1050; 1754-1783 AND
RP 2148-2168.
RX PubMed=2248958; DOI=10.1021/bi00492a019;
RA Hock R.S., Davis G., Speicher D.W.;
RT "Purification of human smooth muscle filamin and characterization of
RT structural domains and functional sites.";
RL Biochemistry 29:9441-9451(1990).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1658-1772.
RX PubMed=7689010; DOI=10.1093/hmg/2.6.761;
RA Maestrini E., Patrosso C., Mancini M., Rivella S., Rocchi M.,
RA Repetto M., Villa A., Frattini A., Zoppe M., Vezzoni P., Toniolo D.;
RT "Mapping of two genes encoding isoforms of the actin binding protein
RT ABP-280, a dystrophin like protein, to Xq28 and to chromosome 7.";
RL Hum. Mol. Genet. 2:761-766(1993).
RN [12]
RP SIMILARITY TO OTHER MEMBERS OF THE FAMILY.
RX PubMed=11153914; DOI=10.1007/s004390000414;
RA Chakarova C., Wehnert M.S., Uhl K., Sakthivel S., Vosberg H.-P.,
RA van der Ven P.F.M., Fuerst D.O.;
RT "Genomic structure and fine mapping of the two human filamin gene
RT paralogues FLNB and FLNC and comparative analysis of the filamin gene
RT family.";
RL Hum. Genet. 107:597-611(2000).
RN [13]
RP INTERACTION WITH PSEN1 AND PSEN2.
RX PubMed=9437013;
RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.;
RT "Interaction of presenilins with the filamin family of actin-binding
RT proteins.";
RL J. Neurosci. 18:914-922(1998).
RN [14]
RP INTERACTION WITH KCND2.
RX PubMed=11102480;
RA Petrecca K., Miller D.M., Shrier A.;
RT "Localization and enhanced current density of the Kv4.2 potassium
RT channel by interaction with the actin-binding protein filamin.";
RL J. Neurosci. 20:8736-8744(2000).
RN [15]
RP INTERACTION WITH INPPL1.
RX PubMed=11739414; DOI=10.1083/jcb.200104005;
RA Dyson J.M., O'Malley C.J., Becanovic J., Munday A.D., Berndt M.C.,
RA Coghill I.D., Nandurkar H.H., Ooms L.M., Mitchell C.A.;
RT "The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2,
RT binds filamin and regulates submembraneous actin.";
RL J. Cell Biol. 155:1065-1079(2001).
RN [16]
RP INTERACTION WITH FLNB.
RX PubMed=12393796; DOI=10.1093/hmg/11.23.2845;
RA Sheen V.L., Feng Y., Graham D., Takafuta T., Shapiro S.S., Walsh C.A.;
RT "Filamin A and filamin B are co-expressed within neurons during
RT periods of neuronal migration and can physically interact.";
RL Hum. Mol. Genet. 11:2845-2854(2002).
RN [17]
RP INTERACTION WITH MYOT AND MYOZ1.
RX PubMed=16076904; DOI=10.1242/jcs.02484;
RA Gontier Y., Taivainen A., Fontao L., Sonnenberg A., van der Flier A.,
RA Carpen O., Faulkner G., Borradori L.;
RT "The Z-disc proteins myotilin and FATZ-1 interact with each other and
RT are connected to the sarcolemma via muscle-specific filamins.";
RL J. Cell Sci. 118:3739-3749(2005).
RN [18]
RP REVIEW.
RX PubMed=11336782; DOI=10.1016/S0167-4889(01)00072-6;
RA van der Flier A., Sonnenberg A.;
RT "Structural and functional aspects of filamins.";
RL Biochim. Biophys. Acta 1538:99-117(2001).
RN [19]
RP REVIEW.
RX PubMed=11252955; DOI=10.1038/35052082;
RA Stossel T.P., Condeelis J., Cooley L., Hartwig J.H., Noegel A.,
RA Schleicher M., Shapiro S.S.;
RT "Filamins as integrators of cell mechanics and signalling.";
RL Nat. Rev. Mol. Cell Biol. 2:138-145(2001).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1089; SER-1459; SER-2152
RP AND SER-2284, AND MASS 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 [21]
RP INVOLVEMENT IN PVNH1.
RX PubMed=16299064; DOI=10.1136/jmg.2005.038505;
RA Hehr U., Hehr A., Uyanik G., Phelan E., Winkler J., Reardon W.;
RT "A filamin A splice mutation resulting in a syndrome of facial
RT dysmorphism, periventricular nodular heterotopia, and severe
RT constipation reminiscent of cerebro-fronto-facial syndrome.";
RL J. Med. Genet. 43:541-544(2006).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084 AND SER-1459, AND
RP 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 [23]
RP INTERACTION WITH ARHGAP24.
RX PubMed=16862148; DOI=10.1038/ncb1437;
RA Ohta Y., Hartwig J.H., Stossel T.P.;
RT "FilGAP, a Rho- and ROCK-regulated GAP for Rac binds filamin A to
RT control actin remodelling.";
RL Nat. Cell Biol. 8:803-814(2006).
RN [24]
RP INVOLVEMENT IN IPOX.
RX PubMed=17357080; DOI=10.1086/513321;
RA Gargiulo A., Auricchio R., Barone M.V., Cotugno G., Reardon W.,
RA Milla P.J., Ballabio A., Ciccodicola A., Auricchio A.;
RT "Filamin A is mutated in X-linked chronic idiopathic intestinal
RT pseudo-obstruction with central nervous system involvement.";
RL Am. J. Hum. Genet. 80:751-758(2007).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084, 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 [26]
RP INTERACTION WITH ECSCR.
RX PubMed=18556573; DOI=10.1161/ATVBAHA.108.162511;
RA Armstrong L.-J., Heath V.L., Sanderson S., Kaur S., Beesley J.F.J.,
RA Herbert J.M.J., Legg J.A., Poulsom R., Bicknell R.;
RT "ECSM2, an endothelial specific filamin a binding protein that
RT mediates chemotaxis.";
RL Arterioscler. Thromb. Vasc. Biol. 28:1640-1646(2008).
RN [27]
RP INTERACTION WITH FCGR1A.
RX PubMed=18322202;
RA Beekman J.M., van der Poel C.E., van der Linden J.A.,
RA van den Berg D.L.C., van den Berghe P.V.E., van de Winkel J.G.J.,
RA Leusen J.H.W.;
RT "Filamin A stabilizes FcgammaRI surface expression and prevents its
RT lysosomal routing.";
RL J. Immunol. 180:3938-3945(2008).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084, 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 [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1459, AND MASS
RP SPECTROMETRY.
RC TISSUE=T-cell;
RX PubMed=19367720; DOI=10.1021/pr800500r;
RA Carrascal M., Ovelleiro D., Casas V., Gay M., Abian J.;
RT "Phosphorylation analysis of primary human T lymphocytes using
RT sequential IMAC and titanium oxide enrichment.";
RL J. Proteome Res. 7:5167-5176(2008).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084; SER-1459; SER-2152
RP AND SER-2158, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1081, 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 [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084; SER-1338;
RP SER-1459; SER-1533; SER-1630; SER-2053; SER-2152; SER-2327; SER-2414
RP AND SER-2510, 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 [33]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
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 [34]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [35]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-508; LYS-700; LYS-781;
RP LYS-837; LYS-2607 AND LYS-2621, 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 [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1081; SER-1084;
RP SER-1459; SER-1533; SER-1734; SER-2053; SER-2152; SER-2284; SER-2327;
RP THR-2336 AND SER-2414, AND 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 [37]
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 [38]
RP INTERACTION WITH TAF1B AND MIS18BP1, AND CHARACTERIZATION OF VARIANTS
RP ALA-1159; THR-1188 AND LEU-1199.
RX PubMed=21228480; DOI=10.1271/bbb.100567;
RA Qiu H., Nomiyama R., Moriguchi K., Fukada T., Sugimoto K.;
RT "Identification of novel nuclear protein interactions with the N-
RT terminal part of filamin A.";
RL Biosci. Biotechnol. Biochem. 75:145-147(2011).
RN [39]
RP INVOLVEMENT IN MACROTHROMBOCYTOPENIA, AND VARIANT LYS-1803.
RX PubMed=21960593; DOI=10.1182/blood-2011-07-365601;
RA Nurden P., Debili N., Coupry I., Bryckaert M., Youlyouz-Marfak I.,
RA Sole G., Pons A.C., Berrou E., Adam F., Kauskot A., Lamaziere J.M.,
RA Rameau P., Fergelot P., Rooryck C., Cailley D., Arveiler B.,
RA Lacombe D., Vainchenker W., Nurden A., Goizet C.;
RT "Thrombocytopenia resulting from mutations in filamin A can be
RT expressed as an isolated syndrome.";
RL Blood 118:5928-5937(2011).
RN [40]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-11; SER-1081; SER-1084;
RP SER-1459; SER-2152 AND SER-2327, 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 [41]
RP FUNCTION IN CILIOGENESIS, AND INTERACTION WITH TMEM67 AND MKS1.
RX PubMed=22121117; DOI=10.1093/hmg/ddr557;
RA Adams M., Simms R.J., Abdelhamed Z., Dawe H.R., Szymanska K.,
RA Logan C.V., Wheway G., Pitt E., Gull K., Knowles M.A., Blair E.,
RA Cross S.H., Sayer J.A., Johnson C.A.;
RT "A meckelin-filamin A interaction mediates ciliogenesis.";
RL Hum. Mol. Genet. 21:1272-1286(2012).
RN [42]
RP INTERACTION WITH MICALL2.
RX PubMed=23890175; DOI=10.1111/gtc.12078;
RA Sakane A., Alamir Mahmoud Abdallah A., Nakano K., Honda K.,
RA Kitamura T., Imoto I., Matsushita N., Sasaki T.;
RT "Junctional Rab13-binding protein (JRAB) regulates cell spreading via
RT filamins.";
RL Genes Cells 18:810-822(2013).
RN [43]
RP INVOLVEMENT IN CSBSX.
RX PubMed=23037936; DOI=10.1038/gim.2012.123;
RA van der Werf C.S., Sribudiani Y., Verheij J.B., Carroll M.,
RA O'Loughlin E., Chen C.H., Brooks A.S., Liszewski M.K., Atkinson J.P.,
RA Hofstra R.M.;
RT "Congenital short bowel syndrome as the presenting symptom in male
RT patients with FLNA mutations.";
RL Genet. Med. 15:310-313(2013).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 2045-2329.
RX PubMed=17690686; DOI=10.1038/sj.emboj.7601827;
RA Lad Y., Kiema T., Jiang P., Pentikainen O.T., Coles C.H.,
RA Campbell I.D., Calderwood D.A., Ylanne J.;
RT "Structure of three tandem filamin domains reveals auto-inhibition of
RT ligand binding.";
RL EMBO J. 26:3993-4004(2007).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 1-278, ACTIN-BINDING REGION,
RP AND SUBUNIT.
RX PubMed=19923718; DOI=10.1107/S0907444909037330;
RA Ruskamo S., Ylanne J.;
RT "Structure of the human filamin A actin-binding domain.";
RL Acta Crystallogr. D 65:1217-1221(2009).
RN [46]
RP STRUCTURE BY NMR OF 1772-1956 AND 1954-2141.
RX PubMed=19622754; DOI=10.1074/jbc.M109.019661;
RA Heikkinen O.K., Ruskamo S., Konarev P.V., Svergun D.I., Iivanainen T.,
RA Heikkinen S.M., Permi P., Koskela H., Kilpelainen I., Ylanne J.;
RT "Atomic structures of two novel immunoglobulin-like domain pairs in
RT the actin cross-linking protein filamin.";
RL J. Biol. Chem. 284:25450-25458(2009).
RN [47]
RP VARIANT PVNH1 PHE-656, AND VARIANT THR-1764.
RX PubMed=11532987; DOI=10.1093/hmg/10.17.1775;
RA Sheen V.L., Dixon P.H., Fox J.W., Hong S.E., Kinton L., Sisodiya S.M.,
RA Duncan J.S., Dubeau F., Scheffer I.E., Schachter S.C., Wilner A.,
RA Henchy R., Crino P., Kamuro K., DiMario F., Berg M., Kuzniecky R.,
RA Cole A.J., Bromfield E., Biber M., Schomer D., Wheless J., Silver K.,
RA Mochida G.H., Berkovic S.F., Andermann F., Andermann E., Dobyns W.B.,
RA Wood N.W., Walsh C.A.;
RT "Mutations in the X-linked filamin 1 gene cause periventricular
RT nodular heterotopia in males as well as in females.";
RL Hum. Mol. Genet. 10:1775-1783(2001).
RN [48]
RP VARIANT PVNH1 MET-528.
RX PubMed=12410386; DOI=10.1007/s00401-002-0594-9;
RA Kakita A., Hayashi S., Moro F., Guerrini R., Ozawa T., Ono K.,
RA Kameyama S., Walsh C.A., Takahashi H.;
RT "Bilateral periventricular nodular heterotopia due to filamin 1 gene
RT mutation: widespread glomeruloid microvascular anomaly and dysplastic
RT cytoarchitecture in the cerebral cortex.";
RL Acta Neuropathol. 104:649-657(2002).
RN [49]
RP VARIANT PVNH1 VAL-82.
RX PubMed=11914408;
RA Moro F., Carrozzo R., Veggiotti P., Tortorella G., Toniolo D.,
RA Volzone A., Guerrini R.;
RT "Familial periventricular heterotopia: missense and distal truncating
RT mutations of the FLN1 gene.";
RL Neurology 58:916-921(2002).
RN [50]
RP VARIANTS OPD1 PHE-172; TRP-196 AND LEU-207, VARIANTS OPD2 PRO-170;
RP GLY-196; SER-200; LYS-254; PRO-273; LYS-555 AND PHE-1645, VARIANTS FMD
RP ALA-1159; LEU-1186 AND ILE-1620 DEL, VARIANTS MNS GLU-1184; THR-1188
RP AND LEU-1199, AND VARIANTS MET-429 AND THR-1764.
RX PubMed=12612583; DOI=10.1038/ng1119;
RA Robertson S.P., Twigg S.R.F., Sutherland-Smith A.J., Biancalana V.,
RA Gorlin R.J., Horn D., Kenwrick S.J., Kim C.A., Morava E.,
RA Newbury-Ecob R., Oerstavik K.H., Quarrell O.W.J., Schwartz C.E.,
RA Shears D.J., Suri M., Kendrick-Jones J., Wilkie A.O.M.;
RT "Localized mutations in the gene encoding the cytoskeletal protein
RT filamin A cause diverse malformations in humans.";
RL Nat. Genet. 33:487-491(2003).
RN [51]
RP VARIANTS PVNH1 VAL-102 AND PHE-149.
RX PubMed=15249610;
RA Guerrini R., Mei D., Sisodiya S.M., Sicca F., Harding B.,
RA Takahashi Y., Dorn T., Yoshida A., Campistol J., Kraemer G., Moro F.,
RA Dobyns W.B., Parrini E.;
RT "Germline and mosaic mutations of FLN1 in men with periventricular
RT heterotopia.";
RL Neurology 63:51-56(2004).
RN [52]
RP VARIANT OTOPALATODIGITAL SPECTRUM DISORDER 1635-ARG--VAL-1637 DEL.
RX PubMed=15654694; DOI=10.1002/ajmg.a.30484;
RA Stefanova M., Meinecke P., Gal A., Bolz H.;
RT "A novel 9 bp deletion in the filamin A gene causes an
RT otopalatodigital-spectrum disorder with a variable, intermediate
RT phenotype.";
RL Am. J. Med. Genet. A 132:386-390(2005).
RN [53]
RP VARIANT OPD1 TYR-203.
RX PubMed=15940695; DOI=10.1002/ajmg.a.30792;
RA Hidalgo-Bravo A., Pompa-Mera E.N., Kofman-Alfaro S.,
RA Gonzalez-Bonilla C.R., Zenteno J.C.;
RT "A novel filamin A D203Y mutation in a female patient with
RT otopalatodigital type 1 syndrome and extremely skewed X chromosome
RT inactivation.";
RL Am. J. Med. Genet. A 136:190-193(2005).
RN [54]
RP VARIANT PVNH4 GLY-39.
RX PubMed=15668422; DOI=10.1212/01.WNL.0000149512.79621.DF;
RA Sheen V.L., Jansen A., Chen M.H., Parrini E., Morgan T.,
RA Ravenscroft R., Ganesh V., Underwood T., Wiley J., Leventer R.,
RA Vaid R.R., Ruiz D.E., Hutchins G.M., Menasha J., Willner J., Geng Y.,
RA Gripp K.W., Nicholson L., Berry-Kravis E., Bodell A., Apse K.,
RA Hill R.S., Dubeau F., Andermann F., Barkovich J., Andermann E.,
RA Shugart Y.Y., Thomas P., Viri M., Veggiotti P., Robertson S.,
RA Guerrini R., Walsh C.A.;
RT "Filamin A mutations cause periventricular heterotopia with Ehlers-
RT Danlos syndrome.";
RL Neurology 64:254-262(2005).
RN [55]
RP VARIANTS FMD LEU-1186 AND CYS-1728.
RX PubMed=16596676; DOI=10.1002/ajmg.a.31213;
RA Zenker M., Naehrlich L., Sticht H., Reis A., Horn D.;
RT "Genotype-epigenotype-phenotype correlations in females with
RT frontometaphyseal dysplasia.";
RL Am. J. Med. Genet. A 140:1069-1073(2006).
RN [56]
RP VARIANT PVNH4 VAL-128.
RX PubMed=15994863; DOI=10.1136/jmg.2004.029173;
RA Gomez-Garre P., Seijo M., Gutierrez-Delicado E., Castro del Rio M.,
RA de la Torre C., Gomez-Abad C., Morales-Corraliza J., Puig M.,
RA Serratosa J.M.;
RT "Ehlers-Danlos syndrome and periventricular nodular heterotopia in a
RT Spanish family with a single FLNA mutation.";
RL J. Med. Genet. 43:232-237(2006).
RN [57]
RP VARIANT OPD2 PHE-210.
RX PubMed=17431908; DOI=10.1002/ajmg.a.31696;
RA Marino-Enriquez A., Lapunzina P., Robertson S.P., Rodriguez J.I.;
RT "Otopalatodigital syndrome type 2 in two siblings with a novel filamin
RT A 629G>T mutation: clinical, pathological, and molecular findings.";
RL Am. J. Med. Genet. A 143:1120-1125(2007).
RN [58]
RP VARIANT FGS2 LEU-1291.
RX PubMed=17632775; DOI=10.1002/ajmg.a.31751;
RA Unger S., Mainberger A., Spitz C., Baehr A., Zeschnigk C., Zabel B.,
RA Superti-Furga A., Morris-Rosendahl D.J.;
RT "Filamin A mutation is one cause of FG syndrome.";
RL Am. J. Med. Genet. A 143:1876-1879(2007).
RN [59]
RP VARIANTS CVDX ARG-288; GLN-637 AND ASP-711.
RX PubMed=17190868; DOI=10.1161/CIRCULATIONAHA.106.622621;
RA Kyndt F., Gueffet J.P., Probst V., Jaafar P., Legendre A.,
RA Le Bouffant F., Toquet C., Roy E., McGregor L., Lynch S.A.,
RA Newbury-Ecob R., Tran V., Young I., Trochu J.N., Le Marec H.,
RA Schott J.J.;
RT "Mutations in the gene encoding filamin A as a cause for familial
RT cardiac valvular dystrophy.";
RL Circulation 115:40-49(2007).
RN [60]
RP VARIANT TOD 1724-VAL--THR-1739 DEL.
RX PubMed=20598277; DOI=10.1016/j.ajhg.2010.06.008;
RA Sun Y., Almomani R., Aten E., Celli J., van der Heijden J.,
RA Venselaar H., Robertson S.P., Baroncini A., Franco B.,
RA Basel-Vanagaite L., Horii E., Drut R., Ariyurek Y., den Dunnen J.T.,
RA Breuning M.H.;
RT "Terminal osseous dysplasia is caused by a single recurrent mutation
RT in the FLNA gene.";
RL Am. J. Hum. Genet. 87:146-153(2010).
CC -!- FUNCTION: Promotes orthogonal branching of actin filaments and
CC links actin filaments to membrane glycoproteins. Anchors various
CC transmembrane proteins to the actin cytoskeleton and serves as a
CC scaffold for a wide range of cytoplasmic signaling proteins.
CC Interaction with FLNA may allow neuroblast migration from the
CC ventricular zone into the cortical plate. Tethers cell surface-
CC localized furin, modulates its rate of internalization and directs
CC its intracellular trafficking (By similarity). Involved in
CC ciliogenesis.
CC -!- SUBUNIT: Homodimer. Interacts with PDLIM2 (By similarity).
CC Interacts with FCGR1A, FLNB, FURIN, HSPB7, INPPL1, KCND2, MYOT,
CC MYOZ1, ARHGAP24, PSEN1, PSEN2 and ECSCR. Interacts also with
CC various other binding partners in addition to filamentous actin.
CC Interacts (via N-terminus) with MIS18BP1 (via N-terminus).
CC Interacts (via N-terminus) with TAF1B. Interacts with TMEM67 (via
CC C-terminus) and MKS1. Interacts (via actin-binding domain) with
CC MICALL2 (via CH domain).
CC -!- INTERACTION:
CC Q9WMX2:- (xeno); NbExp=6; IntAct=EBI-350432, EBI-6863741;
CC Q8N264:ARHGAP24; NbExp=6; IntAct=EBI-350432, EBI-988764;
CC O95067:CCNB2; NbExp=8; IntAct=EBI-350432, EBI-375024;
CC P46108:CRK; NbExp=2; IntAct=EBI-350432, EBI-886;
CC O75369:FLNB; NbExp=5; IntAct=EBI-350432, EBI-352089;
CC Q12948:FOXC1; NbExp=8; IntAct=EBI-350432, EBI-1175253;
CC P62993:GRB2; NbExp=2; IntAct=EBI-350432, EBI-401755;
CC P05556:ITGB1; NbExp=5; IntAct=EBI-350432, EBI-703066;
CC P07228:ITGB1 (xeno); NbExp=2; IntAct=EBI-350432, EBI-5606437;
CC P26010:ITGB7; NbExp=6; IntAct=EBI-350432, EBI-702932;
CC O14786:NRP1; NbExp=2; IntAct=EBI-350432, EBI-1187100;
CC P35372:OPRM1; NbExp=5; IntAct=EBI-350432, EBI-2624570;
CC Q86SQ0:PHLDB2; NbExp=2; IntAct=EBI-350432, EBI-2798483;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cell cortex. Cytoplasm,
CC cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P21333-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P21333-2; Sequence=VSP_035454;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: Comprised of a NH2-terminal actin-binding domain, 24
CC immunoglobulin-like internally homologous repeats and two hinge
CC regions. Repeat 24 and the second hinge domain are important for
CC dimer formation.
CC -!- PTM: Phosphorylation extent changes in response to cell
CC activation.
CC -!- DISEASE: Periventricular nodular heterotopia 1 (PVNH1)
CC [MIM:300049]: A developmental disorder characterized by the
CC presence of periventricular nodules of cerebral gray matter,
CC resulting from a failure of neurons to migrate normally from the
CC lateral ventricular proliferative zone, where they are formed, to
CC the cerebral cortex. PVNH1 is an X-linked dominant form.
CC Heterozygous females have normal intelligence but suffer from
CC seizures and various manifestations outside the central nervous
CC system, especially related to the vascular system. Hemizygous
CC affected males die in the prenatal or perinatal period. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Periventricular nodular heterotopia 4 (PVNH4)
CC [MIM:300537]: A disorder characterized by nodular brain
CC heterotopia, joint hypermobility and development of aortic
CC dilation in early adulthood. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Otopalatodigital syndrome 1 (OPD1) [MIM:311300]: X-linked
CC dominant multiple congenital anomalies disease mainly
CC characterized by a generalized skeletal dysplasia, mild mental
CC retardation, hearing loss, cleft palate, and typical facial
CC anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias
CC known as oto-palato-digital syndrome spectrum disorders that also
CC include OPD2, Melnick-Needles syndrome (MNS), and
CC frontometaphyseal dysplasia (FMD). Remodeling of the cytoskeleton
CC is central to the modulation of cell shape and migration. FLNA is
CC a widely expressed protein that regulates re-organization of the
CC actin cytoskeleton by interacting with integrins, transmembrane
CC receptor complexes and second messengers. Males with OPD1 have
CC cleft palate, malformations of the ossicles causing deafness and
CC milder bone and limb defects than those associated with OPD2.
CC Obligate female carriers of mutations causing both OPD1 and OPD2
CC have variable (often milder) expression of a similar phenotypic
CC spectrum. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Otopalatodigital syndrome 2 (OPD2) [MIM:304120]:
CC Congenital bone disorder that is characterized by abnormally
CC modeled, bowed bones, small or absent first digits and, more
CC variably, cleft palate, posterior fossa brain anomalies,
CC omphalocele and cardiac defects. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Frontometaphyseal dysplasia (FMD) [MIM:305620]:
CC Congenital bone disease characterized by supraorbital
CC hyperostosis, deafness and digital anomalies. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Melnick-Needles syndrome (MNS) [MIM:309350]: Severe
CC congenital bone disorder characterized by typical facies
CC (exophthalmos, full cheeks, micrognathia and malalignment of
CC teeth), flaring of the metaphyses of long bones, s-like curvature
CC of bones of legs, irregular constrictions in the ribs, and
CC sclerosis of base of skull. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Intestinal pseudoobstruction, neuronal, chronic
CC idiopathic, X-linked (IPOX) [MIM:300048]: A disease characterized
CC by a severe abnormality of gastrointestinal motility due to
CC primary qualitative defects of enteric ganglia and nerve fibers.
CC Affected individuals manifest recurrent signs of intestinal
CC obstruction in the absence of any mechanical lesion. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: FG syndrome 2 (FGS2) [MIM:300321]: FG syndrome (FGS) is
CC an X-linked disorder characterized by mental retardation, relative
CC macrocephaly, hypotonia and constipation. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Terminal osseous dysplasia (TOD) [MIM:300244]: A rare X-
CC linked dominant male-lethal disease characterized by skeletal
CC dysplasia of the limbs, pigmentary defects of the skin and
CC recurrent digital fibroma during infancy. A significant phenotypic
CC variability is observed in affected females. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Cardiac valvular dysplasia X-linked (CVDX) [MIM:314400]:
CC A rare X-linked heart disease characterized by mitral and/or
CC aortic valve regurgitation. The histologic features include
CC fragmentation of collagenous bundles within the valve fibrosa and
CC accumulation of proteoglycans, which produces excessive valve
CC tissue leading to billowing of the valve leaflets. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Note=Defects in FLNA may be a cause of
CC macrothrombocytopenia, a disorder characterized by subnormal
CC levels of blood platelets. Blood platelets are abnormally
CC enlarged.
CC -!- DISEASE: Congenital short bowel syndrome, X-linked (CSBSX)
CC [MIM:300048]: A disease characterized by a shortened small
CC intestine, and malabsorption. The mean length of the small
CC intestine in affected individuals is approximately 50 cm, compared
CC with a normal length at birth of 190-280 cm. It is associated with
CC significant mortality and morbidity. Infants usually present with
CC failure to thrive, recurrent vomiting, and diarrhea. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the filamin family.
CC -!- SIMILARITY: Contains 1 actin-binding domain.
CC -!- SIMILARITY: Contains 2 CH (calponin-homology) domains.
CC -!- SIMILARITY: Contains 24 filamin repeats.
CC -!- CAUTION: Variant Thr-1764 has been originally associated with
CC periventricular nodular heterotopia (PubMed:12612583). It has been
CC subsequently reported as a benign polymorphism (PubMed:12612583).
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC03408.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FLNA";
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DR EMBL; X53416; CAA37495.1; -; mRNA.
DR EMBL; L44140; AAA92644.1; -; Genomic_DNA.
DR EMBL; X70082; CAA49687.1; -; Genomic_DNA.
DR EMBL; X70085; CAA49690.1; -; Genomic_DNA.
DR EMBL; GU727643; ADU87644.1; -; mRNA.
DR EMBL; AK090427; BAC03408.2; ALT_INIT; mRNA.
DR EMBL; AB593010; BAJ83965.1; -; mRNA.
DR EMBL; BX664723; CAI43197.1; -; Genomic_DNA.
DR EMBL; BX936346; CAI43197.1; JOINED; Genomic_DNA.
DR EMBL; BX664723; CAI43199.1; -; Genomic_DNA.
DR EMBL; BX936346; CAI43199.1; JOINED; Genomic_DNA.
DR EMBL; BX936346; CAI43225.1; -; Genomic_DNA.
DR EMBL; BX664723; CAI43225.1; JOINED; Genomic_DNA.
DR EMBL; BX936346; CAI43227.1; -; Genomic_DNA.
DR EMBL; BX664723; CAI43227.1; JOINED; Genomic_DNA.
DR EMBL; CH471172; EAW72745.1; -; Genomic_DNA.
DR EMBL; CH471172; EAW72746.1; -; Genomic_DNA.
DR PIR; A37098; A37098.
DR RefSeq; NP_001104026.1; NM_001110556.1.
DR RefSeq; NP_001447.2; NM_001456.3.
DR UniGene; Hs.195464; -.
DR PDB; 2AAV; NMR; -; A=1863-1955.
DR PDB; 2BP3; X-ray; 2.32 A; A/B=1863-1956.
DR PDB; 2BRQ; X-ray; 2.10 A; A/B=2236-2329.
DR PDB; 2J3S; X-ray; 2.50 A; A/B=2045-2329.
DR PDB; 2JF1; X-ray; 2.20 A; A=2236-2329.
DR PDB; 2K3T; NMR; -; A=2427-2522.
DR PDB; 2K7P; NMR; -; A=1772-1956.
DR PDB; 2K7Q; NMR; -; A=1954-2141.
DR PDB; 2W0P; X-ray; 1.90 A; A/B=2236-2329.
DR PDB; 2WFN; X-ray; 3.20 A; A/B=1-278.
DR PDB; 3CNK; X-ray; 1.65 A; A/B=2559-2647.
DR PDB; 3HOC; X-ray; 2.30 A; A/B=2-269.
DR PDB; 3HOP; X-ray; 2.30 A; A/B=2-269.
DR PDB; 3HOR; X-ray; 2.70 A; A/B=2-269.
DR PDB; 3ISW; X-ray; 2.80 A; A/B=2236-2329.
DR PDB; 3RGH; X-ray; 2.44 A; A/B=1158-1252.
DR PDBsum; 2AAV; -.
DR PDBsum; 2BP3; -.
DR PDBsum; 2BRQ; -.
DR PDBsum; 2J3S; -.
DR PDBsum; 2JF1; -.
DR PDBsum; 2K3T; -.
DR PDBsum; 2K7P; -.
DR PDBsum; 2K7Q; -.
DR PDBsum; 2W0P; -.
DR PDBsum; 2WFN; -.
DR PDBsum; 3CNK; -.
DR PDBsum; 3HOC; -.
DR PDBsum; 3HOP; -.
DR PDBsum; 3HOR; -.
DR PDBsum; 3ISW; -.
DR PDBsum; 3RGH; -.
DR ProteinModelPortal; P21333; -.
DR SMR; P21333; 39-2647.
DR DIP; DIP-1136N; -.
DR IntAct; P21333; 55.
DR MINT; MINT-118283; -.
DR STRING; 9606.ENSP00000358866; -.
DR PhosphoSite; P21333; -.
DR DMDM; 116241365; -.
DR OGP; P21333; -.
DR PaxDb; P21333; -.
DR PRIDE; P21333; -.
DR Ensembl; ENST00000360319; ENSP00000353467; ENSG00000196924.
DR Ensembl; ENST00000369850; ENSP00000358866; ENSG00000196924.
DR Ensembl; ENST00000422373; ENSP00000416926; ENSG00000196924.
DR Ensembl; ENST00000596447; ENSP00000469433; ENSG00000269329.
DR Ensembl; ENST00000597475; ENSP00000471999; ENSG00000269329.
DR Ensembl; ENST00000600520; ENSP00000472325; ENSG00000269329.
DR GeneID; 2316; -.
DR KEGG; hsa:2316; -.
DR UCSC; uc004fkk.2; human.
DR CTD; 2316; -.
DR GeneCards; GC0XM153576; -.
DR H-InvDB; HIX0017150; -.
DR HGNC; HGNC:3754; FLNA.
DR HPA; CAB000356; -.
DR HPA; HPA001115; -.
DR HPA; HPA002925; -.
DR MIM; 300017; gene.
DR MIM; 300048; phenotype.
DR MIM; 300049; phenotype.
DR MIM; 300244; phenotype.
DR MIM; 300321; phenotype.
DR MIM; 300537; phenotype.
DR MIM; 304120; phenotype.
DR MIM; 305620; phenotype.
DR MIM; 309350; phenotype.
DR MIM; 311300; phenotype.
DR MIM; 314400; phenotype.
DR neXtProt; NX_P21333; -.
DR Orphanet; 2978; Chronic intestinal pseudo-obstruction.
DR Orphanet; 2301; Congenital short bowel syndrome.
DR Orphanet; 1864; Congenital valvular dysplasia.
DR Orphanet; 82004; Ehlers-Danlos syndrome with periventricular heterotopia.
DR Orphanet; 323; FG syndrome.
DR Orphanet; 1826; Frontometaphyseal dysplasia.
DR Orphanet; 2484; Osteodysplasty, Melnick-Needles type.
DR Orphanet; 90650; Otopalatodigital syndrome type 1.
DR Orphanet; 90652; Otopalatodigital syndrome type 2.
DR Orphanet; 98892; Periventricular nodular heterotopia.
DR Orphanet; 88630; Terminal osseous dysplasia - pigmentary defects.
DR PharmGKB; PA28172; -.
DR eggNOG; COG5069; -.
DR HOGENOM; HOG000044235; -.
DR HOVERGEN; HBG004163; -.
DR InParanoid; P21333; -.
DR KO; K04437; -.
DR OMA; PGVAKTG; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P21333; -.
DR ChiTaRS; FLNA; human.
DR EvolutionaryTrace; P21333; -.
DR GeneWiki; FLNA; -.
DR GenomeRNAi; 2316; -.
DR NextBio; 9405; -.
DR PMAP-CutDB; P21333; -.
DR PRO; PR:P21333; -.
DR ArrayExpress; P21333; -.
DR Bgee; P21333; -.
DR CleanEx; HS_FLNA; -.
DR Genevestigator; P21333; -.
DR GO; GO:0015629; C:actin cytoskeleton; IC:BHF-UCL.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0031523; C:Myb complex; IDA:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl.
DR GO; GO:0051015; F:actin filament binding; IDA:BHF-UCL.
DR GO; GO:0034988; F:Fc-gamma receptor I complex binding; IDA:BHF-UCL.
DR GO; GO:0001948; F:glycoprotein binding; IDA:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0048365; F:Rac GTPase binding; IDA:BHF-UCL.
DR GO; GO:0017160; F:Ral GTPase binding; IDA:BHF-UCL.
DR GO; GO:0004871; F:signal transducer activity; IMP:UniProtKB.
DR GO; GO:0051764; P:actin crosslink formation; IDA:BHF-UCL.
DR GO; GO:0031532; P:actin cytoskeleton reorganization; IDA:BHF-UCL.
DR GO; GO:0007195; P:adenylate cyclase-inhibiting dopamine receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0034329; P:cell junction assembly; TAS:Reactome.
DR GO; GO:0042384; P:cilium assembly; IMP:UniProtKB.
DR GO; GO:0051220; P:cytoplasmic sequestering of protein; IMP:BHF-UCL.
DR GO; GO:0045022; P:early endosome to late endosome transport; IEA:Ensembl.
DR GO; GO:0001837; P:epithelial to mesenchymal transition; IEA:Ensembl.
DR GO; GO:0045184; P:establishment of protein localization; IDA:BHF-UCL.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:BHF-UCL.
DR GO; GO:0043433; P:negative regulation of sequence-specific DNA binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0042993; P:positive regulation of transcription factor import into nucleus; IMP:UniProtKB.
DR GO; GO:0034394; P:protein localization to cell surface; IDA:BHF-UCL.
DR GO; GO:0050821; P:protein stabilization; IMP:BHF-UCL.
DR GO; GO:0043113; P:receptor clustering; IDA:BHF-UCL.
DR GO; GO:0090307; P:spindle assembly involved in mitosis; IDA:MGI.
DR Gene3D; 1.10.418.10; -; 2.
DR Gene3D; 2.60.40.10; -; 24.
DR InterPro; IPR001589; Actinin_actin-bd_CS.
DR InterPro; IPR001715; CH-domain.
DR InterPro; IPR017868; Filamin/ABP280_repeat-like.
DR InterPro; IPR001298; Filamin/ABP280_rpt.
DR InterPro; IPR028559; FLN.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR014756; Ig_E-set.
DR PANTHER; PTHR11915:SF173; PTHR11915:SF173; 1.
DR Pfam; PF00307; CH; 2.
DR Pfam; PF00630; Filamin; 23.
DR SMART; SM00033; CH; 2.
DR SMART; SM00557; IG_FLMN; 24.
DR SUPFAM; SSF47576; SSF47576; 1.
DR SUPFAM; SSF81296; SSF81296; 24.
DR PROSITE; PS00019; ACTININ_1; 1.
DR PROSITE; PS00020; ACTININ_2; 1.
DR PROSITE; PS50021; CH; 2.
DR PROSITE; PS50194; FILAMIN_REPEAT; 24.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alternative splicing;
KW Cilium biogenesis/degradation; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disease mutation;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 2647 Filamin-A.
FT /FTId=PRO_0000087296.
FT DOMAIN 2 274 Actin-binding.
FT DOMAIN 43 149 CH 1.
FT DOMAIN 166 266 CH 2.
FT REPEAT 276 374 Filamin 1.
FT REPEAT 376 474 Filamin 2.
FT REPEAT 475 570 Filamin 3.
FT REPEAT 571 663 Filamin 4.
FT REPEAT 667 763 Filamin 5.
FT REPEAT 764 866 Filamin 6.
FT REPEAT 867 965 Filamin 7.
FT REPEAT 966 1061 Filamin 8.
FT REPEAT 1062 1154 Filamin 9.
FT REPEAT 1155 1249 Filamin 10.
FT REPEAT 1250 1349 Filamin 11.
FT REPEAT 1350 1442 Filamin 12.
FT REPEAT 1443 1539 Filamin 13.
FT REPEAT 1540 1636 Filamin 14.
FT REPEAT 1649 1740 Filamin 15.
FT REPEAT 1779 1860 Filamin 16.
FT REPEAT 1861 1950 Filamin 17.
FT REPEAT 1951 2039 Filamin 18.
FT REPEAT 2042 2131 Filamin 19.
FT REPEAT 2132 2230 Filamin 20.
FT REPEAT 2233 2325 Filamin 21.
FT REPEAT 2327 2420 Filamin 22.
FT REPEAT 2424 2516 Filamin 23.
FT REPEAT 2552 2646 Filamin 24.
FT REGION 1490 1607 Interaction with furin (By similarity).
FT REGION 1741 1778 Hinge 1.
FT REGION 2517 2647 Self-association site, tail.
FT REGION 2517 2551 Hinge 2.
FT SITE 1761 1762 Cleavage; by calpain.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 11 11 Phosphoserine.
FT MOD_RES 508 508 N6-acetyllysine.
FT MOD_RES 700 700 N6-acetyllysine.
FT MOD_RES 781 781 N6-acetyllysine.
FT MOD_RES 837 837 N6-acetyllysine.
FT MOD_RES 1081 1081 Phosphoserine.
FT MOD_RES 1084 1084 Phosphoserine.
FT MOD_RES 1089 1089 Phosphothreonine.
FT MOD_RES 1338 1338 Phosphoserine.
FT MOD_RES 1459 1459 Phosphoserine.
FT MOD_RES 1533 1533 Phosphoserine.
FT MOD_RES 1630 1630 Phosphoserine.
FT MOD_RES 1734 1734 Phosphoserine.
FT MOD_RES 2053 2053 Phosphoserine.
FT MOD_RES 2152 2152 Phosphoserine.
FT MOD_RES 2158 2158 Phosphoserine.
FT MOD_RES 2284 2284 Phosphoserine.
FT MOD_RES 2327 2327 Phosphoserine.
FT MOD_RES 2336 2336 Phosphothreonine.
FT MOD_RES 2414 2414 Phosphoserine.
FT MOD_RES 2510 2510 Phosphoserine.
FT MOD_RES 2607 2607 N6-acetyllysine.
FT MOD_RES 2621 2621 N6-acetyllysine.
FT VAR_SEQ 1649 1656 Missing (in isoform 2).
FT /FTId=VSP_035454.
FT VARIANT 39 39 A -> G (in PVNH4).
FT /FTId=VAR_022734.
FT VARIANT 82 82 E -> V (in PVNH1; dbSNP:rs28935169).
FT /FTId=VAR_015699.
FT VARIANT 102 102 M -> V (in PVNH1).
FT /FTId=VAR_031305.
FT VARIANT 128 128 A -> V (in PVNH4).
FT /FTId=VAR_031306.
FT VARIANT 149 149 S -> F (in PVNH1).
FT /FTId=VAR_031307.
FT VARIANT 170 170 Q -> P (in OPD2).
FT /FTId=VAR_015713.
FT VARIANT 172 172 L -> F (in OPD1).
FT /FTId=VAR_015714.
FT VARIANT 196 196 R -> G (in OPD2).
FT /FTId=VAR_015715.
FT VARIANT 196 196 R -> W (in OPD1).
FT /FTId=VAR_015716.
FT VARIANT 200 200 A -> S (in OPD2).
FT /FTId=VAR_015717.
FT VARIANT 203 203 D -> Y (in OPD1).
FT /FTId=VAR_031308.
FT VARIANT 207 207 P -> L (in OPD1; dbSNP:rs28935469).
FT /FTId=VAR_015700.
FT VARIANT 210 210 C -> F (in OPD2).
FT /FTId=VAR_058720.
FT VARIANT 254 254 E -> K (in OPD2; dbSNP:rs28935470).
FT /FTId=VAR_015701.
FT VARIANT 273 273 A -> P (in OPD2).
FT /FTId=VAR_015718.
FT VARIANT 288 288 G -> R (in CVDX).
FT /FTId=VAR_064156.
FT VARIANT 320 320 V -> A (in dbSNP:rs1064816).
FT /FTId=VAR_012831.
FT VARIANT 370 370 F -> L (in dbSNP:rs1064817).
FT /FTId=VAR_012832.
FT VARIANT 429 429 T -> M.
FT /FTId=VAR_069803.
FT VARIANT 528 528 V -> M (in PVNH1; dbSNP:rs143873938).
FT /FTId=VAR_031309.
FT VARIANT 552 552 V -> A (in dbSNP:rs730319).
FT /FTId=VAR_012833.
FT VARIANT 555 555 T -> K (in OPD2).
FT /FTId=VAR_015719.
FT VARIANT 637 637 P -> Q (in CVDX).
FT /FTId=VAR_064157.
FT VARIANT 656 656 L -> F (in PVNH1).
FT /FTId=VAR_012834.
FT VARIANT 711 711 V -> D (in CVDX).
FT /FTId=VAR_064158.
FT VARIANT 1012 1012 S -> L (in dbSNP:rs17091204).
FT /FTId=VAR_031310.
FT VARIANT 1159 1159 D -> A (in FMD; does not inhibit
FT interaction with MIS18BP1;
FT dbSNP:rs28935471).
FT /FTId=VAR_015702.
FT VARIANT 1184 1184 D -> E (in MNS).
FT /FTId=VAR_015720.
FT VARIANT 1186 1186 S -> L (in FMD).
FT /FTId=VAR_015721.
FT VARIANT 1188 1188 A -> T (in MNS; does not inhibit
FT interaction with MIS18BP1;
FT dbSNP:rs28935472).
FT /FTId=VAR_015703.
FT VARIANT 1199 1199 S -> L (in MNS; does not inhibit
FT interaction with MIS18BP1;
FT dbSNP:rs28935473).
FT /FTId=VAR_015704.
FT VARIANT 1291 1291 P -> L (in FGS2).
FT /FTId=VAR_058721.
FT VARIANT 1419 1419 A -> G (in dbSNP:rs35504556).
FT /FTId=VAR_032083.
FT VARIANT 1620 1620 Missing (in FMD).
FT /FTId=VAR_015722.
FT VARIANT 1635 1637 Missing (in otopalatodigital spectrum
FT disorder).
FT /FTId=VAR_031311.
FT VARIANT 1645 1645 C -> F (in OPD2).
FT /FTId=VAR_015723.
FT VARIANT 1724 1739 Missing (in TOD).
FT /FTId=VAR_064159.
FT VARIANT 1728 1728 G -> C (in FMD).
FT /FTId=VAR_031312.
FT VARIANT 1764 1764 A -> T (in dbSNP:rs57108893).
FT /FTId=VAR_012835.
FT VARIANT 1803 1803 E -> K (probable disease-associated
FT mutation found in a patient with
FT macrothrombocytopenia).
FT /FTId=VAR_067251.
FT CONFLICT 44 44 I -> T (in Ref. 10; AA sequence).
FT CONFLICT 1772 1772 A -> G (in Ref. 11; CAA49687).
FT CONFLICT 2341 2341 Q -> R (in Ref. 5; BAC03408).
FT CONFLICT 2634 2634 D -> H (in Ref. 2; CAA37495).
FT HELIX 40 43
FT HELIX 44 57
FT HELIX 58 60
FT TURN 67 73
FT HELIX 75 85
FT HELIX 100 116
FT HELIX 126 130
FT HELIX 134 149
FT HELIX 168 179
FT STRAND 181 183
FT HELIX 190 192
FT STRAND 193 195
FT HELIX 196 205
FT HELIX 213 215
FT HELIX 221 236
FT HELIX 244 247
FT HELIX 254 261
FT HELIX 263 266
FT HELIX 1160 1162
FT STRAND 1164 1167
FT HELIX 1168 1170
FT STRAND 1172 1174
FT STRAND 1179 1184
FT STRAND 1193 1198
FT STRAND 1206 1211
FT STRAND 1213 1222
FT STRAND 1225 1235
FT STRAND 1244 1250
FT TURN 1785 1787
FT STRAND 1791 1796
FT STRAND 1804 1809
FT STRAND 1819 1822
FT STRAND 1824 1832
FT STRAND 1838 1846
FT STRAND 1855 1860
FT STRAND 1865 1867
FT STRAND 1869 1872
FT HELIX 1873 1875
FT STRAND 1877 1879
FT STRAND 1884 1889
FT TURN 1891 1893
FT STRAND 1895 1906
FT STRAND 1909 1914
FT STRAND 1916 1925
FT STRAND 1930 1938
FT STRAND 1947 1953
FT STRAND 1959 1967
FT STRAND 1980 1988
FT STRAND 1998 2001
FT STRAND 2007 2010
FT STRAND 2014 2025
FT STRAND 2034 2039
FT HELIX 2041 2043
FT HELIX 2047 2049
FT STRAND 2051 2054
FT HELIX 2055 2057
FT STRAND 2059 2061
FT STRAND 2066 2071
FT STRAND 2075 2077
FT STRAND 2080 2088
FT STRAND 2091 2096
FT STRAND 2100 2107
FT STRAND 2112 2120
FT STRAND 2129 2136
FT STRAND 2139 2148
FT STRAND 2174 2179
FT STRAND 2185 2189
FT STRAND 2208 2216
FT STRAND 2225 2231
FT HELIX 2238 2240
FT STRAND 2242 2245
FT HELIX 2246 2248
FT STRAND 2257 2262
FT HELIX 2264 2266
FT STRAND 2271 2279
FT STRAND 2282 2287
FT STRAND 2293 2298
FT STRAND 2303 2311
FT STRAND 2320 2326
FT TURN 2429 2431
FT STRAND 2433 2436
FT HELIX 2437 2439
FT STRAND 2441 2443
FT STRAND 2448 2453
FT TURN 2455 2457
FT STRAND 2462 2470
FT STRAND 2472 2479
FT STRAND 2482 2489
FT STRAND 2491 2506
FT STRAND 2511 2518
FT STRAND 2561 2564
FT HELIX 2565 2567
FT STRAND 2576 2581
FT STRAND 2590 2595
FT STRAND 2597 2599
FT STRAND 2602 2610
FT STRAND 2613 2619
FT STRAND 2624 2632
FT STRAND 2641 2646
SQ SEQUENCE 2647 AA; 280739 MW; 6C1A07041DF50142 CRC64;
MSSSHSRAGQ SAAGAAPGGG VDTRDAEMPA TEKDLAEDAP WKKIQQNTFT RWCNEHLKCV
SKRIANLQTD LSDGLRLIAL LEVLSQKKMH RKHNQRPTFR QMQLENVSVA LEFLDRESIK
LVSIDSKAIV DGNLKLILGL IWTLILHYSI SMPMWDEEED EEAKKQTPKQ RLLGWIQNKL
PQLPITNFSR DWQSGRALGA LVDSCAPGLC PDWDSWDASK PVTNAREAMQ QADDWLGIPQ
VITPEEIVDP NVDEHSVMTY LSQFPKAKLK PGAPLRPKLN PKKARAYGPG IEPTGNMVKK
RAEFTVETRS AGQGEVLVYV EDPAGHQEEA KVTANNDKNR TFSVWYVPEV TGTHKVTVLF
AGQHIAKSPF EVYVDKSQGD ASKVTAQGPG LEPSGNIANK TTYFEIFTAG AGTGEVEVVI
QDPMGQKGTV EPQLEARGDS TYRCSYQPTM EGVHTVHVTF AGVPIPRSPY TVTVGQACNP
SACRAVGRGL QPKGVRVKET ADFKVYTKGA GSGELKVTVK GPKGEERVKQ KDLGDGVYGF
EYYPMVPGTY IVTITWGGQN IGRSPFEVKV GTECGNQKVR AWGPGLEGGV VGKSADFVVE
AIGDDVGTLG FSVEGPSQAK IECDDKGDGS CDVRYWPQEA GEYAVHVLCN SEDIRLSPFM
ADIRDAPQDF HPDRVKARGP GLEKTGVAVN KPAEFTVDAK HGGKAPLRVQ VQDNEGCPVE
ALVKDNGNGT YSCSYVPRKP VKHTAMVSWG GVSIPNSPFR VNVGAGSHPN KVKVYGPGVA
KTGLKAHEPT YFTVDCAEAG QGDVSIGIKC APGVVGPAEA DIDFDIIRND NDTFTVKYTP
RGAGSYTIMV LFADQATPTS PIRVKVEPSH DASKVKAEGP GLSRTGVELG KPTHFTVNAK
AAGKGKLDVQ FSGLTKGDAV RDVDIIDHHD NTYTVKYTPV QQGPVGVNVT YGGDPIPKSP
FSVAVSPSLD LSKIKVSGLG EKVDVGKDQE FTVKSKGAGG QGKVASKIVG PSGAAVPCKV
EPGLGADNSV VRFLPREEGP YEVEVTYDGV PVPGSPFPLE AVAPTKPSKV KAFGPGLQGG
SAGSPARFTI DTKGAGTGGL GLTVEGPCEA QLECLDNGDG TCSVSYVPTE PGDYNINILF
ADTHIPGSPF KAHVVPCFDA SKVKCSGPGL ERATAGEVGQ FQVDCSSAGS AELTIEICSE
AGLPAEVYIQ DHGDGTHTIT YIPLCPGAYT VTIKYGGQPV PNFPSKLQVE PAVDTSGVQC
YGPGIEGQGV FREATTEFSV DARALTQTGG PHVKARVANP SGNLTETYVQ DRGDGMYKVE
YTPYEEGLHS VDVTYDGSPV PSSPFQVPVT EGCDPSRVRV HGPGIQSGTT NKPNKFTVET
RGAGTGGLGL AVEGPSEAKM SCMDNKDGSC SVEYIPYEAG TYSLNVTYGG HQVPGSPFKV
PVHDVTDASK VKCSGPGLSP GMVRANLPQS FQVDTSKAGV APLQVKVQGP KGLVEPVDVV
DNADGTQTVN YVPSREGPYS ISVLYGDEEV PRSPFKVKVL PTHDASKVKA SGPGLNTTGV
PASLPVEFTI DAKDAGEGLL AVQITDPEGK PKKTHIQDNH DGTYTVAYVP DVTGRYTILI
KYGGDEIPFS PYRVRAVPTG DASKCTVTVS IGGHGLGAGI GPTIQIGEET VITVDTKAAG
KGKVTCTVCT PDGSEVDVDV VENEDGTFDI FYTAPQPGKY VICVRFGGEH VPNSPFQVTA
LAGDQPSVQP PLRSQQLAPQ YTYAQGGQQT WAPERPLVGV NGLDVTSLRP FDLVIPFTIK
KGEITGEVRM PSGKVAQPTI TDNKDGTVTV RYAPSEAGLH EMDIRYDNMH IPGSPLQFYV
DYVNCGHVTA YGPGLTHGVV NKPATFTVNT KDAGEGGLSL AIEGPSKAEI SCTDNQDGTC
SVSYLPVLPG DYSILVKYNE QHVPGSPFTA RVTGDDSMRM SHLKVGSAAD IPINISETDL
SLLTATVVPP SGREEPCLLK RLRNGHVGIS FVPKETGEHL VHVKKNGQHV ASSPIPVVIS
QSEIGDASRV RVSGQGLHEG HTFEPAEFII DTRDAGYGGL SLSIEGPSKV DINTEDLEDG
TCRVTYCPTE PGNYIINIKF ADQHVPGSPF SVKVTGEGRV KESITRRRRA PSVANVGSHC
DLSLKIPEIS IQDMTAQVTS PSGKTHEAEI VEGENHTYCI RFVPAEMGTH TVSVKYKGQH
VPGSPFQFTV GPLGEGGAHK VRAGGPGLER AEAGVPAEFS IWTREAGAGG LAIAVEGPSK
AEISFEDRKD GSCGVAYVVQ EPGDYEVSVK FNEEHIPDSP FVVPVASPSG DARRLTVSSL
QESGLKVNQP ASFAVSLNGA KGAIDAKVHS PSGALEECYV TEIDQDKYAV RFIPRENGVY
LIDVKFNGTH IPGSPFKIRV GEPGHGGDPG LVSAYGAGLE GGVTGNPAEF VVNTSNAGAG
ALSVTIDGPS KVKMDCQECP EGYRVTYTPM APGSYLISIK YGGPYHIGGS PFKAKVTGPR
LVSNHSLHET SSVFVDSLTK ATCAPQHGAP GPGPADASKV VAKGLGLSKA YVGQKSSFTV
DCSKAGNNML LVGVHGPRTP CEEILVKHVG SRLYSVSYLL KDKGEYTLVV KWGDEHIPGS
PYRVVVP
//

MIM 300017
*RECORD*
*FIELD* NO
300017
*FIELD* TI
*300017 FILAMIN A; FLNA
;;FILAMIN, ALPHA;;
FILAMIN 1; FLN1;;
FLN;;
ACTIN-BINDING PROTEIN 280; ABP280
read more*FIELD* TX

DESCRIPTION

The FLNA gene encodes filamin A, a widely expressed 280-kD actin-binding
protein that regulates reorganization of the actin cytoskeleton by
interacting with integrins, transmembrane receptor complexes, and second
messengers. Filamins crosslink actin filaments into orthogonal networks
in the cytoplasm and participate in the anchoring of membrane proteins
to the actin cytoskeleton. Remodeling of the cytoskeleton is central to
the modulation of cell shape and migration (Maestrini et al., 1993; Fox
et al., 1998).

CLONING

By analysis of the native ABP280 protein and cloning of the human
endothelial ABP280 cDNA, Gorlin et al. (1990) demonstrated that ABP280
is a 2,647-amino acid protein with 3 functional domains: an N-terminal
filamentous actin-binding domain, a C-terminal self-association domain,
and a membrane glycoprotein-binding domain. The N-terminal actin-binding
domain of ABP280 displays strong structural and functional similarity to
the N-terminal domains of dystrophin (300377), alpha-actinin (102575),
and beta-spectrin (182870).

In a search for muscle- and heart-specific isoforms that might be
involved in Emery muscular dystrophy (EDMD; 310300), Maestrini et al.
(1993) identified several different ABP280 mRNAs. Two were X-linked and
were produced by alternative splicing of a small exon of 24 nucleotides.
Both of these were ubiquitous in distribution. At least 1 additional
gene encoding an RNA more than 70% identical to ABP280 was found and was
shown to map to chromosome 7 by study of human/hamster somatic cell
hybrids (FLNC; 102565).

GENE FUNCTION

Vadlamudi et al. (2002) identified FLNA as a binding partner of PAK1
(602590) in a yeast 2-hybrid screen of a mammary gland cDNA library. By
mutation analysis, they localized the PAK1-binding region in FLNA to
tandem repeat 23 in the C terminus, and the FLNA-binding region in PAK1
between amino acids 52 and 132 in the conserved CDC42 (116952)/RAC
(602048)-interacting domain. Endogenous FLNA was phosphorylated by PAK1
on ser2152 following stimulation with physiologic signaling molecules.
Following stimulation, FLNA colocalized with PAK1 in membrane ruffles.
The ruffle-forming activity of PAK1 was found in FLNA-expressing cells,
but not in cells deficient in FLNA.

Androgen receptor (AR; 313700), a nuclear transcription factor, mediates
male sexual differentiation. Loy et al. (2003) characterized a negative
regulatory domain in the AR hinge region that interacts with filamin A.
Filamin A interferes with AR interdomain interactions and competes with
the coactivator transcriptional intermediary factor-2 (TIF2; 601993) to
downregulate AR function specifically. Although full-length filamin A is
predominantly cytoplasmic, a C-terminal 100-kD fragment colocalized with
AR to the nucleus. This naturally occurring filamin A fragment repressed
AR transactivation and disrupted AR interdomain interactions and
TIF2-activated AR function in a manner reminiscent of full-length
filamin A, raising the possibility that the inhibitory effects of
cytoplasmic filamin A may be transduced through this fragment, which can
localize to the nucleus and form part of the preinitiation complex. This
unanticipated role of filamin A added to the evidence for the
involvement of cytoskeletal proteins in transcription regulation.

Mutation in the X-linked FLNA gene can cause the neurologic disorder
periventricular heterotopia (300049). Although periventricular
heterotopia is characterized by a failure in neuronal migration into the
cerebral cortex with consequent formation of nodules in the ventricular
and subventricular zones, many neurons appear to migrate normally, even
in males, suggesting compensatory mechanisms. Sheen et al. (2002) showed
that, in mice, Flna mRNA was widely expressed in all brain cortical
layers, whereas a homolog, Flnb (603381), was most highly expressed in
the ventricular and subventricular zones during development. In
adulthood, widespread but reduced expression of Flna and Flnb persisted
throughout the cerebral cortex. Flna and Flnb proteins were highly
expressed in both the leading processes and somata of migratory neurons
during corticogenesis. Postnatally, Flna immunoreactivity was largely
localized to the cell body, whereas Flnb was localized to the soma and
neuropil during neuronal differentiation. The putative Flnb
homodimerization domain strongly interacted with itself or the
corresponding homologous region of Flna, as shown by yeast 2-hybrid
interaction. The 2 proteins colocalized within neuronal precursors by
immunocytochemistry, and the existence of Flna-Flnb heterodimers could
be detected by coimmunoprecipitation. Sheen et al. (2002) suggested that
FLNA and FLNB may form both homodimers and heterodimers, and that their
interaction could potentially compensate for the loss of FLNA function
during cortical development within patients with periventricular
heterotopia.

Using a yeast 2-hybrid screen, Grimbert et al. (2004) identified FLNA as
a binding partner for both CMIP (610112) and its truncated isoform,
TCMIP. Coimmunoprecipitation analysis confirmed the interactions.
Immunofluorescence microscopy demonstrated homogeneous colocalization of
CMIP and FLNA in the cytoplasm, but restriction of TCMIP/FLNA
colocalization to points of intercellular contact. Western blot analysis
showed increased FLNA expression in patients with relapse of minimal
change nephrotic syndrome, a glomerular disease thought to result from
abnormal T-cell activation. Grimbert et al. (2004) proposed that FLNA
and CMIP/TCMIP interact in a T-cell signaling pathway.

Using proteomic approaches, Thelin et al. (2007) showed that FLNA
associates with the extreme CFTR (602421) N terminus. Cell studies
revealed that filamin tethers plasma membrane CFTR to the underlying
actin network, stabilizing CFTR at the cell surface and regulating the
plasma membrane dynamics and confinement of the channel. In the absence
of filamin binding, CFTR is rapidly internalized from the cell surface,
where it accumulates prematurely in lysosomes and is ultimately
degraded.

Using yeast 2-hybrid analysis and protein pull-down assays,
Jimenez-Baranda et al. (2007) showed that the human immunodeficiency
virus (HIV)-1 (see 609423) receptor CD4 (186940) and the HIV-1
coreceptors CCR5 (601373) and CXCR4 (162643) interacted with FLNA, which
regulated clustering of the HIV-1 receptors on the cell surface. Binding
of HIV-1 gp120 to the receptors induced transient cofilin (see CFL1;
601442) phosphorylation inactivation through a RHOA (165390)-ROCK (see
601702)-dependent mechanism. Blockade of FLNA interaction with CD4
and/or the coreceptors inhibited gp120-induced RHOA activation and
cofilin inactivation. Jimenez-Baranda et al. (2007) concluded that FLNA
is an adaptor protein that links HIV-1 receptors to the actin skeleton
remodeling machinery, possibly facilitating virus infection.

Ehrlicher et al. (2011) identified the actin-binding protein filamin A
(FLNA) as a central mechanotransduction element of the cytoskeleton, and
reconstituted a minimal system consisting of actin filaments, FLNA, and
2 FLNA-binding partners: the cytoplasmic tail of beta-integrin (135630)
and FilGAP (610586). Integrins form an essential mechanical linkage
between extracellular and intracellular environments, with beta-integrin
tails connecting to the actin cytoskeleton by binding directly to
filamin. FilGAP is an FLNA-binding GTPase-activating protein specific
for RAC, which in vivo regulates cell spreading and bleb formation.
Using fluorescence loss after photoconversion, Ehrlicher et al. (2011)
demonstrated that both externally imposed bulk shear and
myosin-II-driven forces differentially regulate the binding of these
partners to FLNA. Consistent with structural predictions, strain
increases beta-integrin binding to FLNA, whereas it causes FilGAP to
dissociate from FLNA, providing a direct and specific molecular basis
for cellular mechanotransduction. Ehrlicher et al. (2011) concluded that
their results identified a molecular mechanotransduction element within
the actin cytoskeleton, revealing that mechanical strain of key proteins
regulates the binding of signaling molecules.

By yeast 2-hybrid and immunoprecipitation analyses, Adams et al. (2012)
found that the C-terminal cytoplasmic tail of meckelin (TMEM67; 609884)
interacted with filamin A. Loss of filamin A or meckelin in immortalized
fibroblasts from patients with null mutations in the genes or by small
interfering RNA in mouse IMCD3 cells resulted in similar cellular
phenotypes, including abnormal basal body positioning and ciliogenesis,
aberrant remodeling of the actin cytoskeleton, deregulation of RHOA
(165390) activity, and hyperactivation of canonical Wnt (see 606359)
signaling. Adams et al. (2012) concluded that the meckelin-filamin A
signaling axis is a key regulator of ciliogenesis and normal Wnt
signaling.

GENE STRUCTURE

Patrosso et al. (1994) found that the FLN1 gene is composed of 47 exons
spanning approximately 26 kb. The first and part of the second exon are
untranslated. The actin-binding domain at the N terminus is encoded by
exons 2 to 5. The 96-amino acid repeats corresponding to the elongated
backbone of the protein are encoded by the remaining 42 exons.

Fox et al. (1998) stated that FLN1 consists of 48 exons covering 26 kb
of genomic sequence, with a 7.9-kb open reading frame.

Chakarova et al. (2000) compared the genomic structure of the filamin
gene family. A previously unknown intron was found in FLNA. The
comparison of FLNA with the 2 paralogs, FLNB (603381) and FLNC,
demonstrated a highly conserved exon/intron structure with significant
differences in exon 32 of all paralogs encoding the hinge I region, as
well as the insertion of a novel exon 40A in FLNC only.

MAPPING

When sequences from CpG islands in the Xq28 region (Maestrini et al.,
1990) were compared to sequences in databases, the gene for ABP280 was
found. It is located in the distal part of Xq28, 50-60 kb downstream of
the colorblindness genes. A similar localization was reported by Kunst
et al. (1992).

Kunst et al. (1992) mapped the ABP280 cDNA to Xq28 by somatic hybrid
cell panel analysis and fluorescence in situ hybridization (FISH).

Gorlin et al. (1993) mapped the FLN gene to Xq28 by Southern blot
analysis of somatic cell hybrid lines, by FISH, and by identification of
portions of the FLN gene within cosmids and YACs mapped to Xq28.
Specifically, the FLN gene was located within a 200-kb region between
the G6PD locus at the telomeric end and the colorblindness loci and the
DXS52 marker at the proximal end. Because of its similarities to
dystrophin, Gorlin et al. (1993) suggested FLN as a candidate gene for 2
myopathies that map to Xq28: EDMD and Barth syndrome (302060).

Fox et al. (1998) stated that the FLN1 gene is adjacent to the emerin
gene (300384), which is mutant in EDMD, and the 2 genes are flanked by
inverted repeats, causing the genomic segment containing these 2 genes
to be present in 2 orientations in the population at large (Small et
al., 1997). Notably, all large-scale rearrangements of emerin associated
with EDMD failed to include FLN1, suggesting that loss of FLN1 function
might be embryonically lethal.

Gariboldi et al. (1994) mapped the mouse homolog to the X chromosome in
a region of syntenic homology with Xq28.

BIOCHEMICAL FEATURES

- Crystal Structure

Clark et al. (2009) determined the crystal structures of wildtype and
E254K (300017.0010)-mutant FLNA actin-binding domains (ABDs) at
2.3-angstrom resolution, revealing that they adopt similar closed
conformations. The E254K mutation removes a conserved salt bridge but
does not disrupt the ABD structure. The solution structures are also
equivalent as determined by circular dichroism spectroscopy, but
differential scanning fluorimetry denaturation showed reduced thermal
stability for E254K.

MOLECULAR GENETICS

For a review of the disorders caused by mutations in the FLNA gene, see
Robertson (2005).

- X-Linked Dominant Periventricular Heterotopia

X-linked dominant periventricular heterotopia (300049) is a disorder in
which many neurons fail to migrate to the cerebral cortex and persist as
nodules lining the ventricular surface. Heterozygous females with the
disorder present with epilepsy and other signs, including patent ductus
arteriosus (see 607411) and coagulopathy, whereas hemizygous affected
males die embryonically. Fox et al. (1998) identified the cause as
mutations in the FLN1 gene (300017.0001-300017.0005), which is required
for locomotion of many cell types. They demonstrated a previously
unrecognized high level of expression of FLN1 in the developing cortex.
Their studies demonstrated that FLN1 is required for neuronal migration
to the cortex and is essential for embryogenesis.

In identifying filamin-1 as the gene mutant in periventricular
heterotopia, Fox et al. (1998) first narrowed the map location to an
interval approximately 1 cM between marker DXS15 and the pseudoautosomal
region of Xq28 by the study of additional markers. Subsequent analysis
of a large duplication of Xq28 in a male patient with periventricular
heterotopia (Fink et al., 1997) with a severe, albeit nonlethal,
phenotype allowed the candidate interval to be refined even further.
They defined the exact centromeric boundary of the duplicated segment of
Xq28 as base 3377 of 3,395 bases in intron 1 of the isocitrate
dehydrogenase gene (IDH3G; 300089), approximately 600 kb distal to
DXS15. However, none of the genes identified at the breakpoints or
insertion site of the duplication harbored independent mutations in
other patients with periventricular heterotopia. Therefore, Fox et al.
(1998) concluded that the duplication of FLN1 itself was responsible for
the disorder in this patient.

Fox et al. (1998) studied the pattern of X inactivation in females with
FLN1 mutations in nucleated peripheral blood cells. No evidence of
preferential lyonization in these cells was found, suggesting that FLN1
is not required in a cell-autonomous fashion for survival of mixed
peripheral white blood cells. However, an essential cell-autonomous role
for FLN1 in a subset of nucleated cells or nonnucleated cells (e.g.,
platelets) could not be excluded.

Sheen et al. (2001) performed SSCP analysis of FLN1 throughout its
entire coding region in 6 periventricular heterotopia pedigrees, 31
sporadic female patients, and 24 sporadic male periventricular
heterotopia patients. The authors detected FLN1 mutations in 83% of
periventricular heterotopia pedigrees and 19% of sporadic females with
periventricular heterotopia. Moreover, 0 of 7 females with
periventricular heterotopia with atypical radiographic features showed
FLN1 mutations, suggesting that other genes may cause atypical
periventricular heterotopia. Two of 24 males analyzed with
periventricular heterotopia (9%) also carried FLN1 mutations. Whereas
FLN1 mutations in periventricular heterotopia pedigrees caused severe
predicted loss of FLN1 protein function, both male FLN1 mutations were
consistent with partial loss of function of the protein. Moreover,
sporadic female FLN1 mutations associated with periventricular
heterotopia appear to cause either severe or partial loss of function.

Sheen et al. (2005) reported 2 familial cases and 9 sporadic cases of
the Ehlers-Danlos variant of periventricular heterotopia (300537), which
is characterized by nodular brain heterotopia, joint hypermobility, and
development of aortic dilatation in early adulthood. MRI typically
demonstrated bilateral nodular periventricular heterotopia,
indistinguishable from periventricular heterotopia due to FLNA
mutations. Mutations in the FLNA gene were identified in 3 affected
females (300017.0017-300017.0019); in another pedigree with no
detectable exonic mutation, positive linkage to the FLNA locus on Xq28
was demonstrated, and an affected individual in this family had no
detectable FLNA protein.

In 3 female patients from a 3-generation Spanish family with the
Ehlers-Danlos variant of periventricular heterotopia, Gomez-Garre et al.
(2006) identified heterozygosity for a missense mutation in the FLNA
gene (300017.0021).

- Multiple Malformation Syndromes

Loss-of-function mutations of FLNA are, as indicated, embryonic lethal
in males but are manifest in females as a localized neuronal migration
disorder, periventricular nodular heterotopia (PVNH). Robertson et al.
(2003) described localized mutations in FLNA that conserve the reading
frame and lead to a broad range of congenital malformations, affecting
craniofacial structures, skeleton, brain, viscera, and urogenital tract,
in 4 X-linked human disorders: otopalatodigital syndrome types I (OPD1;
311300) and II (OPD2; 304120), frontometaphyseal dysplasia (FMD;
305620), and Melnick-Needles syndrome (MNS; 309350). Several of the
mutations were recurrent, and all were clustered in 4 regions of the
gene: the actin-binding domain and rod domain repeats 3, 10, and 14/15.
The patterns of mutation, X-chromosome inactivation, and phenotypic
manifestations in this class of mutations indicated gain-of-function
effects, implicating filamin A in signaling pathways that mediate
organogenesis in multiple systems during embryonic development.

In a 26-year-old Mexican female with OPD1, Hidalgo-Bravo et al. (2005)
identified a heterozygous missense mutation in the FLNA gene
(300017.0020). The patient had prominent features of OPD1, including
cleft palate; an extremely skewed pattern of X inactivation toward the
maternal allele was noted.

In 6 affected females with cranial hyperostosis and various skeletal
abnormalities from a 4-generation pedigree, Stefanova et al. (2005)
identified heterozygosity for a deletion in the FLNA gene (300017.0016).
The disorder resulted in early lethality in male children in this
family. The phenotype of the females was variable, rather mild, and
bridged the phenotypes of various OPD spectrum disorders (see 311300).

Zenker et al. (2006) reported a gly1728-to-cys mutation (300017.0022) in
repeat 15 of the filamin A rod domain of the FLNA gene in a girl with
manifestations of frontometaphyseal dysplasia and otopalatodigital
syndrome 1. In a second family with FMD, they identified a
ser1186-to-leu mutation (300017.0015) in a mother and her son. In
contrast to most previous reports on manifesting females or carriers of
FLNA-related skeletal dysplasias, the affected females in these 2
families showed only mild to moderate skewing of X-inactivation against
the mutant allele. Zenker et al. (2006) suggested that the data may
indicate that in females, genotype-phenotype correlation between certain
FLNA mutations and OPD1 and FMD, respectively, is less strict than
previously assumed. They proposed that X-inactivation is an important
epigenetic modifier of the phenotype in females with the FLNA-related
skeletal dysplasias.

Hehr et al. (2006) described a male patient with periventricular nodular
heterotopia (PVNH), craniofacial features, and severe constipation. The
phenotype was associated with a splice mutation in exon 13 of the FLNA
gene (300017.0024). Hehr et al. (2006) suggested that the patient
retained enough FLNA function to avoid the usual lethality associated
with loss-of-function mutations in FLNA in males.

In an 18-month-old German boy with FG syndrome-2 (FGS2; 300321), Unger
et al. (2007) identified a hemizygous mutation in the FLNA gene (P1291L;
300017.0028). He had severe constipation, large rounded forehead,
prominent ears, frontal hair upsweep, and mild delay in language
acquisition. The parents declined brain MRI studies. Unger et al. (2007)
suggested that the patient reported by Hehr et al. (2006) actually had
FGS2, due to the presence of severe constipation and dysmorphic facial
features.

- Intestinal Pseudoobstruction/Congenital Short Bowel Syndrome

In an Italian family with an X-linked recessive form of chronic
idiopathic intestinal pseudoobstruction (CIIP) mapping to chromosome
Xq28 (CIIPX; 300048), Gargiulo et al. (2007) detected a 2-bp deletion in
exon 2 of the FLNA gene that was present in heterozygous state in the
carrier females of the family (300017.0025). The frameshift mutation was
located between 2 close methionines at the filamin N terminus and was
predicted to produce a protein truncated shortly after the first
predicted methionine. Because loss-of-function FLNA mutations have been
associated with X-linked dominant nodular ventricular heterotopia (PVNH;
300049), a central nervous system migration defect that presents with
seizures in females and lethality in males, it was notable that the male
bearing the FLNA mutation had signs of central nervous system (CNS)
involvement and possibly PVNH. To understand how the severe frameshift
mutation found by Gargiulo et al. (2007) explained the CIIPX phenotype
and its X-linked recessive inheritance, Gargiulo et al. (2007)
transiently expressed both the wildtype and the mutant filamin in cell
culture and found filamin translation to start from either of the 2
initial methionines in these conditions. Therefore, translation of a
normal, shorter filamin can occur in vitro from the second methionine
downstream of the 2-bp insertion. Gargiulo et al. (2007) confirmed this,
demonstrating that the filamin protein was present in the patient's
lymphoblastoid cell line that shows abnormal cytoskeletal actin
organization compared with normal lymphoblasts. The authors concluded
that the filamin N-terminal region between the initial 2 methionines is
crucial for proper enteric neuron development.

Clayton-Smith et al. (2009) identified a duplication of the FLNA gene in
affected members of 2 families with intestinal pseudoobstruction, patent
ductus arteriosus, and thrombocytopenia with giant platelets (300048).
One of the families had been reported by FitzPatrick et al. (1997).

Van der Werf et al. (2013) reported a 2-basepair deletion in exon 2 of
filamin A (300017.0035) in 1 family segregating X-linked congenital
short bowel syndrome (see 300048) and in an unrelated affected
individual. In the family, all obligate carriers were heterozygous for
the mutation; in the isolated male, the mutation had occurred as a de
novo event. Van der Werf et al. (2013) stated that they could not
exclude involvement of the central nervous system in these patients
because no magnetic resonance imaging brain scans were available.

- Terminal Osseous Dysplasia

In affected members of 3 families segregating terminal osseous dysplasia
(300244), 2 of which were previously described by Breuning et al. (2000)
and Baroncini et al. (2007), and in 3 sporadic case individuals, who
were previously described by Horii et al. (1998), Drut et al., (2005),
and Breuning et al. (2000), respectively, Sun et al. (2010) identified a
causative mutation in the FLNA gene: a 5217G-A transition activated a
cryptic splice site, removing the last 48 nucleotides from exon 31 and
resulting in a loss of 16 amino acids (300017.0029). In the families,
the variant segregated with the disease. Sun et al. (2010) showed that
because of nonrandom X chromosome inactivation, the mutant allele was
not expressed in the patient fibroblasts. RNA expression of the mutant
allele was detected only in cultured fibroma cells obtained from
15-year-old surgically removed material. The mutation was not found in
400 control X chromosomes, pilot data from 1000 Genomes Project, or the
FLNA gene variant database. Because the mutation was predicted to remove
a sequence at the surface of filamin repeat 15, Sun et al. (2010)
suggested that the missing region in the filamin A protein affects or
prevents the interaction of filamin A with other proteins.

- X-Linked Cardiac Valvular Dysplasia

In a large 5-generation French pedigree with X-linked cardiac valvular
disease (CVD1; 314400) mapping to Xq28, originally reported by Benichou
et al. (1997) and Kyndt et al. (1998), Kyndt et al. (2007) analyzed
candidate genes and identified a missense mutation in the FLNA gene that
segregated with disease (P637Q; 300017.0030). In 3 more families with
cardiac valvular disease, Kyndt et al. (2007) identified 2 different
missense mutations and an in-frame deletion (300017.0031-300017.0033,
respectively). No signs of periventricular heterotopia, otopalatodigital
syndrome, frontometaphyseal dysplasia, or Melnick-Needles or
Ehlers-Danlos syndromes were observed in these families. The missense
mutations all involve highly conserved residues within the first,
fourth, and fifth repeat consensus sequences of FLNA, respectively, and
the deletion results in a truncated protein lacking repeats 5 through 7.

HISTORY

Robert J. Gorlin (2003) was responsible for the initial description of 3
of the conditions that had been shown to be caused by mutations in the
FLNA gene: OPD1, OPD2, and frontometaphyseal dysplasia. Furthermore, he
correctly interpreted the genetics of Melnick-Needles syndrome as
X-linked recessive rather than autosomal recessive. His son, Jed Gorlin,
sequenced the FLNA gene (Gorlin et al., 1990) and mapped it to
chromosome Xq28 (Gorlin et al., 1993).

ANIMAL MODEL

Feng et al. (2006) noted that hemizygous human males with FLNA mutations
die prenatally or survive after birth with cardiac malformations, often
dying postnatally from blood vessel rupture. They found that Flna-null
mice died at midgestation with widespread hemorrhage from abnormal
vessels, persistent truncus arteriosus, and incomplete cardiac
septation. Conditional Flna knockout in the neural crest caused
abnormalities of the cardiac outflow tract despite apparently normal
migration of Flna-deficient neural crest cells. Flna-null vascular
endothelial cells displayed abnormal adherens junctions and defects in
cell-cell contacts. Feng et al. (2006) suggested that cell
motility-independent functions of FLNA at cell-cell contacts and
adherens junctions affect the development of organs.

Adams et al. (2012) found that knockdown of Mks3 or the Flna ortholog in
zebrafish resulted in similar phenotypes, including brain and body axis
defects, cardiac edema, and otic placode and eye defects. Combined low
doses of both Mks3 and Flna morpholinos increased both the incidence and
severity of developmental defects. An Flna-null mouse strain showed
similar defects. At embryonic day 13.5, male Flna hemizygous embryos
were highly dysmorphic, with extensive disruption of ventricular zone of
the neocortex and severe periventricular heterotopia. Basal body
position was disrupted and neuroepithelial layer showed impaired
ciliogenesis.

*FIELD* AV
.0001
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, GLN182TER

In the largest reported pedigree with periventricular heterotopia
(300049) (Huttenlocher et al., 1994), Fox et al. (1998) found a C-to-T
substitution in exon 3 of the FLN1 gene, which converted a CAG (gln) to
a TAG (stop) codon and truncated the FLN1 protein at amino acid residue
182 of the 2,647 total amino acids in the normal protein.

.0002
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, IVS4DS, T-C, +2

In affected members of a family with periventricular heterotopia
(300049), Fox et al. (1998) found a T-to-C substitution at the second
base of intron 4 in the splice donor sequence of the FLN1 gene. The
mutation was predicted to cause either exon skipping or a read-through
of intron 4 which would introduce a stop codon after the translation of
30 additional amino acids. The mutation was present in both a mother and
daughter with periventricular heterotopia but not in the unaffected
maternal grandmother. Therefore, this mutation most likely arose de novo
in this pedigree in the germline of either the maternal grandmother or
grandfather, both of whom were clinically unaffected.

.0003
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, IVS3AS, C-G, -3

In a sporadic case of periventricular heterotopia (300049), Fox et al.
(1998) found that the consensus splice acceptor at the end of intron 3
(3 bases from exon 4) of the FLN1 gene was mutated by a C-to-G
substitution. The 'C' at position -3 is conserved among more than 70% of
vertebrate splice junctions, and the 'G' at this position is seen in
only 1% (Shapiro and Senapathy, 1987). The mutation appeared to have
arisen de novo in the germline of the patient's mother or father.

.0004
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, IVS2DS, G-A, +1

In a sporadic case of periventricular heterotopia (300049), Fox et al.
(1998) found a G-to-A mutation at the first base of intron 2 of the FLN1
gene. The 'G' at position +1 of the intron is conserved in 100% of
splice donor sequences of vertebrate genes (Shapiro and Senapathy,
1987).

.0005
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, 5-BP DEL, NT287

In a sporadic case of periventricular heterotopia (300049), Fox et al.
(1998) found deletion of 5 bases from the coding region of exon 2 of the
FLN1 gene. Bases 287-291 were removed, producing a frameshift and the
introduction of a premature stop codon after the addition of 8
inappropriate amino acids.

.0006
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, LEU656PHE

In a sporadic male patient with unilateral periventricular heterotopia
(300049), epilepsy, and normal intellect, Sheen et al. (2001) found a
C-to-T transition at position 1966, resulting in a leu656-to-phe (L656F)
amino acid substitution in the fifth Ig-like domain of the FLN1 gene.

.0007
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, 5915C-G

In a sporadic male patient with periventricular heterotopia (300049),
epilepsy, and normal intellect, Sheen et al. (2001) found a C-to-G
transversion at position 6915. This was predicted to result in
termination at residue 2305 and loss of the 344 C-terminal amino acids
of the FLN1 gene, which include the receptor-binding region.

.0008
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, GLU82VAL

In a family with periventricular heterotopia (300049), Moro et al.
(2002) identified a 245A-T mutation in exon 2 of the FLNA gene, leading
to a glu82-to-val substitution (E82V) in the N-terminal part of the
protein. The mutation likely modifies protein activity without complete
loss of function. Affected females with the mutation showed a mild
anatomic phenotype with few asymmetric, noncontiguous nodules on MRI,
and gave birth to 5 presumably affected boys who died within a few days
to several weeks or months of life.

.0009
OTOPALATODIGITAL SYNDROME, TYPE I
FLNA, PRO207LEU

In 2 presumably unrelated families, Robertson et al. (2003) found that
individuals with otopalatodigital syndrome type I (OPD1; 311300) had a
620C-T transition in exon 3 of the FLNA gene, predicted to result in a
pro207-to-leu (P207L) amino acid substitution. All affected members had
bowed bones and abnormal digits as well as cleft palate.

Robertson et al. (2006) identified the P207L mutation in 2 brothers with
OPD1. The mutation was not identified in leukocytes of the mother,
suggesting germline mosaicism. The authors emphasized the importance of
the finding for genetic counseling.

.0010
OTOPALATODIGITAL SYNDROME, TYPE II
FLNA, GLU254LYS

In 4 presumably unrelated families, each with at least 1 affected male,
Robertson et al. (2003) found that individuals with otopalatodigital
syndrome type II (OPD2; 304120) had a 760G-A transition in exon 5 of the
FLNA gene, predicted to cause a glu254-to-lys (E254K) amino acid
substitution. All 4 patients had omphalocele, perinatal death, bowed
bones, and abnormal digits; 1 also had cleft palate, and 2 had
hydrocephalus.

Clark et al. (2009) showed that OPD E254K fibroblast lysates had
equivalent concentrations of FLNA compared with controls, and that
recombinant FLNA E254K actin-binding domain (ABD) had increased in vitro
F-actin binding compared with wildtype. The FLNA ABD adopts a canonical
compact conformation that is not greatly disturbed by the E254K mutation
either in solution or in the crystal structure. Ex vivo characterization
of E254K OPD patient fibroblasts revealed that they have similar
motility and adhesion as control cells, implying that many core
functions mediated by FLNA are unaffected, consistent with OPD affecting
only specific tissues despite FLNA being widely expressed. The authors
proposed a gain-of-function mechanism for the OPD disorders, which
mechanistically distinguishes them from the loss-of-function phenotypes
that manifest as disorders of neuronal migration.

.0011
FRONTOMETAPHYSEAL DYSPLASIA
FLNA, ASP1159ALA

In 2 affected members of a family, Robertson et al. (2003) found that
frontometaphyseal dysplasia (305620) was related to a 3476A-C
transversion in exon 22 of the FLNA gene, predicted to result in an
asp1159-to-ala (D1159A) amino acid change.

.0012
MELNICK-NEEDLES SYNDROME
FLNA, ALA1188THR

In 5 presumably unrelated patients with Melnick-Needles syndrome
(309350), Robertson et al. (2003) found a 3562G-A transition in exon 22
of the FLNA gene, predicted to result in an ala1188-to-thr (A1188T)
amino acid change. All 5 patients had bowed bones and abnormal digits
and all but one had short stature.

.0013
MELNICK-NEEDLES SYNDROME
FLNA, SER1199LEU

In 6 presumably unrelated females with Melnick-Needles syndrome
(309350), Robertson et al. (2003) found a 3596C-T transition in exon 22
of the FLNA gene, predicted to cause an ser1199-to-leu (S1199L) amino
acid change. All 6 females were of short stature and had bowed bones and
abnormal digits.

Robertson et al. (2006) identified the S1199L mutation in a girl with
Melnick-Needles syndrome. The girl had an unaffected twin sister who did
not carry the mutation; the unaffected mother also did not carry the
mutation. The twins were born with separate amniotic sacs within a
single chorion, and zygosity analysis indicated a high probability that
the girls were monozygotic twins. Robertson et al. (2006) concluded that
the FLNA mutation occurred postzygotically in the affected twin and
emphasized the importance of the finding for genetic counseling.

.0014
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED, WITH FRONTOMETAPHYSEAL
DYSPLASIA
FLNA, 7315C-A

Periventricular nodular heterotopia (300049) and a group of skeletal
dysplasias belonging to the otopalatodigital (OPD) spectrum are caused
by mutation in the FLNA gene. They are considered mutually exclusive
because of the different presumed effects of the respective FLNA gene
mutations, leading to loss of function in PVNH and gain of function in
OPD. In a girl manifesting PVNH in combination with frontometaphyseal
dysplasia (305620), a skeletal dysplasia of the OPD spectrum, Zenker et
al. (2004) identified a de novo 7315C-A transversion in exon 45 of the
FLNA gene, resulting in 2 aberrant transcripts: 1 full-length transcript
with a point mutation causing a substitution of a highly conserved
leu2439 residue by met (L2439M) and a second shortened transcript
lacking 21 bp due to the creation of an ectopic splice donor site in
exon 45. Zenker et al. (2004) proposed that the dual phenotype was
caused by 2 functionally different, aberrant filamin A proteins and
therefore represented an exceptional case of allelic gain-of-function
and loss-of-function phenotypes due to a single mutation event.

.0015
FRONTOMETAPHYSEAL DYSPLASIA
FLNA, SER1186LEU

In a male patient with frontometaphyseal dysplasia (305620), Robertson
et al. (2003) identified a 3557C-T transition in exon 22 of the FLNA
gene, resulting in a ser1186-to-leu (S1186L) amino acid change.

Giuliano et al. (2005) reported a 3-generation family with FMD and
identified the S1186L mutation in the proband and his mother.

The S1186L missense mutation in repeat 10 of the filamin A rod domain
was reported in patients with frontometaphyseal dysplasia by Zenker et
al. (2006). The proposita in the family reported by Zenker et al. (2006)
was a 68-year-old woman whose son had died with a diagnosis of FMD. She
had had scoliosis from childhood. Prominent supraorbital ridges,
hypertelorism, and a small pointed chin as well as moderate
thoracolumbar scoliosis were noted. The son developed massive frontal
hyperostosis from childhood leading to the diagnosis of FMD with
hypertelorism, micrognathia, oligodontia, progressive sensorineural
hearing loss, amblyopia, pectus excavatum, and scoliosis. During
adolescence, he developed sleep apnea and had been treated with
continuous positive airway pressure. Ehrenstein et al. (1997) reported
the radiologic findings. The patient died unexpectedly at the age of 25
years. In contrast to most previous reports on manifesting females or
carriers of the FLNA-related skeletal dysplasias, the proband showed
only mild to moderate skewing of X inactivation against the mutant
allele.

.0016
OTOPALATODIGITAL SPECTRUM DISORDER
FLNA, 9-BP DEL, NT4904

In 6 affected females with cranial hyperostosis and various skeletal
abnormalities from a 4-generation pedigree, Stefanova et al. (2005)
identified heterozygosity for a 9-bp deletion from position 4904 to 4912
in exon 29 of the FLNA gene, predicting the loss of 3 amino acid
residues (codons 1635-1637) in rod domain repeat 14. The mutation was
not found in 2 unaffected females. The phenotype of affected females
resembled frontometaphyseal dysplasia with some overlap to
otopalatodigital syndrome types 1 and 2, but no signs specific for
Melnick-Needles syndrome. However, males had severe extraskeletal
malformations and died early, thus constituting an overlap with OPD2 and
MNS. Stefanova et al. (2005) concluded that the disorder in this family
is best described as an intermediate OPD spectrum phenotype that bridges
the FMD and OPD2 phenotypes; see 311300.

.0017
HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT
FLNA, 1-BP DEL, 2762G

In a 13-year-old female with the Ehlers-Danlos variant of
periventricular heterotopia (300537), Sheen et al. (2005) found a 1-bp
deletion in exon 19 of the FLNA gene (2762delG). The patient showed
typical features of EDS including joint hypermobility as well as
myxomatous borders along the mitral and aortic valves.

.0018
HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT
FLNA, 1-BP DEL, 4147G

In a 16-year-old female with the Ehlers-Danlos variant of
periventricular heterotopia (300537), Sheen et al. (2005) found a 1-bp
deletion in exon 25 of the FLNA gene (4147delG). The patient had aortic
aneurysm and joint hypermobility.

.0019
HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT
FLNA, ALA39GLY

In a 15-year-old female with the Ehlers-Danlos variant of
periventricular heterotopia (300537), Sheen et al. (2005) identified a
116C-G transversion in exon 2 of the FLNA gene, resulting in an
ala39-to-gly (A39G) substitution. The patient had radiologic findings of
periventricular heterotopia, seizures, mild cognitive delay with
psychotic behavior, joint hypermobility, and aortic aneurysm.

.0020
OTOPALATODIGITAL SYNDROME, TYPE I
FLNA, ASP203TYR

In a 26-year-old Mexican female with OPD1 (311300), Hidalgo-Bravo et al.
(2005) identified heterozygosity for a 607G-T transversion in exon 3 of
the FLNA gene, resulting in an asp203-to-tyr (D203Y) substitution in the
actin binding domain. Her parents did not have the mutation. The patient
had prominent features of OPD1, including cleft palate; an extremely
skewed pattern of X inactivation toward the maternal allele was noted.

.0021
HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT
FLNA, ALA128VAL

In 3 female patients from a 3-generation Spanish family with the
Ehlers-Danlos variant of periventricular heterotopia (300537),
Gomez-Garre et al. (2006) identified heterozygosity for a 383C-T
transition in exon 3 of the FLNA gene, resulting in an ala128-to-val
(A128V) substitution. The mutation was not found in unaffected family
members or in 184 control chromosomes.

.0022
OTOPALATODIGITAL SPECTRUM DISORDER
FLNA, GLY1728CYS

Zenker et al. (2006) described a de novo mutation in the FLNA gene in a
girl with manifestations of frontometaphyseal dysplasia and
otopalatodigital syndrome type 1 (see 311300). The 5182G-T mutation in
exon 31 was predicted to lead to the exchange of a highly conserved
glycine residue at position 1728 by cysteine (G1728C) in repeat 15 of
the filamin A rod domain. A short neck and deep-set ears were noted at
birth. On the first day of life, presence of inspiratory stridor and
episodic cyanosis led to the diagnosis of laryngomalacia and a large
atrial septal defect with signs of persistent pulmonary hypertension
which resolved spontaneously within 24 hours. Echocardiography showed
dysplastic tricuspid valve and noncompaction of the right ventricular
myocardium. The latter disappeared during infancy. The atrial septal
defect was corrected at age 9 years. Conductive hearing deficit, first
diagnosed in childhood, was progressive, necessitating hearing aids by
the age of 12 years. At age 16 years, typical craniofacial findings of
FMD were impressive supraorbital hyperostosis, hypertelorism,
antimongoloid palpebral fissures, a deeply grooved philtrum, and a
pointed and slightly receding chin. The terminal phalanges of thumbs and
halluces were short and broad.

.0023
MOVED TO 300017.0015
.0024
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, 1923C-T

Hehr et al. (2006) described a male patient with periventricular nodular
heterotopia (300049) associated with a splice mutation in exon 13 of the
FLNA gene (1923C-T). In addition to PVNH, the patient also presented
with craniofacial features and severe constipation. Hehr et al. (2006)
postulated that the predominant expression of the full-length mRNA in
addition to a mutant shorter transcript lacking the 3-prime part of exon
13 had rescued a sufficient amount of FLNA protein function to result in
this novel phenotype.

Unger et al. (2007) suggested that the patient reported by Hehr et al.
(2006) actually had FGS2 (300321), especially given the presence of
craniofacial dysmorphic features and severe constipation. Unger et al.
(2007) identified a different mutation in the FLNA gene (300017.0028) in
a patient with FGS2.

.0025
INTESTINAL PSEUDOOBSTRUCTION, NEURONAL, CHRONIC IDIOPATHIC, X-LINKED
FLNA, 2-BP DEL, 65AC

In an affected male in the Italian family of X-linked chronic idiopathic
intestinal pseudoobstruction (300048) described originally be Auricchio
et al. (1996), Gargiulo et al. (2007) found a 2-bp deletion in exon 2 of
the FLNA gene: 65-66delAC. Segregation analysis of the FLNA mutation
confirmed that all obligate carriers, by pedigree or established by
linkage analysis, were heterozygous for the 2-bp deletion. The mutation
was absent in 164 control X chromosomes.

.0026
OTOPALATODIGITAL SYNDROME, TYPE I
OTOPALATODIGITAL SYNDROME, TYPE II, INCLUDED
FLNA, ARG196TRP

In a patient with OPD type I (311300), Robertson et al. (2003)
identified a 586C-T transition in exon 3 of the FLNA gene, resulting in
an arg196-to-trp (R196W) substitution.

Kondoh et al. (2007) identified the R196W mutation in a 12-year-old
Japanese boy with OPD type II (304120). The patient had some additional
unusual features, including congenital cataract, glaucoma, and
congenital heart defects. Kondoh et al. (2007) noted the different
phenotype caused by the same mutation and suggested that additional
factors play a role in the pathogenesis of OPD spectrum disorders.

.0027
OTOPALATODIGITAL SYNDROME, TYPE II
FLNA, CYS210PHE

In a male fetus with otopalatodigital syndrome type II (304120),
Marino-Enriquez et al. (2007) identified a 629G-T transversion in exon 3
of the FLNA gene, predicted to cause a cys210-to-phe (C210F)
substitution within the second calponin homology domain of the
actin-binding domain. Analysis of exon 3 in relatives revealed that the
mutation had arisen de novo in the mother; a previous pregnancy had
ended in stillbirth of a male diagnosed with OPD2.

.0028
FG SYNDROME 2
FLNA, PRO1291LEU

In an 18-month-old boy with FG syndrome-2 (FGS2; 300321), Unger et al.
(2007) identified a hemizygous 3872C-T transition in exon 23 of the FLNA
gene, resulting in a pro1291-to-leu (P1291L) substitution. His
asymptomatic mother also carried the mutation, which was absent in 100
control chromosomes. The patient had severe constipation, large rounded
forehead, prominent ears, frontal hair upsweep, and mild delay in
language acquisition. Although the authors noted that the mutation does
not affect a highly conserved residue, they referred to a patient
reported by Hehr et al. (2006) with periventricular nodular heterotopia
(300049) and a FLNA mutation (300017.0024), who also had craniofacial
dysmorphic features and severe constipation. Unger et al. (2007)
suggested that the patient reported by Hehr et al. (2006) actually had
FGS2.

.0029
TERMINAL OSSEOUS DYSPLASIA
FLNA, 5217G-A, 48-BP DEL

In affected members of 3 families segregating terminal osseous dysplasia
(300244), 2 of which were previously described by Breuning et al. (2000)
and Baroncini et al. (2007), and in 3 sporadic case individuals, who
were previously described by Horii et al. (1998), Drut et al., (2005),
and Breuning et al. (2000), respectively, Sun et al. (2010) identified a
causative mutation in the last nucleotide of exon 31 of the FLNA gene: a
5217G-A transition activated a cryptic splice site, removing the last 48
nucleotides from exon 31 and resulting in a loss of 16 amino acids
(val1724_thr1739del). Sun et al. (2010) showed that because of nonrandom
X chromosome inactivation, the mutant allele was not expressed in the
patient fibroblasts. RNA expression of the mutant allele was detected
only in cultured fibroma cells obtained from 15-year-old surgically
removed material. The mutation was not found in 400 control X
chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene
variant database. Because the mutation was predicted to remove a
sequence at the surface of filamin repeat 15, Sun et al. (2010)
suggested that the missing region in the filamin A protein affects or
prevents the interaction of filamin A with other proteins.

.0030
CARDIAC VALVULAR DYSPLASIA, X-LINKED
FLNA, PRO637GLN

In a large 5-generation Caucasian French pedigree with X-linked cardiac
valvular dysplasia (314400), originally reported by Benichou et al.
(1997) and Kyndt et al. (1998), Kyndt et al. (2007) identified a 1910C-A
transversion in exon 13 of the FLNA gene, resulting in a pro637-to-gln
(P637Q) substitution at a highly conserved residue within the fourth
repeat consensus sequence. The mutation segregated with disease in the
family and was not found in 500 control chromosomes of white or African
origin.

.0031
CARDIAC VALVULAR DYSPLASIA, X-LINKED
FLNA, GLY288ARG

In a British family with X-linked cardiac valvular dysplasia (314400),
originally described by Newbury-Ecob et al. (1993), Kyndt et al. (2007)
identified an 862G-A transition in exon 5 of the FLNA gene, resulting in
a gly288-to-arg (G288R) substitution at a highly conserved residue
within the first repeat consensus sequence. The mutation segregated with
disease in the family and was not found in 500 control chromosomes of
white or African origin.

.0032
CARDIAC VALVULAR DYSPLASIA, X-LINKED
FLNA, VAL711ASP

In a 4-month-old boy with cardiac valvular dysplasia (314400), born of
black African parents, Kyndt et al. (2007) identified a 2132T-A
transversion in exon 14 of the FLNA gene, resulting in a val711-to-asp
(V711D) substitution at a highly conserved residue in the fifth repeat
consensus sequence. The patient was diagnosed prenatally with abnormally
thick cardiac valves by ultrasound and fetal echocardiography; postnatal
echocardiography confirmed that all valves were thickened and
dystrophic, with moderate tricuspid incompetence, trivial mitral and
pulmonary incompetence, and mild aortic incompetence. His carrier mother
showed no evidence of cardiac involvement on clinical examination. The
mutation was not found in 500 control chromosomes of white or African
origin.

.0033
CARDIAC VALVULAR DYSPLASIA, X-LINKED
FLNA, 1,944-BP DEL

In 2 brothers of Hong Kong Chinese origin with cardiac valvular
dysplasia (314400), Kyndt et al. (2007) identified a 1,944-bp genomic
deletion from intron 15 to intron 19 of the FLNA gene, predicting an
in-frame deletion of 182 residues from val761 to gln943 that results in
a truncated protein lacking repeat consensus sequences 5 to 7. The
deletion was not found in 200 control chromosomes, including 100 Asian
chromosomes. In the 12-year-old proband, a heart murmur was detected at
4 months of age, and echocardiography revealed myxomatous thickening of
the mitral, tricuspid, and aortic valves; he had significant mitral and
tricuspid regurgitation and mild aortic regurgitation. His 4-year-old
brother was found to have mitral incompetence and stenosis, tricuspid
regurgitation, and mild aortic regurgitation. Their 38-year-old
asymptomatic carrier mother had mild aortic and pulmonary incompetence
on echocardiography.

.0034
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT
FLNA, TRP2632TER

In an 18-month-old girl with periventricular nodular heterotopia
(300049) and seizures, Jefferies et al. (2010) identified a heterozygous
7896G-A transition in the FLNA gene, resulting in a trp2632-to-ter
(W2632X) substitution. Echocardiogram showed a redundant and
unobstructed pulmonary valve, a cleft in the anterior leaflet of the
mitral valve with mitral regurgitation, and a patent foramen ovale with
mild left-to-right shunting. There was no evidence of a persistent
patent ductus arteriosus. Since there was no family history of the
disorder, the mutation was assumed to have occurred de novo. Jefferies
et al. (2010) noted that other cardiac defects, such as patent ductus
arteriosus, bicuspid aortic valve, and dilation of the sinuses of
Valsalva, had been reported in patients with X-linked periventricular
heterotopia, and that myxomatous valvular disease (XMVD; 314400) was
also associated with FLNA mutations, but emphasized that the findings in
this patient had not previously been reported.

.0035
CONGENITAL SHORT BOWEL SYNDROME, X-LINKED
FLNA, 2-BP DEL, 16TC

In affected members of an Italian family segregating isolated congenital
X-linked short bowel syndrome (see 300048) and in an unrelated singleton
with the disorder, van der Werf et al. (2013) identified a 2-bp deletion
in exon 2 of the FLNA gene (16_17delTC). The family had been reported by
Kern et al. (1990) and the single patient by Siva et al. (2002). In the
family, all obligate carriers were heterozygous for the deletion. The
mother of the isolated case did not carry the deletion, indicating that
it occurred as a de novo event. Van der Werf et al. (2013) stated that
they could not exclude involvement of the central nervous system in
these patients because no magnetic resonance imaging brain scans were
available. This mutation was absent in 92 controls and was not reported
in the Exome Variant Server database. The 16_17delTC mutation is located
between the first and second methionines and results in frameshift and
premature termination at amino acid 103. Based on its location, van der
Werf et al. (2013) predicted that the 16_17delTC mutation has a similar
effect to the 65delAC mutation (300017.0025) reported by Auricchio et
al. (1996) and Gargiulo et al. (2007), which results in loss of only the
long form of FLNA.

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33. Kyndt, F.; Gueffet, J.-P.; Probst, V.; Jaafar, P.; Legendre, A.;
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Newbury-Ecob, R.; Tran, V.; Young, I.; Trochu, J.-N.; Le Marec, H.;
Schott, J.-J.: Mutations in the gene encoding filamin A as a cause
for familial cardiac valvular dystrophy. Circulation 115: 40-49,
2007.

34. Kyndt, F.; Schott, J.-J.; Trochu, J.-N.; Baranger, F.; Herbert,
O.; Scott, V.; Fressinaud, E.; David, A.; Moisan, J.-P.; Bouhour,
J.-B.; Le Marec, H.; Benichou, B.: Mapping of X-linked myxomatous
valvular dystrophy to chromosome Xq28. Am. J. Hum. Genet. 62: 627-632,
1998.

35. Loy, C. J.; Sim, K. S.; Yong, E. L.: Filamin-A fragment localizes
to the nucleus to regulate androgen receptor and coactivator functions. Proc.
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36. Maestrini, E.; Patrosso, C.; Mancini, M.; Rivella, S.; Rocchi,
M.; Repetto, M.; Villa, A.; Frattini, A.; Zoppe, M.; Vezzoni, P.;
Toniolo, D.: Mapping of two genes encoding isoforms of the actin
binding protein ABP-280, a dystrophin like protein, to Xq28 and to
chromosome 7. Hum. Molec. Genet. 2: 761-766, 1993.

37. Maestrini, E.; Rivella, S.; Tribioli, C.; Purtilo, D.; Rocchi,
M.; Archidiacono, N.; Toniolo, D.: Probes for CpG islands on the
distal long arm of the human X chromosome are clustered in Xq24 and
Xq28. Genomics 8: 664-670, 1990.

38. Marino-Enriquez, A.; Lapunzina, P.; Robertson, S. P.; Rodriguez,
J. I.: Otopalatodigital syndrome type 2 in two siblings with a novel
filamin A 629G-T mutation: clinical, pathological, and molecular findings. Am.
J. Med. Genet. 143A: 1120-1125, 2007.

39. Moro, F.; Carrozzo, R.; Veggiotti, P.; Tortorella, G.; Toniolo,
D.; Volzone, A.; Guerrini, R.: Familial periventricular heterotopia:
missense and distal truncating mutations of the FLN1 gene. Neurology 58:
916-921, 2002.

40. Newbury-Ecob, R. A.; Zuccollo, J. M.; Rutter, N.; Young, I. D.
: Sex linked valvular dysplasia. J. Med. Genet. 30: 873-874, 1993.

41. Patrosso, M. C.; Repetto, M.; Villa, A.; Milanesi, L.; Frattini,
A.; Faranda, S.; Mancini, M.; Maestrini, E.; Toniolo, D.; Vezzoni,
P.: The exon-intron organization of the human X-linked gene (FLN1)
encoding actin-binding protein 280. Genomics 21: 71-76, 1994.

42. Robertson, S. P.: Filamin A: phenotypic diversity. Curr. Opin.
Genet. Dev. 15: 301-307, 2005.

43. Robertson, S. P.; Thompson, S.; Morgan, T.; Holder-Espinasse,
M.; Martinot-Duquenoy, V.; Wilkie, A. O. M.; Manouvrier-Hanu, S.:
Postzygotic mutation and germline mosaicism in the otopalatodigital
syndrome spectrum disorders. Europ. J. Hum. Genet. 14: 549-554,
2006.

44. Robertson, S. P.; Twigg, S. R. F.; Sutherland-Smith, A. J.; Biancalana,
V.; Gorlin, R. J.; Horn, D.; Kenwrick, S. J.; Kim, C. A.; Morava,
E.; Newbury-Ecob, R.; Orstavik, K. H.; Quarrell, O. W. J.; Schwartz,
C. E.; Shears, D. J.; Suri, M.; Kendrick-Jones, J.; OPD-spectrum
Disorders Clinical Collaborative Group; Wilkie, A. O. M.: Localized
mutations in the gene encoding the cytoskeletal protein filamin A
cause diverse malformations in humans. Nature Genet. 33: 487-491,
2003.

45. Shapiro, M. B.; Senapathy, P.: RNA splice junctions of different
classes of eukaryotes: sequence statistics and functional implications
in gene expression. Nucleic Acids Res. 15: 7155-7174, 1987.

46. Sheen, V. L.; Dixon, P. H.; Fox, J. W.; Hong, S. E.; Kinton, L.;
Sisodiya, S. M.; Duncan, J. S.; Dubeau, F.; Scheffer, I. E.; Schachter,
S. C.; Wilner, A.; Henchy, R.; and 18 others: Mutations in the
X-linked filamin 1 gene cause periventricular nodular heterotopia
in males as well as in females. Hum. Molec. Genet. 10: 1775-1783,
2001.

47. Sheen, V. L.; Feng, Y.; Graham, D.; Takafuta, T.; Shapiro, S.
S.; Walsh, C. A.: Filamin A and filamin B are co-expressed within
neurons during periods of neuronal migration and can physically interact. Hum.
Molec. Genet. 11: 2845-2854, 2002.

48. Sheen, V. L.; Jansen, A.; Chen, M. H.; Parrini, E.; Morgan, T.;
Ravenscroft, R.; Ganesh, V.; Underwood, T.; Wiley, J.; Leventer, R.;
Vaid, R. R.; Ruiz, D. E.; and 21 others: Filamin A mutations cause
periventricular heterotopia with Ehlers-Danlos syndrome. Neurology 64:
254-262, 2005.

49. Siva, C.; Brasington, R.; Totty, W.; Sotelo, A.; Atkinson, J.
: Synovial lipomatosis (lipoma arborescens) affecting multiple joints
in a patient with congenital short bowel syndrome. J. Rheum. 29:
1088-1092, 2002.

50. Small, K.; Wagener, M.; Warren, S. T.: Isolation and characterization
of the complete mouse emerin gene. Mammalian Genome 8: 337-341,
1997.

51. Stefanova, M.; Meinecke, P.; Gal, A.; Bolz, H.: A novel 9 bp
deletion in the filamin A gene causes an otopalatodigital-spectrum
disorder with a variable, intermediate phenotype. Am. J. Med. Genet. 132A:
386-390, 2005.

52. Sun, Y.; Almomani, R.; Aten, E.; Celli, J.; van der Heijden, J.;
Venselaar, H.; Robertson, S. P.; Baroncini, A.; Franco, B.; Basel-Vanagaite,
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M. H.: Terminal osseous dysplasia is caused by a single recurrent
mutation in the FLNA gene. Am. J. Hum. Genet. 87: 146-153, 2010.

53. Thelin, W. R.; Chen, Y.; Gentzsch, M.; Kreda, S. M.; Sallee, J.
L.; Scarlett, C. O.; Borchers, C. H.; Jacobson, K.; Stutts, M. J.;
Milgram, S. L.: Direct interaction with filamins modulates the stability
and plasma membrane expression of CFTR. J. Clin. Invest. 117: 364-374,
2007.

54. Unger, S.; Mainberger, A.; Spitz, C.; Bahr, A.; Zeschnigk, C.;
Zabel, B.; Superti-Furga, A.; Morris-Rosendahl, D. J.: Filamin A
mutation is one cause of FG syndrome. Am. J. Med. Genet. 143A: 1876-1879,
2007.

55. Vadlamudi, R. K.; Li, F.; Adam, L.; Nguyen, D.; Ohta, Y.; Stossel,
T. P.; Kumar, R.: Filamin is essential in actin cytoskeletal assembly
mediated by p21-activated kinase 1. Nature Cell Biol. 4: 681-690,
2002.

56. van der Werf, C. S.; Sribudiani, Y.; Verheij, J. B. G. M.; Carroll,
M.; O'Loughlin, E.; Chen, C.-H.; Brooks, A. S.; Liszewski, M. K.;
Atkinson, J. P.; Hofstra, R. M. W.: Congenital short bowel syndrome
as the presenting symptom in male patients with FLNA mutations. Genet.
Med. 15: 310-313, 2013.

57. Zenker, M.; Nahrlich, L.; Sticht, H.; Reis, A.; Horn, D.: Genotype-epigenotype-phenotype
correlations in females with frontometaphyseal dysplasia. Am. J.
Med. Genet. 140A: 1069-1073, 2006.

58. Zenker, M.; Rauch, A.; Winterpacht, A.; Tagariello, A.; Kraus,
C.; Rupprecht, T.; Sticht, H.; Reis, A.: A dual phenotype of periventricular
nodular heterotopia and frontometaphyseal dysplasia in one patient
caused by a single FLNA mutation leading to two functionally different
aberrant transcripts. Am. J. Hum. Genet. 74: 731-737, 2004.

*FIELD* CN
Patricia A. Hartz - updated: 07/12/2013
Ada Hamosh - updated: 5/2/2013
Ada Hamosh - updated: 11/21/2011
Cassandra L. Kniffin - updated: 1/5/2011
George E. Tiller - updated: 11/1/2010
Marla J. F. O'Neill - updated: 10/28/2010
Nara Sobreira - updated: 10/22/2010
Cassandra L. Kniffin - updated: 5/19/2009
Cassandra L. Kniffin - updated: 4/17/2009
Paul J. Converse - updated: 7/24/2008
Marla J. F. O'Neill - updated: 2/1/2008
Cassandra L. Kniffin - updated: 5/15/2007
Patricia A. Hartz - updated: 4/23/2007
Victor A. McKusick - updated: 3/27/2007
Marla J. F. O'Neill - updated: 3/15/2007
Victor A. McKusick - updated: 7/5/2006
Victor A. McKusick - updated: 6/9/2006
Cassandra L. Kniffin - updated: 6/2/2006
Marla J. F. O'Neill - updated: 5/11/2006
Paul J. Converse - updated: 4/4/2006
Marla J. F. O'Neill - updated: 12/28/2005
Victor A. McKusick - updated: 5/10/2005
Marla J. F. O'Neill - updated: 3/1/2005
Marla J. F. O'Neill - updated: 1/28/2005
Victor A. McKusick - updated: 4/8/2004
George E. Tiller - updated: 3/31/2004
Victor A. McKusick - updated: 6/5/2003
Victor A. McKusick - updated: 5/16/2003
Victor A. McKusick - updated: 3/19/2003
Cassandra L. Kniffin - updated: 11/8/2002
Patricia A. Hartz - updated: 10/28/2002
George E. Tiller - updated: 1/24/2002
Victor A. McKusick - updated: 12/18/2000
Victor A. McKusick - updated: 4/13/1999

*FIELD* CD
Victor A. McKusick: 7/8/1993

*FIELD* ED
mgross: 07/12/2013
carol: 7/10/2013
alopez: 5/2/2013
carol: 7/17/2012
alopez: 11/28/2011
terry: 11/21/2011
wwang: 4/7/2011
carol: 1/28/2011
wwang: 1/24/2011
ckniffin: 1/5/2011
alopez: 11/5/2010
terry: 11/1/2010
wwang: 10/28/2010
terry: 10/28/2010
carol: 10/27/2010
terry: 10/22/2010
carol: 2/24/2010
carol: 7/28/2009
carol: 7/23/2009
wwang: 5/29/2009
ckniffin: 5/19/2009
wwang: 4/30/2009
ckniffin: 4/17/2009
carol: 1/21/2009
mgross: 8/15/2008
terry: 7/24/2008
carol: 6/10/2008
wwang: 2/7/2008
terry: 2/1/2008
terry: 9/18/2007
wwang: 5/17/2007
ckniffin: 5/15/2007
wwang: 4/23/2007
alopez: 3/28/2007
terry: 3/27/2007
wwang: 3/16/2007
terry: 3/15/2007
terry: 8/24/2006
alopez: 7/10/2006
terry: 7/5/2006
carol: 6/22/2006
alopez: 6/9/2006
wwang: 6/5/2006
ckniffin: 6/2/2006
wwang: 5/11/2006
mgross: 5/11/2006
terry: 4/4/2006
wwang: 12/29/2005
terry: 12/28/2005
wwang: 5/17/2005
wwang: 5/11/2005
terry: 5/10/2005
wwang: 3/7/2005
terry: 3/1/2005
carol: 2/3/2005
terry: 1/28/2005
ckniffin: 10/25/2004
tkritzer: 4/26/2004
tkritzer: 4/16/2004
terry: 4/8/2004
tkritzer: 3/31/2004
tkritzer: 6/19/2003
tkritzer: 6/13/2003
terry: 6/5/2003
tkritzer: 5/27/2003
terry: 5/16/2003
alopez: 4/2/2003
alopez: 3/21/2003
terry: 3/19/2003
mgross: 12/10/2002
carol: 11/13/2002
ckniffin: 11/8/2002
mgross: 10/28/2002
carol: 4/2/2002
cwells: 3/13/2002
cwells: 2/14/2002
cwells: 1/24/2002
mcapotos: 1/18/2001
mcapotos: 1/5/2001
terry: 12/18/2000
alopez: 9/5/2000
terry: 4/14/1999
terry: 4/13/1999
alopez: 12/4/1998
terry: 11/18/1998
dkim: 7/17/1998
mark: 4/10/1997
joanna: 1/31/1996
jason: 6/7/1994
mimadm: 2/27/1994
carol: 8/23/1993
carol: 8/16/1993
carol: 7/13/1993
carol: 7/8/1993

MIM 300048
*RECORD*
*FIELD* NO
300048
*FIELD* TI
#300048 INTESTINAL PSEUDOOBSTRUCTION, NEURONAL, CHRONIC IDIOPATHIC, X-LINKED
;;IPOX;;
read moreCONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION; CIIP;;
CIIP, X-LINKED; CIIPX;;
INTESTINAL PSEUDOOBSTRUCTION, NEURONAL, CHRONIC IDIOPATHIC, WITH CENTRAL
NERVOUS SYSTEM INVOLVEMENT
CONGENITAL SHORT BOWEL SYNDROME, X-LINKED, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder can be caused by mutation or duplication in the gene encoding
filamin A (FLNA; 300017).

DESCRIPTION

Chronic idiopathic intestinal pseudoobstruction (CIIP) is caused by
severe abnormality of gastrointestinal motility. Patients have recurrent
symptoms and signs of intestinal obstruction without any mechanical
lesion (Auricchio et al., 1996).

Some primary forms of CIIP are caused by defects of enteric neuronal
cells: see Hirschsprung disease (see, e.g., HSCR1; 142623) and autosomal
recessive visceral neuropathy (243180) (Tanner et al., 1976).

CLINICAL FEATURES

FitzPatrick et al. (1997) reported 2 brothers and a maternal uncle with
CIIP. All 3 had a patent duct arteriosus (see 607411), an association
which FitzPatrick et al. (1997) pointed out had been reported by Harris
et al. (1976). The 2 brothers had chronic thrombocytopenia with large
platelets which, again, FitzPatrick et al. (1997) reported was described
by Pollock et al. (1991) in association with CIIP. The 2 brothers had
mild facial dysmorphism. One of the brothers and maternal uncle had gut
malrotation, which FitzPatrick et al. (1997) noted was present in the
cases described by Harris et al. (1976), Pollock et al. (1991), and in
some members of the Italian family described by Auricchio et al. (1996).
FitzPatrick et al. (1997) suggested that gut malrotation may be a useful
phenotypic marker for an X-linked form of CIIP. FitzPatrick et al.
(1997) concluded that the additional clinical features in this family
may be the result of an Xq28 microdeletion, or that the CIIPX gene may
have a role in developmental regulation of multiple systems, with
different mutations causing a different spectrum of abnormalities.

Gargiulo et al. (2007) described an affected male in the Italian family
with X-linked chronic idiopathic intestinal pseudoobstruction reported
by Auricchio et al. (1996). The patient presented at 3 days of life with
bilious vomiting, and laparotomy showed a short small bowel with
intestinal malrotation, pyloric hypertrophy, and an ileal volvulus.
Fifteen days later, he required additional surgery for intestinal
obstruction, and an ileostomy was created. Other surgical procedures
were required including an ileorectal anastomosis to restore bowel
continuity at age 3 years. In addition to the severe CIIP, by age 7
years, an asymmetric spastic diplegia with impairment of fine finger
movements became apparent. MRI of the brain showed an abnormal
intermediate signal in the peritrigonal white matter. The patient
required lengthening operations for both Achilles tendons. He also had
seizures, the first time after surgery during his first month of life,
then again at ages 8 and 18 years. He required supplemental parenteral
nutrition to maintain good health. Of the 10 affected males in 4
generations in this family, all except this patient died in the first
months of life.

- Congenital Short Bowel Syndrome

Kern et al. (1990) reported a nonconsanguineous Italian family in which
3 male sibs were born with a short small bowel, malrotation, and
functional bowel obstruction. One child was a long-term survivor. Two of
the sibs presented with bilious vomiting at 1 month and 6 days of age,
respectively; the latter sib passed frank blood rectally. Both had
midgut volvulus. Length of the small intestine in the first sib was 112
cm from the ligament of Trietz to the ileocecal valve. The second sib
required resection of a 15-cm necrotic segment of jejunum, after which
the remaining small bowel measured only 55 cm from the ligament of
Trietz to the ileocecal valve. Both of these sibs died in infancy. The
third sib was the second male child of the couple. He presented at 3
months of age with failure to thrive, but had a formula change and did
well. Following the birth of his younger brother he was reinvestigated
and found to have a malrotation, for which the parents refused surgical
treatment. At age 14 he had developed partial duodenal and jejunal
obstruction. At laparotomy, the small intestine was found to be short
(235 cm from ligament of Trietz to the ileocecal valve), dilated, and
thick-walled. After Ladd's procedure and a second laparotomy, the
patient was well for the subsequent 3 years.

Siva et al. (2002) reported a 35-year-old male with synovial lipomatosis
and congenital short bowel syndrome. At 15 years of age the length of
his small intestine was found to be 90 inches, about one-third of
normal. At more than 40 years of age, the patient was doing well and the
arthropathy had resolved spontaneously (van der Werf et al., 2013).

CYTOGENETICS

Clayton-Smith et al. (2009) reported 20 males from 10 families with
intestinal pseudoobstruction associated with duplications of chromosome
Xq28 including the FLNA gene. The duplication was restricted to the FLNA
gene alone in 2 families, including the family reported by FitzPatrick
et al. (1997). The phenotype in these patients was restricted to
intestinal pseudoobstruction, patent ductus arteriosus, and
thrombocytopenia with giant platelets. None of these patients had mental
retardation, spasticity, or chest infections, although some had mild
facial dysmorphism. The Xq28 duplication was larger in the remaining 8
families reported by Clayton-Smith et al.(2009), and may have included
the MECP2 (300005), SLC6A8 (300036), L1CAM (308840) genes in addition to
FLNA, although detailed mapping was not reported. The phenotype in all
patients with larger Xq28 duplications included pseudoobstruction with
severe constipation from infancy and clearly dysmorphic facies. Other
common but variable features included recurrent chest infections, mental
retardation, some evidence of periventricular nodular heterotopia or
abnormalities of the corpus callosum, hypotonia, and spasticity. Many of
these features overlapped with that of the MECP2 duplication syndrome
(300260). Clayton-Smith et al. (2009) also commented on a facial
phenotype associated with Xq28 duplications: a narrow pinched appearance
of the nose, deep-set eyes, prominent chin, small everted lower lip, and
flat nasal bridge. The authors concluded that involvement of the FLNA
gene was responsible for intestinal pseudoobstruction in these patients.

MAPPING

Auricchio et al. (1996) described a family in which the disorder
appeared to be segregating as an X-linked recessive trait and in which
they were able to map the disease locus (symbolized CIIPX by them) to
Xq28. The microsatellite marker DXYS154, located in the distal part of
Xq28, showed no recombination with a maximum lod score of 2.32.
Multipoint analysis excluded linkage with markers spanning other regions
of the X chromosome. On the basis of analysis of recombinants, Auricchio
et al. (1996) concluded that the critical region for the disease gene is
limited by DXS15 toward the centromere and by the pseudoautosomal
boundary toward the telomere. Auricchio et al. (1996) raised the
intriguing hypothesis that CIIPX may represent an additional
susceptibility locus in Hirschsprung disease (142623). (Hirschsprung
disease is the most common form of neuronal intestinal
pseudoobstruction.) A higher penetrance of Hirschsprung disease has been
observed in males compared to females in the case of both RET (164761)
and EDNRB (131244) mutations (Badner et al., 1990).

In the family reported by them with CIIP, FitzPatrick et al. (1997)
demonstrated cosegregation of a maternal grandmaternal Xq28 haplotype
with the disease by DNA analysis of the brothers, their unaffected
mother, and maternal grandmother using markers DXS1108, DXS15, F8C, and
DXYS154.

MOLECULAR GENETICS

To select candidate genes for the CIIP in the Italian family of
Auricchio et al. (1996), Gargiulo et al. (2007) analyzed the expression
in murine fetal brain and intestine of 56 genes from the critical
region. They selected and sequenced 7 genes and found that 1 affected
male from the Italian kindred bore a 2-bp deletion in exon 2 of the FLNA
gene that was present in heterozygous state in the carrier females of
the family (300017.0025).

Because X-linked dominant nodular ventricular heterotopia (PVNH;
300049), a central nervous system migration defect that presents with
seizures in females and lethality in males, has been associated with
loss-of-function FLNA mutations, Gargiulo et al. (2007) considered it
notable that the male bearing the FLNA mutation had signs of central
nervous system (CNS) involvement and possibly PVNH. They noted that,
different from the male with PVNH and constipation described by Hehr et
al. (2006) (see 300017.0024), the phenotype in the family originally
described by Auricchio et al. (1996) was most distinguished by severe
CIIP, present at birth, that was lethal unless promptly corrected by
surgery.

- Congenital Short Bowel Syndrome

Van der Werf et al. (2013) reported that the sibs reported by Kern et
al. (1990) and the unrelated singleton reported by Siva et al. (2002)
with X-linked congenital short bowel syndrome all had the same
2-basepair deletion in FLNA (300017.0035). In the family, all obligate
carriers were heterozygous for the mutation; in the isolated male, the
mutation had occurred as a de novo event. Van der Werf et al. (2013)
stated that they could not exclude involvement of the central nervous
system in these patients because no magnetic resonance imaging brain
scans were available.

*FIELD* RF
1. Auricchio, A.; Brancolini, V.; Casari, G.; Milla, P. J.; Smith,
V. V.; Devoto, M.; Ballabio, A.: The locus for a novel syndromic
form of neuronal intestinal pseudoobstruction maps to Xq28. Am. J.
Hum. Genet. 58: 743-748, 1996.

2. Badner, J. A.; Sieber, W. K.; Garver, K. L.; Chakravarti, A.:
A genetic study of Hirschsprung disease. Am. J. Hum. Genet. 46:
568-580, 1990.

3. Clayton-Smith, J.; Walters, S.; Hobson, E.; Burkitt-Wright, E.;
Smith, R.; Toutain, A.; Amiel, J.; Lyonnet, S.; Mansour, S.; Fitzpatrick,
D.; Ciccone, R.; Ricca, I.; Zuffardi, O.; Donnai, D.: Xq28 duplication
presenting with intestinal and bladder dysfunction and a distinctive
facial appearance. Europ. J. Hum. Genet. 17: 434-443, 2009.

4. FitzPatrick, D. R.; Strain, L.; Thomas, A. E.; Barr, D. G. D.;
Todd, A.; Smith, N. M.; Scobie, W. G.: Neurogenic chronic idiopathic
intestinal pseudo-obstruction, patent ductus arteriosus, and thrombocytopenia
segregating as an X linked recessive disorder. J. Med. Genet. 34:
666-669, 1997.

5. Gargiulo, A.; Auricchio, R.; Barone, M. V.; Cotugno, G.; Reardon,
W.; Milla, P. J.; Ballabio, A.; Ciccodicola, A.; Auricchio, A.: Filamin
A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction
with central nervous system involvement. Am. J. Hum. Genet. 80:
751-758, 2007.

6. Harris, D. J.; Ashcraft, K. W.; Beatty, E. C.; Holder, T. M.; Leonidas,
J. C.: Natal teeth, patent ductus arteriosus and intestinal pseudo-obstruction:
a lethal syndrome in the newborn. Clin. Genet. 9: 479-482, 1976.

7. Hehr, U.; Hehr, A.; Uyanik, G.; Phelan, E.; Winkler, J.; Reardon,
W.: A filamin A splice mutation resulting in a syndrome of facial
dysmorphism, periventricular nodular heterotopia, and severe constipation
reminiscent of cerebro-fronto-facial syndrome. (Letter) J. Med. Genet. 43:
541-544, 2006.

8. Kern, I. B.; Leece, A.; Bohane, T.: Congenital short gut, malrotation,
and dysmotility of the small bowel. J. Pediat. Gastroent. Nutr. 11:
411-415, 1990.

9. Pollock, I.; Holmes, S. J. K.; Patton, M. A.; Hamilton, P. A.;
Stacey, T. E.: Congenital intestinal pseudo-obstruction associated
with a giant platelet disorder. J. Med. Genet. 28: 495-496, 1991.

10. Siva, C.; Brasington, R.; Totty, W.; Sotelo, A.; Atkinson, J.
: Synovial lipomatosis (lipoma arborescens) affecting multiple joints
in a patient with congenital short bowel syndrome. J. Rheum. 29:
1088-1092, 2002.

11. Tanner, M. S.; Smith, B.; Lloyd, J. K.: Functional intestinal
obstruction due to deficiency of argyrophil neurones in the myenteric
plexus: familial syndrome presenting with short small bowel, malrotation,
and pyloric hypertrophy. Arch. Dis. Child. 51: 837-841, 1976.

12. van der Werf, C. S.; Sribudiani, Y.; Verheij, J. B. G. M.; Carroll,
M.; O'Loughlin, E.; Chen, C.-H.; Brooks, A. S.; Liszewski, M. K.;
Atkinson, J. P.; Hofstra, R. M. W.: Congenital short bowel syndrome
as the presenting symptom in male patients with FLNA mutations. Genet.
Med. 15: 310-313, 2013.

*FIELD* CS
INHERITANCE:
X-linked recessive

HEAD AND NECK:
[Face];
Facial dysmorphism, mild;
Smooth philtrum;
Large jaw;
[Ears];
Low-set ears;
[Eyes];
Hypertelorism;
Downslanting palpebral fissures

CARDIOVASCULAR:
[Vascular];
Patent ductus arteriosus

ABDOMEN:
[External features];
Abdominal distention;
[Gastrointestinal];
Poor feeding;
Vomiting;
Intestinal pseudoobstruction, chronic;
Abnormal gastrointestinal motility;
Abnormal argyrophilic neurons in the myenteric and submucosal plexuses;
No mechanical intestinal obstructive lesion;
Short bowel (in some patients);
Gut malrotation;
Pyloric stenosis (1 patient)

GENITOURINARY:
[Kidneys];
Hydronephrosis (1 patient)

NEUROLOGIC:
[Central nervous system];
Spastic diplegia (1 patient);
Seizures (1 patient)

HEMATOLOGY:
Thrombocytopenia;
Large platelets

MISCELLANEOUS:
Onset in infancy;
Mild facial dysmorphism is associated with duplication of the FLNA
gene

MOLECULAR BASIS:
Caused by mutation in the filamin A gene (FLNA, 300017.0025)

*FIELD* CN
Ada Hamosh - updated: 05/01/2013
Cassandra L. Kniffin - revised: 4/17/2009

*FIELD* CD
John F. Jackson: 10/8/1998

*FIELD* ED
joanna: 05/01/2013
joanna: 1/6/2010
ckniffin: 4/17/2009
alopez: 3/28/2007

*FIELD* CN
Ada Hamosh - updated: 5/2/2013
Cassandra L. Kniffin - updated: 4/17/2009
Victor A. McKusick - updated: 3/27/2007
Victor A. McKusick - updated: 12/1/2004
Michael J. Wright - updated: 2/11/1998

*FIELD* CD
VIctor A. McKusick: 4/25/1996

*FIELD* ED
carol: 07/09/2013
alopez: 5/2/2013
wwang: 4/30/2009
ckniffin: 4/17/2009
alopez: 3/28/2007
terry: 3/27/2007
tkritzer: 12/8/2004
terry: 12/1/2004
joanna: 3/18/2004
mgross: 12/10/2002
dholmes: 3/9/1998
alopez: 2/18/1998
terry: 2/11/1998
terry: 5/2/1996
mark: 4/29/1996
mark: 4/25/1996

MIM 300049
*RECORD*
*FIELD* NO
300049
*FIELD* TI
#300049 HETEROTOPIA, PERIVENTRICULAR, X-LINKED DOMINANT
;;HETEROTOPIA, FAMILIAL NODULAR;;
read morePERIVENTRICULAR NODULAR HETEROTOPIA 1; PVNH1;;
NODULAR HETEROTOPIA, BILATERAL PERIVENTRICULAR; NHBP; BPNH
HETEROTOPIA, PERIVENTRICULAR NODULAR, WITH FRONTOMETAPHYSEAL DYSPLASIA,
INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because X-linked
periventricular heterotopia (PVNH) is caused by heterozygous mutation in
the gene encoding filamin-A (FLNA; 300017), which maps to chromosome
Xq28.

DESCRIPTION

Periventricular nodular heterotopia is a disorder of neuronal migration
in which neurons fail to migrate appropriately from the ventricular zone
to the cortex during development, resulting in the formation of nodular
brain tissue lining the ventricles. Most affected individuals with the
X-linked form are female, while hemizygous males tend to die in utero.
Affected females usually present with epilepsy, but have normal
intelligence. Additional features include defects of the cardiovascular
system, such as patent ductus arteriosus, bicuspid aortic valve, and
dilation of the sinuses of Valsalva or the thoracic aorta (summary by
Fox et al., 1998).

- Genetic Heterogeneity of Periventricular Nodular Heterotopia

Periventricular nodular heterotopia is a genetically heterogeneous
condition: see also PVNH2 (608097), caused by mutation in the ARFGEF2
gene (605371) on chromosome 20q13; PVNH3 (608098), associated with
anomalies of 5p; PVNH4 (300537), also caused by FLNA mutations and
associated with Ehlers-Danlos syndrome; PVNH5 (612881), associated with
deletions of chromosome 5q; and PVNH6 (615544), caused by mutation in
the ERMARD gene (615532) on chromosome 6q27.

CLINICAL FEATURES

Kamuro and Tenokuchi (1993) described periventricular heterotopic
nodules in a 13-year-old girl, her 34-year-old mother, and her
60-year-old grandmother. The mother had suffered from epileptic seizures
since she was 15 years old, but the daughter and grandmother were
seizure-free. All 3 showed multiple uncalcified nodules on the lateral
ventricular walls on CT. On magnetic resonance imaging (MRI), the
intensity of the nodules were the same as that of the cerebral gray
matter, suggesting heterotopia, and no other cerebral abnormalities were
observed. Extensive examinations failed to show signs of tuberous
sclerosis (191100). Kamuro and Tenokuchi (1993) suggested that
periventricular nodular heterotopia in this family represented a unique
form of migration disorder inherited as a dominant. In a Japanese
family, Oda et al. (1993) described a mother and 2 daughters, half
sisters, in whom MRI demonstrated multiple bilateral subependymal
nodules that were of the same intensity as gray matter. The mother and
the younger of the 2 sisters had seizures. None of the patients showed
signs of tuberous sclerosis.

The confusion of bilateral periventricular nodular heterotopia with
tuberous sclerosis (191000; 191092) was indicated by the cases reported
by Jardine et al. (1996). Tuberous sclerosis was the initial diagnosis
in a mother and daughter. The daughter presented with partial seizures
at the age of 8 months. CT showed uncalcified periventricular nodules,
which on MRI were ovoid, almost contiguous, of gray matter density, and
did not enhance with gadolinium. Brain imaging of the asymptomatic
mother yielded similar results. Absence of severe mental retardation,
extracranial hamartomas, and depigmented patches distinguishes familial
bilateral periventricular nodular heterotopia from tuberous sclerosis.
Jardine et al. (1996) used the symbol FNH for this disorder and
suggested that it is inherited as an X-linked dominant with lethality in
males. This was based on the fact that 16 females from 5 families had
been reported. Partial and secondary generalized seizures were the most
common presenting feature, although some affected adults were seizure
free. Seizures starting in infancy had not been reported before the
report by Jardine et al. (1996).

Eksioglu et al. (1996) discussed the genetics and biology of this
disorder, which can be diagnosed unambiguously on MRI. The lesions form
continuous bands throughout the periventricular region, and may appear
as beads on a string. Histologic studies revealed that the nodules
consist of highly differentiated neurons oriented in multiple directions
that have failed to migrate into the developing cerebral cortex.
Remarkably, most females with the disorder show normal intelligence but
suffer from seizures and various extra-CNS manifestations, especially
relating to the vascular system.

Puche et al. (1998) identified a family in which the mother had from
epilepsy and the oldest daughter had epilepsy and mental retardation.
Both patients showed subcortical laminar heterotopia on MRI. The
youngest son presented a severe encephalopathy with early-onset
seizures, and was found to have lissencephaly on MRI.

Using PET and fMRI imaging to study a woman with genetically confirmed
PVNH1, Lange et al. (2004) found that the ectopic nodular
periventricular cortical tissue was functionally active and integrated
into motor circuits.

Jefferies et al. (2010) reported an 18-month-old girl with
periventricular nodular heterotopia who also had mild cardiac defects.
Echocardiogram showed a redundant and unobstructed pulmonary valve, a
cleft in the anterior leaflet of the mitral valve with mitral
regurgitation, and a patent foramen ovale with mild left-to-right
shunting. There was no evidence of a persistent patent ductus
arteriosus. Genetic analysis identified a heterozygous truncating
mutation in the FLNA gene (W2632X; 300017.0034). Jefferies et al. (2010)
noted that other cardiac defects, such as patent ductus arteriosus,
bicuspid aortic valve, and dilation of the sinuses of Valsalva, had been
reported in patients with X-linked periventricular heterotopia, and that
myxomatous valvular disease (XMVD; 314400) was also associated with FLNA
mutations, but emphasized that the findings in this patient had not
previously been reported.

- Periventricular Nodular Heterotopia With Frontometaphyseal
Dysplasia

In a girl with PVNH in combination with frontometaphyseal dysplasia
(304120), a skeletal dysplasia of the otopalatodigital (OPD) spectrum,
Zenker et al. (2004) identified a de novo 7315C-A transversion in exon
45 of the FLNA gene (300017.0014), resulting in 2 aberrant transcripts.
Zenker et al. (2004) proposed that the dual phenotype was caused by 2
functionally different, aberrant filamin A proteins and therefore
represented an exceptional case of allelic gain-of-function and
loss-of-function phenotypes due to a single mutation event.

- Affected Males

Most patients with bilateral periventricular nodular heterotopia (BPNH)
are female and have epilepsy as a sole clinical manifestation of their
disease. Males with PVNH are rare and may present with mental
retardation and congenital anomalies in addition to epilepsy. The
disorder in 3 boys with PVNH, cerebellar hypoplasia, severe mental
retardation, epilepsy, and syndactyly was designated the BPNH/MR
syndrome (Fink et al., 1997).

Guerrini and Dobyns (1998) described a 'new' syndrome of BPNH with
frontonasal malformation and mild mental retardation in 2 unrelated
boys, aged 8 and 5.5 years. Both had a broad nasal root, hypertelorism,
and a widow's peak. The 5.5-year-old patient had several additional
features of Aarskog syndrome (100050), including shawl scrotum and
cryptorchidism. The combination of widow's peak and shawl scrotum has
also been reported in autosomal dominant Teebi hypertelorism (145420),
autosomal recessive Aarskog-like faciodigitogenital syndrome (227330),
and X-linked Aarskog-Scott syndrome (305400). Mild mental retardation is
infrequently found in frontonasal dysplasia (136760), as is micropenis,
which was present in the 5.5-year-old patient of Guerrini and Dobyns
(1998). In addition to their novel BPNH/frontonasal dysplasia syndrome
and the previously reported BPNH/MR syndrome, Guerrini and Dobyns (1998)
referred to the association of BPNH with congenital nephrosis (251300),
with short gut and intestinal malrotation (Nezelof et al., 1976), and
with agenesis of the corpus callosum (Vles et al., 1990, 1993).

Guerrini et al. (2004) reported 4 families in which males were affected
by PVNH caused by FLN1 mutations. In 2 families, missense mutations
causing mild phenotypes were transmitted from a mother to son and from a
father to daughter, respectively. Both mutations occurred in
nonconserved residues. One patient was a 3-year-old boy with mildly
delayed milestones, bilateral nodules, cerebellar hypoplasia, and patent
ductus arteriosus. In the second family, the proband was a 49-year-old
Japanese man with normal cognition who developed seizures at age 38
years. Brain MRI showed an isolated unilateral nodule, and
cardiovascular examination showed aortic insufficiency. Interestingly,
his affected daughter had a more severe phenotype. In a third family, an
affected man was somatic mosaic for the FLN1 mutation, and in a fourth
family, a truncating mutation led to early postnatal death in a boy. The
man with somatic mosaicism had borderline cognition, bilateral nodules,
seizures and aortic aneurysm; he did not transmit the mutation to his
daughter. The findings indicated that PVNH in men caused by FLN1
mutations can occur with variable severity and results from different
genetic mechanisms.

INHERITANCE

X-linked periventricular heterotopia is inherited in an X-linked
dominant pattern. Eksioglu et al. (1996) noted that in all 4 pedigrees
they studied, the disorder was inherited as a dominant trait with full
penetrance in females. The male offspring of affected females were
normal, but there was a shortage of male offspring and an excess of
spontaneous abortions, suggesting that males with the hemizygous
mutation die during early embryogenesis (Eksioglu et al., 1996).

Jardine et al. (1996) noted that there was a high frequency of
spontaneous abortions in a family reported by Huttenlocher et al.
(1994), which was compatible with X-linked dominant inheritance with
lethality in males.

Sporadic nodular heterotopia has also been described (Raymond et al.,
1994), but the sporadic form was distinguished from the presumably
X-linked form by occurrence in males, later seizure onset, and fewer
nodules.

- Somatic Mosaicism

Parrini et al. (2004) reported 2 unrelated mildly affected PVNH patients
with somatic mosaicism for mutations in the FLNA gene. The first
individual was a 28-year-old woman with no family history of neurologic
disorders who had generalized seizures since age 14 years and thin
noncontiguous heterotopic nodules on MRI. Heart ultrasonography and
clotting studies were normal. Mutation analysis identified a mutation in
the FLNA gene that was present in approximately 17% of her DNA. The
patient's daughter did not carry the mutation. The second individual was
a 49-year-old man with no family history of neurologic disorders. At age
15 years, he developed complex partial seizures with secondary
generalization that were resistant to treatment. A brain MRI prior to
surgery for an aortic aneurysm showed classical bilateral PVNH and
cerebellar hypoplasia. Cognitive level was borderline. Mutation analysis
identified a mutation in the FLNA gene that was present in 42% of
blood-derived DNA and 69% of hair-derived DNA. The patient's unaffected
daughter did not inherit the mutation. Parrini et al. (2004) noted that
somatic mosaicism has been reported in patients with neuronal migration
disorders due to mutations in the DCX (300121) and LIS1 (601545) genes,
and concluded that the mild phenotypes in these 2 cases and the
phenotypic heterogeneity of PVNH in general resulted from somatic
mosaicism.

MAPPING

Walsh et al. (1995) mapped familial nodular heterotopia to Xq28 by
linkage analysis in one family. Since the L1CAM gene (308840), a neural
cell adhesion molecule, is located in the same region, Jardine et al.
(1996) suggested that it is a candidate gene for nodular heterotopia.
Eksioglu et al. (1996) reported that NHBP is closely linked to markers
in distal Xq28; the maximum 2-point lod score was 4.7 at theta = 0
between NHBP and F8C (300841). NHBP maps to a physical region
encompassing 7 Mb on Xq28. Eksioglu et al. (1996) noted that candidate
genes within this region include L1CAM and the alpha-3 subunit of the
gamma-aminobutyric acid receptor (305660).

Fink et al. (1997) reported that high-resolution chromosomal analysis
revealed a subtle abnormality of Xq28 in 1 of 3 boys with BPNH/MR
syndrome. Fluorescence in situ hybridization (FISH) with cosmids and
YACs from Xq28 further characterized this abnormality as a 2.25- to
3.25-Mb inverted duplication. No abnormality of Xq28 was detected by
G-binding or FISH in the other 2 boys. These data supported the linkage
assignment of BPNH to Xq28 and narrowed the critical region to the
distal 2.25 to 3.25 Mb of Xq28. A gene-dosage model for BPHN/MR is
supported by observations in boys with the X-Y(Xq) syndrome (Lahn et
al., 1994). The X-Y(Xq) syndrome results from aberrant meiotic exchange
between Xq and Yq in the fathers, which produces translocation of a
portion of distal Xq28 to the Y chromosome inherited by each boy. In 3
of 8 boys with the X-Y(Xq) syndrome, Lahn et al. (1994) found a large
duplication of the distal 4 Mb of Xq28, including all of the loci
duplicated in the BPNH patient. Fink et al. (1997) noted that the 2
syndromes share many clinical manifestations, including severe mental
retardation, microcephaly, aphasia, seizures, hypotonia, and short
stature, but they noted that no syndactyly or BPNH was described in the
boys reported by Lahn et al. (1994).

MOLECULAR GENETICS

In patients with X-linked periventricular nodular heterotopia, Fox et
al. (1998) identified heterozygous mutations in the FLNA gene
(300017.0001-300017.00015). The FLNA encodes an actin-crosslinking
phosphoprotein that transduces ligand-receptor binding into actin
reorganization, and which is required for locomotion of many cell types.
Fox et al. (1998) demonstrated a previously unrecognized high level of
expression of FLN1 in the developing cortex. The findings indicated that
FLN1 is required for neuronal migration to the cortex. The lethality of
the mutant in males suggested that it is essential for embryogenesis and
has a function in developing nonneural tissues.

Hehr et al. (2006) reported a boy with periventricular nodular
heterotopia, craniofacial features, and severe constipation who carried
a mutation in the FLNA gene (300017.0024). Hehr et al. (2006) noted that
the initial working diagnosis made in this subject was that of
cerebrofrontofacial syndrome (see 608578), and remarked that the
patient's unique clinical phenotype overlapped in many respects 'the
rather ill-defined condition of cerebro-fronto-facial syndrome, of which
condition our case may well be an example.' Unger et al. (2007)
suggested that the patient reported by Hehr et al. (2006) may have had
FG syndrome-2 (FGS2; 300321), given his constipation and dysmorphic
facial features. Unger et al. (2007) identified a FLNA mutation
(300017.0028) in a patient with FGS2.

GENOTYPE/PHENOTYPE CORRELATIONS

After mutations in FLN1 were identified in periventricular heterotopia,
Fox et al. (1998) reviewed clinical histories of cases and discovered a
number of additional congenital anomalies common to patients with FLN1
mutations. For example, 3 of 11 affected females (showing 3 distinct
mutations) were born with patent ductus arteriosus requiring surgical
correction. In addition, 3 of 11 females with periventricular
heterotopia suffered strokes at young ages, whereas unaffected females
in the same pedigree showed none. One affected female and the male
carrying the Xq28 duplication had shortened digits, with the male also
showing syndactyly and clinodactyly. Other CNS malformations included
decreased size of the corpus callosum and a cerebellar anomaly described
as an enlarged cisterna magna or cerebellar cyst, but may represent
cerebellar hypoplasia. A high incidence of patent ductus arteriosus was
found in other patients in whom FLN1 mutations had not yet been
determined. In the pedigree reported by Huttenlocher et al. (1994), a
male offspring of an affected female who carried the disease-linked
haplotype was born alive but died from severe systemic bleeding and
organ failure 3 days later. On postmortem examination, there was severe
arrest of myeloid and erythroid differentiation in bone marrow and
lymphoid depletion of the thymus.

Moro et al. (2002) reported 7 affected females from 2 families with BPNH
segregating 2 novel mutations in the FLN1 gene. Affected females in both
families showed the classic clinical phenotype with mild mental
retardation and epilepsy. However, affected females in the family
harboring a partially functional missense mutation (300017.0008) showed
a milder anatomic phenotype with few asymmetric, noncontiguous nodules
on MRI, and gave birth to 5 presumably affected boys who died within a
few days to several weeks or months of life. Family 2 harbored a small
deletion leading to complete inactivation of the protein. Moro et al.
(2002) noted that differences in the severity of the ventricular
heterotopia do not strictly correspond to variations in overall clinical
expression of the disorder.

*FIELD* RF
1. Eksioglu, Y. Z.; Scheffer, I. E.; Cardenas, P.; Knoll, J.; DiMario,
F.; Ramsby, G.; Berg, M.; Kamuro, K.; Berkovic, S. F.; Duyk, G. M.;
Parisi, J.; Huttenlocher, P. R.; Walsh, C. A.: Periventricular heterotopia:
an X-linked dominant epilepsy locus causing aberrant cerebral cortical
development. Neuron 16: 77-87, 1996.

2. Fink, J. M.; Dobyns, W. B.; Guerrini, R.; Hirsch, B. A.: Identification
of a duplication of Xq28 associated with bilateral periventricular
nodular heterotopia. Am. J. Hum. Genet. 61: 379-387, 1997.

3. Fox, J. W.; Lamperti, E. D.; Eksioglu, Y. Z.; Hong, S. E.; Feng,
Y.; Graham, D. A.; Scheffer, I. E.; Dobyns, W. B.; Hirsch, B. A.;
Radtke, R. A.; Berkovic, S. F.; Huttenlocher, P. R.; Walsh, C. A.
: Mutations in filamin 1 prevent migration of cerebral cortical neurons
in human periventricular heterotopia. Neuron 21: 1315-1325, 1998.

4. Guerrini, R.; Dobyns, W. B.: Bilateral periventricular nodular
heterotopia with mental retardation and frontonasal malformation. Neurology 51:
499-503, 1998.

5. Guerrini, R.; Mei, D.; Sisodiya, S.; Sicca, F.; Harding, B.; Takahashi,
Y.; Dorn, T.; Yoshida, A.; Campistol, J.; Kramer, G.; Moro, F.; Dobyns,
W. B.; Parrini, E.: Germline and mosaic mutations of FLN1 in men
with periventricular heterotopia. Neurology 63: 51-56, 2004.

6. Hehr, U.; Hehr, A.; Uyanik, G.; Phelan, E.; Winkler, J.; Reardon,
W.: A filamin A splice mutation resulting in a syndrome of facial
dysmorphism, periventricular nodular heterotopia, and severe constipation
reminiscent of cerebro-fronto-facial syndrome. (Letter) J. Med.
Genet. 43: 541-544, 2006.

7. Huttenlocher, P. R.; Taravath, S.; Mojtahedi, S.: Periventricular
heterotopia and epilepsy. Neurology 44: 51-55, 1994.

8. Jardine, P. E.; Clarke, M. A.; Super, M.: Familial bilateral periventricular
nodular heterotopia mimics tuberous sclerosis. Arch. Dis. Child. 74:
244-246, 1996.

9. Jefferies, J. L.; Taylor, M. D.; Rossano, J.; Belmont, J. W.; Craigen,
W. J.: Novel cardiac findings in periventricular nodular heterotopia. Am.
J. Med. Genet. 152A: 165-168, 2010.

10. Kamuro, K.; Tenokuchi, Y.: Familial periventricular nodular heterotopia. Brain
Dev. 15: 237-241, 1993.

11. Lahn, B. T.; Ma, N.; Breg, W. R.; Stratton, R.; Surti, U.; Page,
D. C.: Xq-Yq interchange resulting in supernormal X-linked gene expression
in severely retarded males with 46,XYq-karyotype. Nature Genet. 8:
243-250, 1994.

12. Lange, M.; Winner, B.; Muller, J. L.; Marienhagen, J.; Schroder,
M.; Aigner, L.; Uyanik, G.; Winkler, J.: Functional imaging in PNH
caused by a new filamin A mutation. Neurology 62: 151-152, 2004.

13. Moro, F.; Carrozzo, R.; Veggiotti, P.; Tortorella, G.; Toniolo,
D.; Volzone, A.; Guerrini, R.: Familial periventricular heterotopia:
missense and distal truncating mutations of the FLN1 gene. Neurology 58:
916-921, 2002.

14. Nezelof, C.; Jaubert, F.; Lyon, G.: Familial syndrome combining
short small intestine, intestinal malrotation, pyloric hypertrophy
and brain malformation. 3 anatomoclinical case reports. Ann. Anat.
Path. (Paris) 21: 401-412, 1976.

15. Oda, T.; Nagai, Y.; Fujimoto, S.; Sobajima, H.; Kobayashi, M.;
Togari, H.; Wada, Y.: Hereditary nodular heterotopia accompanied
by mega cisterna magna. Am. J. Med. Genet. 47: 268-271, 1993.

16. Parrini, E.; Mei, D.; Wright, M.; Dorn, T.; Guerrini, R.: Mosaic
mutations of the FLN1 gene cause a mild phenotype in patients with
periventricular heterotopia. Neurogenetics 5: 191-196, 2004.

17. Puche, A.; Rodriguez, T.; Domingo, R.; Casas, C.; Vicente, T.;
Martinez-Lage, J. F.: X-linked subcortical laminar heterotopia and
lissencephaly: a new family. Neuropediatrics 29: 276-278, 1998.

18. Raymond, A. A.; Fish, D. R.; Stevens, J. M.; Sisodiya, S. M.;
Alsanjari, N.; Shorvon, S. D.: Subependymal heterotopia: a distinct
neuronal migration disorder associated with epilepsy. J. Neurol.
Neurosurg. Psychiat. 57: 1195-1202, 1994.

19. Unger, S.; Mainberger, A.; Spitz, C.; Bahr, A.; Zeschnigk, C.;
Zabel, B.; Superti-Furga, A.; Morris-Rosendahl, D. J.: Filamin A
mutation is one cause of FG syndrome. Am. J. Med. Genet. 143A: 1876-1879,
2007.

20. Vles, J. S.; de Die-Smulders, C.; van der Hoeven, M.; Fryns, J.
P.: Corpus callosum agenesis in two male infants of a heterozygotic
triplet pregnancy. Genet. Counsel. 4: 239-240, 1993.

21. Vles, J. S.; Fryns, J. P.; Folmer, K.; Boon, P.; Buttiens, M.;
Grubben, C.; Janevski, B.: Corpus callosum agenesis, spastic quadriparesis
and irregular lining of the lateral ventricles on CT-scan. A distinct
X-linked mental retardation syndrome? Genet. Counsel. 1: 97-102,
1990.

22. Walsh, C. A.; Cardenas, P.; Ji, B.; Duyk, G. M.; Knoll, J.; Berg,
M.; DiMario, F.; Huttenlocher, P.: Linkage of cerebral cortical periventricular
heterotopia and epilepsy to markers in Xq28. (Abstract) Neurology 45
(suppl. 4): A440 only, 1995.

23. Zenker, M.; Rauch, A.; Winterpacht, A.; Tagariello, A.; Kraus,
C.; Rupprecht, T.; Sticht, H.; Reis, A.: A dual phenotype of periventricular
nodular heterotopia and frontometaphyseal dysplasia in one patient
caused by a single FLNA mutation leading to two functionally different
aberrant transcripts. Am. J. Hum. Genet. 74: 731-737, 2004.

*FIELD* CS
INHERITANCE:
X-linked dominant

CARDIOVASCULAR:
[Heart];
Bicuspid aortic valve;
[Vascular];
Patent ductus arteriosus;
Dilation of the sinuses of Valsalva;
Dilation of the thoracic aorta

NEUROLOGIC:
[Central nervous system];
Seizures, refractory to treatment;
Imaging shows noncalcified subependymal periventricular heterotopic
nodules of gray matter;
Mental retardation, mild (in some patients);
Strokes due to coagulopathy;
Neuronal migration disorder

HEMATOLOGY:
Coagulopathy

MISCELLANEOUS:
Prenatal or perinatal lethality in hemizygous males;
Often confused with tuberous sclerosis (191000);
Otopalatodigital syndrome type I (OPD1, 311300) is an allelic disorder;
Otopalatodigital syndrome type II (OPD2, 304120) is an allelic disorder;
Frontometaphyseal dysplasia (FMD, 305620) is an allelic disorder;
Melnick-Needles syndrome (MNS, 309350) is an allelic disorder

MOLECULAR BASIS:
Caused by mutation in the filamin A gene (FLNA, 300017.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 1/5/2011
Cassandra L. Kniffin - revised: 10/25/2004

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

*FIELD* ED
joanna: 09/13/2012
joanna: 6/7/2012
ckniffin: 1/5/2011
joanna: 10/28/2010
ckniffin: 5/22/2007
ckniffin: 2/23/2005
ckniffin: 10/25/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 1/5/2011
Cassandra L. Kniffin - updated: 5/19/2009
Cassandra L. Kniffin - updated: 10/25/2004
Cassandra L. Kniffin - updated: 9/1/2004
Victor A. McKusick - updated: 4/26/2004
Victor A. McKusick - updated: 9/15/2003
Cassandra L. Kniffin - updated: 11/8/2002
Orest Hurko - updated: 7/1/1999
Victor A. McKusick - updated: 4/13/1999
Victor A. McKusick - updated: 2/2/1999
Victor A. McKusick - updated: 9/24/1997
Moyra Smith - Updated: 5/23/1996

*FIELD* CD
Victor A. McKusick: 4/26/1996

*FIELD* ED
carol: 11/25/2013
ckniffin: 11/25/2013
carol: 4/7/2011
wwang: 1/24/2011
ckniffin: 1/5/2011
wwang: 7/24/2009
ckniffin: 6/29/2009
wwang: 5/29/2009
ckniffin: 5/19/2009
carol: 1/21/2009
wwang: 5/17/2005
wwang: 5/11/2005
wwang: 3/1/2005
ckniffin: 2/23/2005
tkritzer: 10/29/2004
ckniffin: 10/25/2004
carol: 9/7/2004
ckniffin: 9/1/2004
terry: 6/2/2004
tkritzer: 4/26/2004
mgross: 9/15/2003
alopez: 3/21/2003
terry: 3/19/2003
mgross: 12/10/2002
carol: 11/13/2002
ckniffin: 11/8/2002
alopez: 3/3/2000
terry: 12/6/1999
mgross: 7/2/1999
kayiaros: 7/1/1999
carol: 4/15/1999
terry: 4/14/1999
terry: 4/13/1999
carol: 2/12/1999
terry: 2/2/1999
terry: 9/30/1997
terry: 9/24/1997
alopez: 7/3/1997
joanna: 3/14/1997
carol: 5/25/1996
carol: 5/23/1996
mark: 5/2/1996

MIM 300244
*RECORD*
*FIELD* NO
300244
*FIELD* TI
#300244 TERMINAL OSSEOUS DYSPLASIA; TOD
;;TERMINAL OSSEOUS DYSPLASIA AND PIGMENTARY DEFECTS; TODPD;;
read moreODPD;;
OSSEOUS DYSPLASIA, DIGITAL, WITH FACIAL PIGMENTARY DEFECTS AND MULTIPLE
FRENULA; ODPF;;
ODPF SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
terminal osseous dysplasia is caused by mutation in the FLNA gene
(300017).

DESCRIPTION

Terminal osseous dysplasia is an X-linked dominant male-lethal disease
characterized by skeletal dysplasia of the limbs, pigmentary defects of
the skin, and recurrent digital fibroma during infancy (Sun et al.,
2010).

CLINICAL FEATURES

Zhang et al. (2000) identified a novel limb-malformation syndrome in a
4-generation family. The syndrome was characterized by abnormal and
delayed ossification of bones in the hands and feet, leading to
brachydactyly, camptodactyly, and clinodactyly, severe limb deformities,
and joint contractures. In addition, affected individuals had pigmentary
skin lesions on the face and scalp, dysmorphic features including
hypertelorism, and multiple frenula. The phenotype was reminiscent of
those described by Bloem et al. (1974) and Horii et al. (1998) in
sporadic cases.

Bacino et al. (2000) gave a full description of the family reported by
Zhang et al. (2000). The syndrome was present in 10 females in 4
generations. It was ascertained through a 4-month-old female with
multiple anomalies including hypertelorism, iris colobomas, low-set
ears, midface hypoplasia, 'punched-out' pigmentary abnormalities over
the face and scalp, generalized brachydactyly, and digital fibromatosis.
Affected females had a reduced male-to-female ratio of liveborn
offspring, and some of them also had a history of multiple miscarriages.
Some of the affected family members showed mesomelic bowing and/or
shortening of arms and legs, suggesting that the skeletal dysplasia may
not be limited to the hands and feet. The digital fibromata observed in
the proband was reported to be present in most of the affected females
but regressed with age. In some instances, affected females had
vestigial and linear scar-like lesions on the fingertips. The lack of
affected males, decreased number of male progeny in the pedigree, and
the number of spontaneous abortions in the family supported a
male-lethal X-linked dominant etiology.

Breuning et al. (2000) described 5 female patients with this condition,
2 of whom were related (a mother and her daughter). The mother,
previously described by Bloem et al. (1974), had recurrent digital
fibromas, ptosis of the right eyelid, and pigmentary anomalies of the
forehead. Her daughter had focal dermal hypoplasia, coloboma of the iris
and eyelids, anal stenosis, and extensive limb malformations; she
developed digital fibromas at age 3 months. The 3 sporadic cases, one of
whom was previously described by Bloem et al. (1974), had multiple
digital fibromas, pigmented lesions in the temporal region, and limb
malformations.

Baroncini et al. (2007) described a 2-year-old Italian girl with full
expression of the syndrome, including skin defects, skeletal anomalies,
and recurrent fibromatosis of fingers and toes. Her mother had only
multiple hypertrophic oral frenula. X-chromosome inactivation studies
revealed extremely skewed X inactivation (100%) with silencing of the
maternal X chromosome in the daughter; the mother also had extremely
skewed X inactivation (100%).

Kokitsu-Nakata et al. (2008) described a Brazilian girl with typical
features of this disorder, including skin defects, skeletal anomalies,
and recurrent fibromatosis of fingers and toes.

Brunetti-Pierri et al. (2010) restudied the family with terminal osseous
dysplasia and pigmentary defects originally reported by Zhang et al.
(2000), reviewing clinical and radiologic characteristics. The digital
fibromata originally observed in the proband were not present at later
evaluations, and she had particularly striking carpal and tarsal
coalitions that were not noted in the earlier reports, because the
carpal bones had not yet ossified. Although the skeletal manifestations
of the disorder mostly involve hands and feet, Brunetti-Pierri et al.
(2010) observed a more generalized bone involvement including bowing,
mesomelic shortening, abnormal bony texture, areas of localized
osteoporosis, cystic-like lesions, and amorphous ossification that
suggested a possible defect of matrix degradation. They also noted that
in this family, the degree of hand and foot involvement was more severe
laterally compared to medially.

MAPPING

Using a methylation assay at the androgen receptor locus for evaluation
of X inactivation, Zhang et al. (2000) found that all 7 affected females
studied demonstrated preferential inactivation of their maternal X
chromosomes carrying the mutation, whereas 2 unaffected females showed a
random pattern. This finding indicated that the disorder is linked to
the X chromosome. In linkage studies, a maximum lod score of 3.16 at a
recombination fraction of zero was obtained for 5 markers mapping to
Xq27.3-q28.

Brunetti-Pierri et al. (2010) restudied the family with terminal osseous
dysplasia and pigmentary defects originally reported by Zhang et al.
(2000), obtaining a maximum multipoint lod score of 2.9 from marker
dbSNP rs1860929 to qter; an identical haplotype was found only in
affected individuals. The reduced genetic interval was refined to
Xq28-qter, a region containing more than 100 genes.

MOLECULAR GENETICS

In a family with terminal osseous dysplasia and pigmentary defects
mapping to Xq28-qter, originally reported by Zhang et al. (2000),
Brunetti-Pierri et al. (2010) sequenced the intron-exon junctions and
exons of the candidate FAM58A (300708) and FLNA genes but did not find
any mutations.

In affected members of 3 families segregating terminal osseous
dysplasia, 2 of which were previously described by Breuning et al.
(2000) and Baroncini et al. (2007), and in 3 sporadic case individuals,
who were previously described by Horii et al. (1998), Drut et al.,
(2005), and Breuning et al. (2000), Sun et al. (2010) identified a
causative mutation in the FLNA gene: a 5217G-A transition activated a
cryptic splice site, removing the last 48 nucleotides from exon 31 and
resulting in a loss of 16 amino acids (300017.0029). In the families,
the variant segregated with the disease. Sun et al. (2010) showed that
because of nonrandom X chromosome inactivation, the mutant allele was
not expressed in the patient fibroblasts. RNA expression of the mutant
allele was detected only in cultured fibroma cells obtained from
15-year-old surgically removed material. The mutation was not found in
400 control X chromosomes, pilot data from 1000 Genomes Project, or the
FLNA gene variant database. Because the mutation was predicted to remove
a sequence at the surface of filamin repeat 15, Sun et al. (2010)
suggested that the missing region in the filamin A protein affects or
prevents the interaction of filamin A with other proteins.

*FIELD* RF
1. Bacino, C. A.; Stockton, D. W.; Sierra, R. A.; Heilstedt, H. A.;
Lewandowski, R.; Van den Veyver, I. B.: Terminal osseous dysplasia
and pigmentary defects: clinical characterization of a novel male
lethal X-linked syndrome. Am. J. Med. Genet. 94: 102-112, 2000.

2. Baroncini, A.; Castelluccio, P.; Morleo, M.; Soli, F.; Franco,
B.: Terminal osseous dysplasia with pigmentary defects: clinical
description of a new family. Am. J. Med. Genet. 143A: 51-57, 2007.

3. Bloem, J. J.; Vuzevski, V. D.; Huffstadt, A. J. C.: Recurring
digital fibroma of infancy. J. Bone Joint Surg. Br. 56: 746-751,
1974.

4. Breuning, M. H.; Oranje, A. P.; Langemeijer, R. A. T. M.; Hovius,
S. E. R.; Diepstraten, A. F. M.; den Hollander, J. C.; Baumgartner,
N.; Dwek, J. R.; Sommer, A.; Toriello, H.: Recurrent digital fibroma,
focal dermal hypoplasia, and limb malformations. Am. J. Med. Genet. 94:
91-101, 2000.

5. Brunetti-Pierri, N.; Lachman, R.; Lee, K.; Leal, S. M.; Piccolo,
P.; Van den Veyver, I. B.; Bacino, C. A.: Terminal osseous dysplasia
with pigmentary defects (TODPD): follow-up of the first reported family,
characterization of the radiological phenotype, and refinement of
the linkage region. Am. J. Med. Genet. 152A: 1825-1831, 2010.

6. Drut, R.; Pedemonte, L.; Rositto, A.: Noninclusion-body infantile
digital fibromatosis: a lesion heralding terminal osseous dysplasia
and pigmentary defects syndrome. Int. J. Surg. Path. 13: 181-184,
2005.

7. Horii, E.; Sugiura, Y.; Nakamura, R.: A syndrome of digital fibromas,
facial pigmentary dysplasia, and metacarpal and metatarsal disorganization. Am.
J. Med. Genet. 80: 1-5, 1998.

8. Kokitsu-Nakata, N. M.; Antunes, L. F. B. B.; Guion-Almeida, M.
L.: Terminal osseous dysplasia and pigmentary defects in a Brazilian
girl. Am. J. Med. Genet. 146A: 2698-2700, 2008.

9. Sun, Y.; Almomani, R.; Aten, E.; Celli, J.; van der Heijden, J.;
Venselaar, H.; Robertson, S. P.; Baroncini, A.; Franco, B.; Basel-Vanagaite,
L.; Horii, E.; Drut, R.; Ariyurek, Y.; den Dunnen, J. T.; Breuning,
M. H.: Terminal osseous dysplasia is caused by a single recurrent
mutation in the FLNA gene. Am. J. Hum. Genet. 87: 146-153, 2010.

10. Zhang, W.; Amir, R.; Stockton, D. W.; Van den Veyver, I. B.; Bacino,
C. A.; Zoghbi, H. Y.: Terminal osseous dysplasia with pigmentary
defects maps to human chromosome Xq27.3-Xqter. Am. J. Hum. Genet. 66:
1461-1464, 2000.

*FIELD* CN
Marla J. F. O'Neill - updated: 11/11/2010
Nara Sobreira - updated: 10/22/2010
Nara Sobreira - updated: 7/31/2009
Marla J. F. O'Neill - updated: 6/22/2007
Sonja A. Rasmussen - updated: 9/22/2000
Victor A. McKusick - updated: 6/13/2000

*FIELD* CD
Victor A. McKusick: 5/1/2000

*FIELD* ED
terry: 01/13/2011
wwang: 11/11/2010
terry: 11/11/2010
carol: 10/27/2010
terry: 10/22/2010
carol: 7/31/2009
wwang: 6/26/2007
terry: 6/22/2007
mgross: 3/17/2004
cwells: 1/5/2001
cwells: 1/4/2001
mcapotos: 9/25/2000
mcapotos: 9/22/2000
carol: 6/15/2000
terry: 6/13/2000
carol: 5/1/2000

MIM 300321
*RECORD*
*FIELD* NO
300321
*FIELD* TI
#300321 FG SYNDROME 2; FGS2
*FIELD* TX
A number sign (#) is used with this entry because FG syndrome-2 (FGS2)
read moreis caused by mutation in the gene encoding filamin A (FLNA; 300017).

For a general phenotypic description and a discussion of genetic
heterogeneity of FG syndrome, see FGS1 (305450).

DESCRIPTION

Although the phenotypic spectrum and severity of FG syndrome is wide,
the cardinal features include congenital hypotonia, delayed speech
development, relative macrocephaly, dysmorphic facies, and anal
anomalies or severe constipation (Unger et al., 2007).

CLINICAL FEATURES

Briault et al. (1999) reported a French boy with FG syndrome. His
maternal uncle was mentally retarded. The proband had mental
retardation, facial anomalies, prominent forehead, hypotonia, failure to
thrive, constipation, and anteriorly placed anus, while his maternal
uncle had mental retardation, facial anomalies, constipation, and
bronchopulmonary infections, but no macrocephaly, frontal bossing, or
anal anomalies.

Unger et al. (2007) reported an 18-month-old German boy with severe
constipation, large rounded forehead, prominent ears, frontal hair
upsweep, and mild delay in language acquisition. The parents declined
brain MRI studies.

MAPPING

In a French boy with FG syndrome and in his mentally retarded maternal
uncle, Briault et al. (1999) identified an X-chromosome inversion,
inv(X)(q12q28). Using FISH in further studies of this family, Briault et
al. (2000) identified 2 clones that crossed the breakpoints, one located
at Xq11.2 and the other at Xq28 (FGS2).

MOLECULAR GENETICS

In a German boy with FGS2, Unger et al. (2007) identified a hemizygous
mutation in the FLNA gene (P1291L; 300017.0028). His asymptomatic mother
also carried the mutation, which was absent in 100 control chromosomes.
Unger et al. (2007) also suggested that a patient reported by Hehr et
al. (2006) with a FLNA mutation (300017.0024) and periventricular
heterotopia, facial dysmorphism, and constipation may have also had
FGS2.

*FIELD* RF
1. Briault, S.; Odent, S.; Lucas, J.; Le Merrer, M.; Turleau, C.;
Munnich, A.; Moraine, C.: Paracentric inversion of the X chromosome
[inv(X)(q12q28)] in familial FG syndrome. Am. J. Med. Genet. 86:
112-114, 1999.

2. Briault, S.; Villard, L.; Rogner, U.; Coy, J.; Odent, S.; Lucas,
J.; Passage, E.; Zhu, D.; Shrimpton, A.; Pembrey, M.; Till, M.; Guichet,
A.; Dessay, S.; Fontes, M.; Poustka, A.; Moraine, C.: Mapping of
X chromosome inversion breakpoints [inv(X)(q11q28)] associated with
FG syndrome: a second FG locus [FGS2]? Am. J. Med. Genet. 95: 178-181,
2000.

3. Hehr, U.; Hehr, A.; Uyanik, G.; Phelan, E.; Winkler, J.; Reardon,
W.: A filamin A splice mutation resulting in a syndrome of facial
dysmorphism, periventricular nodular heterotopia, and severe constipation
reminiscent of cerebro-fronto-facial syndrome. (Letter) J. Med. Genet. 43:
541-544, 2006.

4. Unger, S.; Mainberger, A.; Spitz, C.; Bahr, A.; Zeschnigk, C.;
Zabel, B.; Superti-Furga, A.; Morris-Rosendahl, D. J.: Filamin A
mutation is one cause of FG syndrome. Am. J. Med. Genet. 143A: 1876-1879,
2007.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/19/2009
Victor A. McKusick - updated: 4/26/2007
Victor A. McKusick - updated: 10/7/2002

*FIELD* CD
Ada Hamosh: 4/4/2001

*FIELD* ED
wwang: 05/29/2009
ckniffin: 5/19/2009
alopez: 4/27/2007
terry: 4/26/2007
carol: 3/14/2006
mgross: 3/17/2004
tkritzer: 10/9/2002
terry: 10/7/2002
carol: 4/4/2001

MIM 300537
*RECORD*
*FIELD* NO
300537
*FIELD* TI
#300537 HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT
;;PERIVENTRICULAR NODULAR HETEROTOPIA 4; PVNH4
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
Ehlers-Danlos variant form of periventricular heterotopia is caused by
heterozygous mutation in the filamin A gene (FLNA; 300017).

For a phenotypic description and a discussion of genetic heterogeneity
of periventricular heterotopia, see 300049.

CLINICAL FEATURES

A relationship between Ehlers-Danlos syndrome (EDS; see 130000) and
periventricular heterotopia (PVNH) was suggested by 2 single-case
reports (Cupo et al., 1981; Thomas et al., 1996). In both instances the
affected females showed focal seizures, irregular collagen fibrils, and
aneurysms of the sinuses of Valsalva. Agenesis of the posterior corpus
callosum, enlarged cisterna magna, panacinar emphysema, and myocardial
infarction were observed in either one but not both individuals. Sheen
et al. (2005) pointed out that many of the same clinical and radiologic
features seen in these 2 case reports can sometimes be encountered in
X-linked PVNH due to FLNA mutations (300049). For example, most
individuals with known FLNA mutations are female, present with seizures,
and more variably, have vascular anomalies including aortic aneurysm,
patent ductus arteriosus, and bicuspid aortic valve.

Sheen et al. (2005) reported 2 familial cases and 9 sporadic cases of an
Ehlers-Danlos variant form of periventricular heterotopia. The variant
was characterized by joint hypermobility and the development of aortic
dilatation in early adulthood, in addition to nodular brain heterotopia.
MRI typically demonstrated bilateral PVNH, indistinguishable from the
PVNH due to FLNA mutations.

MOLECULAR GENETICS

In 3 patients with the Ehlers-Danlos variant form of periventricular
heterotopia, Sheen et al. (2005) identified heterozygous mutations in
the FLNA gene (300017.0017-300017.0019). One pedigree with no detectable
exonic FLNA mutation demonstrated positive linkage to the FLNA locus on
Xq28, and an affected member of this family had no detectable FLNA
protein.

In 3 female patients from a 3-generation Spanish family with the
Ehlers-Danlos variant of periventricular heterotopia, Gomez-Garre et al.
(2006) identified heterozygosity for a missense mutation in the FLNA
gene (300017.0021). In addition to bilateral nodular heterotopia on
brain MRI, the main clinical findings in the affected females were
hyperextensible skin and joint hypermobility, initially suggesting a
diagnosis of EDS type III (130020). However, additional clinical
findings such as scoliosis, hyperlordosis or pectum excavatum,
high-arched palate, and subarachnoid hemorrhage in 1 patient and
visceral hernias in 2 exceeded the typical features of EDS type III.

*FIELD* RF
1. Cupo, L. N.; Pyeritz, R. E.; Olson, J. L.; McPhee, S. J.; Hutchins,
G. M.; McKusick, V. A.: Ehlers-Danlos syndrome with abnormal collagen
fibrils, sinus of Valsalva aneurysms, myocardial infarction, panacinar
emphysema and cerebral heterotopias. Am. J. Med. 71: 1051-1058,
1981.

2. Gomez-Garre, P.; Seijo, M.; Gutierrez-Delicado, E.; Castro del
Rio, M.; de la Torre, C.; Gomez-Abad, C.; Morales-Corraliza, J.; Puig,
M.; Serratosa, J. M.: Ehlers-Danlos syndrome and periventricular
nodular heterotopia in a Spanish family with a single FLNA mutation. J.
Med. Genet. 43: 232-237, 2006.

3. Sheen, V. L.; Jansen, A.; Chen, M. H.; Parrini, E.; Morgan, T.;
Ravenscroft, R.; Ganesh, V.; Underwood, T.; Wiley, J.; Leventer, R.;
Vaid, R. R.; Ruiz, D. E.; and 21 others: Filamin A mutations cause
periventricular heterotopia with Ehlers-Danlos syndrome. Neurology 64:
254-262, 2005.

4. Thomas, P.; Bossan, A.; Lacour, J. P.; Chanalet, S.; Ortonne, J.
P.; Chatel, M.: Ehlers-Danlos syndrome with subependymal periventricular
heterotopias. Neurology 46: 1165-1167, 1996.

*FIELD* CN
Marla J. F. O'Neill - updated: 4/21/2006

*FIELD* CD
Victor A. McKusick: 5/11/2005

*FIELD* ED
carol: 11/25/2013
carol: 1/21/2011
ckniffin: 1/5/2011
wwang: 4/21/2006
wwang: 5/17/2005
wwang: 5/11/2005

MIM 304120
*RECORD*
*FIELD* NO
304120
*FIELD* TI
#304120 OTOPALATODIGITAL SYNDROME, TYPE II; OPD2
;;OPD II SYNDROME;;
OPD SYNDROME 2;;
read moreCRANIOORODIGITAL SYNDROME;;
FACIOPALATOOSSEOUS SYNDROME; FPO
*FIELD* TX
A number sign (#) is used with this entry because otopalatodigital
syndrome-2 is caused by mutation in the gene encoding filamin A (FLNA;
300017).

DESCRIPTION

Otopalatodigital syndrome-2 is 1 of 4 otopalatodigital syndromes caused
by mutations in the FLNA gene. The disorders, which include
frontometaphyseal dysplasia (FMD; 305620), otopalatodigital syndrome-1
(OPD1; 311300), and Melnick-Needles syndrome (MNS; 309350), constitute a
phenotypic spectrum. At the mild end of the spectrum, males with OPD1
have cleft palate and mild skeletal anomalies with conductive deafness
caused by ossicular anomalies. FMD is characterized by a generalized
skeletal dysplasia, deafness and urogenital defects. Males with OPD2
have disabling skeletal anomalies in addition to variable malformations
in the hindbrain, heart, intestines, and kidneys that frequently lead to
perinatal death. The most severe phenotype, MNS, is characterized by a
skeletal dysplasia in the heterozygote. Affected males exhibit severe
malformations similar to those observed in individuals with OPD2,
resulting in prenatal lethality or death in the first few months of life
(review by Robertson, 2005). Verloes et al. (2000) suggested that these
disorders constitute a single entity, which they termed
'frontootopalatodigital osteodysplasia.'

CLINICAL FEATURES

Fitch et al. (1976) described a male infant with microcephaly, small
mouth, cleft palate, flexed overlapping fingers with syndactyly of
digits 3 and 4, and syndactyly of toes 2 to 5. An earlier born half sib,
who died at the age of 10 days, had the same features. Although the
features suggested trisomy 18, karyotype was normal. The mother had a
high-arched palate, bifid uvula, slight ulnar deviation of the terminal
phalanges of the third fingers, radial deviation of the terminal phalanx
of the right fourth finger, and slight clinodactyly of the fifth
fingers. The half sibs had different fathers. The mother had a normal
son and daughter. Similar cases were found in the literature among those
reported as trisomy 18 phenotype with normal karyotype. Kozlowski et al.
(1977) described 2 half brothers (with the same mother) who may have had
the same disorder. Andre et al. (1981) described a family in which 3
male first cousins, sons of 3 sisters, had a phenotype almost identical
to that in the patients described by Fitch et al. (1976). The sisters, 2
of whom had the same father, had minor anomalies typical of OPD I. Fitch
et al. (1983) suggested that all these patients had the same disorder,
presented a follow-up of their original patient, and pointed out
similarities to OPD I. The follow-up radiographs on the Fitch patient
(Fitch et al., 1983) showed extraordinary changes in the hands and feet:
short great toe (short first ray) and relatively long second ray in the
feet, abnormal epiphyses of the proximal phalanges of the hands, short
first metacarpal, and extra bone in the capitate-hamate complex. The
maternal grandmother had cleft palate. Fitch et al. (1983) suggested
that the cranioorodigital syndrome be called OPD II and that it may be
due to an allelic gene or even the same gene as OPD I.

Brewster et al. (1985) described a male infant and his maternal uncle,
also an infant, with a lethal skeletal dysplasia characterized by cleft
palate, midface hypoplasia, downward-slanting palpebral fissures, small
thorax, and bowed limbs with absent fibulae. Heterozygous females are
more mildly affected in this syndrome; the woman who was mother of 1
infant and sister of the other was 142 cm tall and had mild frontal
bossing and downward-slanting palpebral fissures. Chondroosseous
histology was normal.

Holder and Winter (1993) suggested that the disorder is X-linked
semidominant: carrier females may exhibit mild dysmorphic features such
as broad face, antimongoloid slant of the palpebral fissures, cleft
palate, or bifid uvula (Andre et al., 1981). Radiologic features, such
as hyperostosis of the skull bones, may also be present in carrier
females.

Ogata et al. (1990) suggested that the clinical, radiologic, and
histologic findings indicated that defective intramembranous
ossification is a principal abnormality in OPD type II.

Stratton and Bluestone (1991) described a family in which an infant
propositus had abnormalities that appeared to combine features of OPD II
with those of the syndrome of hydrocephalus and cerebellar hypoplasia
(307010); 2 maternal uncles died neonatally with congenital
hydrocephalus and digital abnormalities consistent with OPD II. Stratton
and Bluestone (1991) suggested that these 2 entities may be caused by
mutations at neighboring loci on the X chromosome.

Young et al. (1993) described 3 cases of OPD II with omphalocele; 2 of
the patients were brothers. In addition, the 3 males had other
anomalies: hypospadias in 1, hydronephrosis in 2, hydroureter in 2,
chordee in all 3, and hydrocephalus in 2. Young et al. (1993) pointed to
reports of omphalocele in 3 other cases of OPD I or II.

Small or absent fibula and the presence of only 4 toes is typical of OPD
II (Kozlowski, 1993).

Preis et al. (1994) reported the cases of 2 unrelated boys who showed
growth retardation, bowed long bones, missing hypoplastic fibulas,
sclerosis of the skull base, and wavy, irregular clavicles and ribs. The
facial appearance was distinguished by a prominent forehead, widely
spaced eyes, antimongoloid slant of palpebral fissures, flattened nasal
bridge, and retrogenia. One boy suffered a spontaneous fracture of one
rib at the age of 3 years 5 months. The mother of the other affected boy
had a large skull with prominent forehead, hypertelorism, low-set ears,
high-arched palate, and retrogenia. She had a persistent deciduous
incisor in the left maxilla, and several permanent teeth were missing
due to agenesis or extraction. In addition, she had hearing loss and
mild flexion contracture of the right elbow. On radiologic examination,
the maxillary sinuses were absent, and the bone density of the skull
bones and long bones was increased. In the opinion of Preis et al.
(1994), the mother was mildly affected by the same condition. They found
reports of 20 fully affected patients and 9 partially affected mothers,
including their patient.

Stoll and Alembik (1994) reported a sporadic case of OPD II. At 26 years
of age, the patient had conductive hearing impairment, cleft palate,
prominent forehead, flat facies, and a broad nasal base resulting in the
characteristic 'pugilist' appearance. Extension and supination were
limited at the elbows; thumbs and halluces were broad. Radiologic
abnormalities noted included malformations of the cervical spine, pelvic
abnormalities, bilateral coxa valga, genu valgum, small fibulae, pes
equinovarus, and supernumerary carpal bones. IQ had been measured as 65
at the age of 3 years when operation for pes equinovarus was performed.
Bilateral conductive hearing loss was noted at the age of 6 years and
malformed ossicles were seen at surgery at age 13 years. At the age of
27 years, IQ was measured as 95. He had been fitted with hearing aids
since the age of 13.

Nishimura et al. (1997) described 2 males with many manifestations
suggestive of OPD2; however, atypical skeletal changes cause some
diagnostic confusion with lethal or semilethal bone dysplasias,
including boomerang dysplasia (112310), type I atelosteogenesis
(108720), type III atelosteogenesis (108721), and the lethal male
phenotype of Melnick-Needles syndrome. The observations were thought to
expand the entities that constitute the OPD-Larsen spectrum or family of
skeletal dysplasias as postulated by Spranger (1985).

Savarirayan et al. (2000) reported 3 cases of OPD II emphasizing
chondroosseous morphology. Although endochondral ossification was
normal, periosteal ossification was defective with islands of cortical
bone aplasia and hyperplasia of the periosteum. The trabecular bone was
also very poorly formed and markedly hypercellular. Both membranous
ossification and bone remodeling appear to be defective in OPD II and
should account for part of the observed phenotype. Savarirayan et al.
(2000) pointed out that the biglycan gene (BGN; 301870) maps to Xq28 and
is involved in bone formation; however, they excluded BGN as a candidate
by direct sequencing of cDNA in 1 case. Savarirayan et al. (2000)
commented that their patient 1, who died shortly after birth due to
severe pulmonary hypoplasia, had downslanting palpebral fissures and
small mouth; the pelvic bones were deformed, the femurs and tibias were
bowed, and the fibulas absent. The feet showed a 4-toed ('tree frog')
configuration. The mother had hypertelorism and downslanting palpebral
fissures. The mother and maternal grandfather of patient 2 had
acromegaly, but this was probably unrelated to the OPD II. There was a
family history of a 'maternal nephew' born with multiple malformations.

Verloes et al. (2000) reported a mild case of OPD2, a severe case of
OPD2 with anomalies of the central nervous system and some
manifestations of frontometaphyseal dysplasia, a lethal case of OPD2
with similarities to Melnick-Needles syndrome, and 3 unrelated boys born
to mothers with MNS (1 with a severe form, 1 with a lethal form, and an
aborted fetus). They reviewed the features in these disorders and in
OPD1 and suggested that these disorders constitute a single entity.
Verloes et al. (2000) also discussed the relationship to similar
syndromes, such as Yunis-Varon syndrome (216340), type III
atelosteogenesis (108721), and boomerang dysplasia (112310).

Morava et al. (2003) described 2 families in which both males and
females showed the facial and skeletal characteristics of FMD in
association with severe progressive scoliosis. Some also had hearing
loss and urogenital anomalies, leading Morava et al. (2003) to suggest
that these were examples of frontootopalatodigital osteodysplasia as
described by Verloes et al. (2000).

Johnson et al. (2008) reported a brother and sister with a clinical
diagnosis of OPD2 who both had tracheomalacia requiring tracheostomy to
relieve lower airway obstruction.

MAPPING

OPD1 (311300) is an X-linked semidominant condition characterized by
malformations of the skeleton, auditory apparatus, and palate. Linkage
studies mapped the responsible gene to a 16-cM region of Xq27-q28. A
proposed allelic variant of OPD1, termed OPD2, is associated with a more
severe, frequently lethal phenotype with visceral and brain anomalies in
addition to skeletal, auditory, and palatal defects. Robertson et al.
(2001) reported linkage of the OPD2 phenotype to a 2-cM region of distal
Xq28 in a Maori kindred, with a maximum multipoint lod score of 3.31
between the markers DXS1073 and DXS1108. This provided support for
allelism between OPD1 and OPD2 and reduced the size of the disease
interval to 1.8 to 2.1 Mb. They also demonstrated that female carriers
of this disorder exhibit skewed inactivation that segregates with the
high-risk haplotype and may be inversely related to the severity with
which they manifest features of the disorder.

MOLECULAR GENETICS

Robertson et al. (2003) demonstrated that OPD2 is caused by
gain-of-function mutations in the gene encoding filamin A (FLNA;
300017). Loss-of-function mutations in FLNA result in an embryonic
lethal state in males and manifest in females as a localized neuronal
migration disorder, called periventricular nodular heterotopia (PVNH;
300049).

In a 12-year-old Japanese boy with OPD2, Kondoh et al. (2007) identified
a mutation in the FLNA gene (R196W; 300017.0026). The patient had some
additional unusual features, including congenital cataract, glaucoma,
and congenital heart defects. Kondoh et al. (2007) noted that Robertson
et al. (2003) had identified the same mutation in a patient with OPD
type I, suggesting that additional factors play a role in OPD spectrum
disorders.

In a male fetus with OPD2, Marino-Enriquez et al. (2007) identified a
mutation in the FLNA gene (C210F; 300017.0027); analysis of relatives
revealed that the mutation had arisen de novo in the mother. A previous
pregnancy had ended in stillbirth of a male also diagnosed with OPD2,
who on autopsy was noted to have deficiency of the lower thoracic,
lumbar, and upper sacral vertebral arches. Histopathologic studies of
the second fetus revealed osseous sclerosis rather than the previously
reported membranous ossification defect observed in this condition.

In 6 females with cranial hyperostosis and various skeletal
abnormalities from a 4-generation pedigree, Stefanova et al. (2005)
identified heterozygosity for a deletion in the FLNA gene (300017.0016).
The phenotype of affected females resembled FMD with some overlap to
OPD1 and OPD2, but no signs specific for MNS. However, males had severe
extraskeletal malformations and died early, thus constituting an overlap
with OPD2 and MNS. Stefanova et al. (2005) concluded that the disorder
in this family is best described as an intermediate OPD-spectrum
phenotype that bridges the FMD and OPD2 phenotypes.

*FIELD* SA
Robertson (2007)
*FIELD* RF
1. Andre, M.; Vigneron, J.; Didier, F.: Abnormal facies, cleft palate
and generalized dysostosis: a lethal X-linked syndrome. J. Pediat. 98:
747-752, 1981.

2. Brewster, T. G.; Lachman, R. S.; Kushner, D. C.; Holmes, L. B.;
Isler, R. J.; Rimoin, D. L.: Oto-palato-digital syndrome, type II--an
X-linked skeletal dysplasia. Am. J. Med. Genet. 20: 249-254, 1985.

3. Fitch, N.; Jequier, S.; Gorlin, R.: The oto-palato-digital syndrome,
proposed type II. Am. J. Med. Genet. 15: 655-664, 1983.

4. Fitch, N.; Jequier, S.; Papageorgiou, A.: A familial syndrome
of cranial, facial, oral and limb anomalies. Clin. Genet. 10: 226-231,
1976.

5. Holder, S. E.; Winter, R. M.: Otopalatodigital syndrome type II. J.
Med. Genet. 30: 310-313, 1993.

6. Johnson, J. N.; Hartman, T. K.; Krych, E. H.; Seferian, E. G.;
Ouellette, Y.: Tracheomalacia in siblings with otopalatodigital syndrome.
(Letter) Am. J. Med. Genet. 146A: 1347-1349, 2008.

7. Kondoh, T.; Okamoto, N.; Norimatsu, N.; Uetani, M.; Nishimura,
G.; Moriuchi, H.: A Japanese case of oto-palato-digital syndrome
type II: an apparent lack of phenotype-genotype correlation. J. Hum.
Genet. 52: 370-373, 2007.

8. Kozlowski, K.: Personal Communication. Sydney, Australia 5/30/1993.

9. Kozlowski, K.; Turner, G.; Scougall, J.; Harrington, J.: Oto-palato-digital
syndrome with severe x-ray changes in two half brothers. Pediat.
Radiol. 6: 97-102, 1977.

10. Marino-Enriquez, A.; Lapunzina, P.; Robertson, S. P.; Rodriguez,
J. I.: Otopalatodigital syndrome type 2 in two siblings with a novel
filamin A 629G-T mutation: clinical, pathological, and molecular findings. Am.
J. Med. Genet. 143A: 1120-1125, 2007.

11. Morava, E.; Illes, T.; Weisenbach, J.; Karteszi, J.; Kosztolanyi,
G.: Clinical and genetic heterogeneity in frontometaphyseal dysplasia:
severe progressive scoliosis in two families. Am. J. Med. Genet. 116A:
272-277, 2003.

12. Nishimura, G.; Horiuchi, T.; Kim, O. H.; Sasamoto, Y.: Atypical
skeletal changes in otopalatodigital syndrome type II: phenotypic
overlap among otopalatodigital syndrome type II, boomerang dysplasia,
atelosteogenesis type I and type III, and lethal male phenotype of
Melnick-Needles syndrome. Am. J. Med. Genet. 73: 132-138, 1997.

13. Ogata, T.; Matsuo, N.; Nishimura, G.; Hajikano, H.: Oto-palato-digital
syndrome, type II: evidence for defective intramembranous ossification. Am.
J. Med. Genet. 36: 226-231, 1990.

14. Preis, S.; Kemperdick, H.; Majewski, F.: Oto-palato-digital syndrome
type II in two unrelated boys. Clin. Genet. 45: 154-161, 1994.

15. Robertson, S. P.: Otopalatodigital syndrome spectrum disorders:
otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia
and Melnick-Needles syndrome. Europ. J. Hum. Genet. 15: 3-9, 2007.

16. Robertson, S. P.: Filamin A: phenotypic diversity. Curr. Opinion
Genet. Dev. 15: 301-307, 2005.

17. Robertson, S. P.; Twigg, S. R. F.; Sutherland-Smith, A. J.; Biancalana,
V.; Gorlin, R. J.; Horn, D.; Kenwrick, S. J.; Kim, C. A.; Morava,
E.; Newbury-Ecob, R.; Orstavik, K. H.; Quarrell, O. W. J.; Schwartz,
C. E.; Shears, D. J.; Suri, M.; Kendrick-Jones, J.; OPD-spectrum
Disorders Clinical Collaborative Group; Wilkie, A. O. M.: Localized
mutations in the gene encoding the cytoskeletal protein filamin A
cause diverse malformations in humans. Nature Genet. 33: 487-491,
2003.

18. Robertson, S. P.; Walsh, S.; Oldridge, M.; Gunn, T.; Becroft,
D.; Wilkie, A. O. M.: Linkage of otopalatodigital syndrome type 2
(OPD2) to distal Xq28: evidence for allelism with OPD1. Am. J. Hum.
Genet. 69: 223-227, 2001.

19. Savarirayan, R.; Cormier-Daire, V.; Unger, S.; Lachman, R. S.;
Roughley, P. J.; Wagner, S. F.; Rimoin, D. L.; Wilcox, W. R.: Oto-palato-digital
syndrome, type II: report of three cases with further delineation
of the chondro-osseous morphology. Am. J. Med. Genet. 95: 193-200,
2000.

20. Spranger, J.: Pattern recognition in bone dysplasias.In: Papadatos,
C. J.; Bartsocas, C. S.: Endocrine Genetics and Genetics of Growth.
New York: Alan R. Liss (pub.) 1985. Pp. 315-342.

21. Stefanova, M.; Meinecke, P.; Gal, A.; Bolz, H.: A novel 9 bp
deletion in the filamin A gene causes an otopalatodigital-spectrum
disorder with a variable, intermediate phenotype. Am. J. Med. Genet. 132A:
386-390, 2005.

22. Stoll, C.; Alembik, Y.: Oto-palato-digital syndrome type II. Genet.
Counsel. 5: 61-66, 1994.

23. Stratton, R. F.; Bluestone, D. L.: Oto-palatal-digital syndrome
type II with X-linked cerebellar hypoplasia/hydrocephalus. Am. J.
Med. Genet. 41: 169-172, 1991.

24. Verloes, A.; Lesenfants, S.; Barr, M.; Grange, D. K.; Journel,
H.; Lombet, J.; Mortier, G.; Roeder, E.: Fronto-otopalatodigital
osteodysplasia: clinical evidence for a single entity encompassing
Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2,
and frontometaphyseal dysplasia. Am. J. Med. Genet. 90: 407-422,
2000.

25. Young, K.; Barth, C. K.; Moore, C.; Weaver, D. D.: Otopalatodigital
syndrome type II associated with omphalocele: report of three cases. Am.
J. Med. Genet. 45: 481-487, 1993.

*FIELD* CS
INHERITANCE:
X-linked dominant

GROWTH:
[Height];
Short stature;
[Other];
Postnatal growth retardation

HEAD AND NECK:
[Head];
Large anterior fontanel;
[Face];
Prominent forehead;
Severe micrognathia;
Midface hypoplasia;
[Ears];
Low-set ears;
Conductive hearing loss;
Posteriorly rotated ears;
[Eyes];
Hypertelorism;
Downslanting palpebral fissures;
[Nose];
Flat nasal bridge;
[Mouth];
Small mouth;
Cleft palate

RESPIRATORY:
Respiratory failure

CHEST:
[External features];
Narrow chest;
[Ribs, sternum, clavicles, and scapulae];
Pectus excavatum;
Thin, wavy clavicles;
Wavy, short ribs

ABDOMEN:
[Gastrointestinal];
Omphalocele

GENITOURINARY:
[External genitalia, male];
Hypospadias;
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Hydronephrosis

SKELETAL:
Dysharmonic bone maturation;
[Skull];
Late closure of large anterior fontanel;
Wide sutures;
Midface hypoplasia;
Vertical clivus;
Small mandible;
Sclerotic skull base;
Wormian bones;
[Spine];
Flattened vertebrae;
Spondylolysis;
[Pelvis];
Congenital hip dislocation;
Hypoplastic ilia;
[Limbs];
Dense long bones;
Radial bowing;
Ulnar bowing;
Femoral bowing;
Tibial bowing;
Small to absent fibula;
Subluxed elbow, wrist, and knee;
[Hands];
Flexed, overlapping fingers;
Short, broad thumbs;
Postaxial polydactyly;
Syndactyly;
Second finger clinodactyly;
Hypoplastic, irregular metacarpals;
'Tree-frog' hands;
[Feet];
Short, broad halluces;
Syndactyly;
Nonossified fifth metatarsal;
Rocker-bottom feet;
'Tree-frog' feet;
Hypoplastic metatarsals

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Hydrocephalus

MISCELLANEOUS:
Majority of patients are stillborn or die before 5 months of age;
Milder manifestations in heterozygous females (broad face, downslanting
palpebral fissures, and cleft palate);
Otopalatodigital syndrome type I (OPD1, 311300) is an allelic disorder;
Frontometaphyseal dysplasia (FMD, 305620) is an allelic disorder;
Melnick-Needles syndrome (MNS, 309350) is an allelic disorder;
Periventricular heterotopia (300049) is an allelic disorder

MOLECULAR BASIS:
Caused by mutation in the filamin A gene (FLNA, 300017.0010)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/25/2004
Kelly A. Przylepa - revised: 4/25/2002

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

*FIELD* ED
joanna: 05/25/2012
joanna: 5/25/2012
joanna: 10/20/2011
joanna: 11/1/2004
ckniffin: 10/25/2004
joanna: 4/25/2002

*FIELD* CN
Carol A. Bocchini - updated: 07/28/2009
Cassandra L. Kniffin - updated: 6/16/2008
Marla J. F. O'Neill - updated: 2/1/2008
Cassandra L. Kniffin - updated: 5/15/2007
Victor A. McKusick - updated: 3/19/2003
Victor A. McKusick - updated: 8/16/2001
Victor A. McKusick - updated: 11/10/2000
Victor A. McKusick - updated: 2/25/2000
Victor A. McKusick - updated: 1/8/1998

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

*FIELD* ED
carol: 07/28/2009
wwang: 6/30/2008
ckniffin: 6/16/2008
wwang: 2/7/2008
terry: 2/1/2008
wwang: 5/17/2007
ckniffin: 5/15/2007
terry: 6/2/2004
alopez: 4/2/2003
alopez: 3/21/2003
terry: 3/19/2003
alopez: 9/18/2001
cwells: 9/7/2001
cwells: 8/28/2001
terry: 8/16/2001
mcapotos: 11/16/2000
mcapotos: 11/15/2000
terry: 11/10/2000
mgross: 3/17/2000
terry: 2/25/2000
terry: 1/8/1998
carol: 9/15/1994
jason: 6/16/1994
terry: 4/21/1994
mimadm: 4/1/1994
carol: 6/3/1993
carol: 6/1/1993

MIM 305620
*RECORD*
*FIELD* NO
305620
*FIELD* TI
#305620 FRONTOMETAPHYSEAL DYSPLASIA; FMD
*FIELD* TX
A number sign (#) is used with this entry because frontometaphyseal
read moredysplasia is caused by gain-of-function mutations in the gene encoding
filamin A (FLNA; 300017).

DESCRIPTION

Frontometaphyseal dysplasia is 1 of 4 otopalatodigital syndromes caused
by mutations in the FLNA gene. The disorders, which include
otopalatodigital syndrome-1 (OPD1; 311300), otopalatodigital syndrome-2
(OPD2; 304120), and Melnick-Needles syndrome (MNS; 309350), constitute a
phenotypic spectrum. At the mild end of the spectrum, males with OPD1
have cleft palate and mild skeletal anomalies with conductive deafness
caused by ossicular anomalies. FMD is characterized by a generalized
skeletal dysplasia, deafness, and urogenital defects. Males with OPD2
have disabling skeletal anomalies in addition to variable malformations
in the hindbrain, heart, intestines, and kidneys that frequently lead to
perinatal death. The most severe phenotype, MNS, is characterized by a
skeletal dysplasia in the heterozygote. Affected males exhibit severe
malformations similar to those observed in individuals with OPD2,
resulting in prenatal lethality or death in the first few months of life
(review by Robertson, 2005). Verloes et al. (2000) suggested that these
disorders constitute a single entity, which they termed
'frontootopalatodigital osteodysplasia.'

CLINICAL FEATURES

Gorlin and Cohen (1969) described a male patient with extraordinarily
marked frontal hyperostosis giving great prominence to the supraciliary
ridges, underdeveloped mandible, cryptorchidism, subluxated radial
heads, and metaphyseal dysplasia resembling that in Pyle disease
(metaphyseal dysplasia). This may be the disorder present in the case
described by Walker (1969). Striking overgrowth of bone in the
superciliary region was repaired by removal of excess bone.

Holt et al. (1972) reported 2 unrelated patients. Danks et al. (1972)
studied an isolated case in which progressive contracture of the fingers
and lysis and fusion of carpal bones were features. The patient had
progressive osteosclerosis also. Fibroblasts showed metachromasia. All 3
patients were males.

Weiss et al. (1976) observed the disorder in a black male whose mother
had the same disorder. The thumbs in the son were strikingly broad.
'Metaphyseal' is a misnomer since striking diaphyseal changes with lack
of molding of the shafts of the long bones are found.

Kassner et al. (1976) reported an affected 8-year-old whose mother was
thought to have mild metaphyseal dysplasia and several minor skeletal
abnormalities that have occurred in patients with the syndrome; they
also described the disorder in maternal half brothers.

Medlar and Crawford (1978) described an affected male who presented with
scoliosis and had 2 of 3 sibs with significant scoliosis and similar
facial abnormalities.

Ullrich et al. (1979) reported the radiographic findings in a severely
affected boy and his mildly affected mother.

Abuelo and Ehrlich (1981) described a typically affected male whose
mother showed no evidence of the disorder in her facial features.
However, x-rays revealed marked hyperostosis of the mandible, scoliosis,
and other abnormalities.

Gorlin and Winter (1980) pointed out that dorsiflexion of the wrists and
extension of the elbows are reduced, with very limited pronation and
supination. Flexion deformities of the fingers and ulnar deviation of
the wrists are progressive. Missing permanent teeth and retained
deciduous teeth have been noted in most patients.

Beighton and Hamersma (1980) raised the question of whether
osteodysplasty of Melnick and Needles is the same as frontometaphyseal
dysplasia. They suggested that the disorder in males may be labeled
frontometaphyseal dysplasia and that in females called osteodysplasty.

Fitzsimmons et al. (1982) reported 4 cases in 1 family: grandmother,
mother, son and daughter. The male had obstructive uropathy at birth;
the authors found reports of associated renal abnormalities in 3 other
males. The male also had severe congenital stridor from subglottic
stenosis and a tracheal web. Both children had recurrent respiratory
tract infections.

Superti-Furga and Gimelli (1987) reexamined the patient reported as
having FMD by Danks et al. (1972) and concluded that the findings were
consistent with the diagnosis of otopalatodigital syndrome. A review of
10 male subjects with frontometaphyseal dysplasia and 13 male subjects
with the OPD syndrome from the literature revealed substantial
phenotypic overlap between the 2 disorders, which share an X-linked
inheritance pattern. They suggested that these may be the same disorder.

On the basis of experience with 2 newborn sons of an affected mother,
Glass and Rosenbaum (1995) commented on the difficulties in diagnosing
FMD in the neonatal period. In both boys, bone density was generally
increased, but most markedly so in the skull base. The coronal skull
sutures were partially fused. The metaphyses of all the long bones were
flared. As in the mother, the ribs were unusually shaped and there was
an anterior bony spur from the mandible. Both boys died neonatally of
severe congenital heart disease.

Franceschini et al. (1997) described a male infant in whom
frontometaphyseal dysplasia was complicated by esophageal atresia with
distal tracheoesophageal fistula. In a review of the literature they
noted that malformation of the bronchial tree, respiratory distress and
wheezing, narrowing of the subglottic area, and subglottic stenosis with
anterior web had been reported in individual cases previously.

Morava et al. (2003) described 2 families in which both males and
females showed the facial and skeletal characteristics of FMD in
association with severe progressive scoliosis. Some also had hearing
loss and urogenital anomalies, leading Morava et al. (2003) to suggest
that these were examples of frontootopalatodigital osteodysplasia as
described by Verloes et al. (2000).

INHERITANCE

Gorlin and Winter (1980) marshalled evidence for X-linked inheritance
with severe manifestations in males and variable manifestations in
females.

MOLECULAR GENETICS

Robertson et al. (2003) demonstrated gain-of-function mutations in the
filamin A gene in patients with frontometaphyseal dysplasia; see, e.g.,
300017.0011 (D1159A) and 300017.0015 (S1186L).

Giuliano et al. (2005) identified the S1186L mutation in the FLNA gene
in affected members of a 3-generation family with FMD.

Robertson et al. (2006) performed clinical and molecular analysis of 23
unrelated probands with FMD. No mutation in the FLNA gene was identified
in 10 of the 23 patients (43%), suggesting genetic heterogeneity.

*FIELD* SA
Sauvegrain et al. (1975); Stern et al. (1972)
*FIELD* RF
1. Abuelo, D. N.; Ehrlich, O.: Heterozygote detection in frontometaphyseal
dysplasia. (Abstract) Sixth Int. Cong. Hum. Genet., Jerusalem 258
only, 1981.

2. Beighton, P.; Hamersma, H.: Frontometaphyseal dysplasia: autosomal
dominant or X-linked? J. Med. Genet. 17: 53-56, 1980.

3. Danks, D. M.; Mayne, V.; Hall, R. K.; McKinnon, M. C.: Frontometaphyseal
dysplasia: a progressive disease of bone and connective tissue. Am.
J. Dis. Child. 123: 254-258, 1972.

4. Fitzsimmons, J. S.; Fitzsimmons, E. M.; Barrow, M.; Gilbert, G.
B.: Fronto-metaphyseal dysplasia: further delineation of the clinical
syndrome. Clin. Genet. 22: 195-205, 1982.

5. Franceschini, P.; Guala, A.; Licata, D.; Franceschini, D.; Signorile,
F.; Di Cara, G.: Esophageal atresia with distal tracheoesophageal
fistula in a patient with fronto-metaphyseal dysplasia. Am. J. Med.
Genet. 73: 10-14, 1997.

6. Giuliano, F.; Paquis-Flucklinger, V.; Collignon, P.; Philip, N.;
Bardot, J.: A new three-generational family with frontometaphyseal
dysplasia, male-to-female transmission, and a previously reported
FLNA mutation. (Letter) Am. J. Med. Genet. 132A: 222, 2005.

7. Glass, R. B. J.; Rosenbaum, K. N.: Frontometaphyseal dysplasia:
neonatal radiographic diagnosis. Am. J. Med. Genet. 57: 1-5, 1995.

8. Gorlin, R. J.; Cohen, M. M., Jr.: Frontometaphyseal dysplasia:
a new syndrome. Am. J. Dis. Child. 118: 487-494, 1969.

9. Gorlin, R. J.; Winter, R. B.: Frontometaphyseal dysplasia--evidence
for X-linked inheritance. Am. J. Med. Genet. 5: 81-84, 1980.

10. Holt, J. F.; Thompson, G. R.; Arenberg, I. K.: Frontometaphyseal
dysplasia. Radiol. Clin. N. Am. 10: 225-243, 1972.

11. Kassner, E. G.; Haller, J. O.; Reddy, V. H.; Mitarotundo, A.;
Katz, I.: Frontometaphyseal dysplasia: evidence for autosomal dominant
inheritance. Am. J. Roentgen. 127: 927-933, 1976.

12. Medlar, R. C.; Crawford, A. H.: Frontometaphyseal dysplasia presenting
as scoliosis. J. Bone Joint Surg. Am. 60: 392-394, 1978.

13. Morava, E.; Illes, T.; Weisenbach, J.; Karteszi, J.; Kosztolanyi,
G.: Clinical and genetic heterogeneity in frontometaphyseal dysplasia:
severe progressive scoliosis in two families. Am. J. Med. Genet. 116A:
272-277, 2003.

14. Robertson, S. P.: Filamin A: phenotypic diversity. Curr. Opinion
Genet. Dev. 15: 301-307, 2005.

15. Robertson, S. P.; Jenkins, Z. A.; Morgan, T.; Ades, L.; Aftimos,
S.; Boute, O.; Fiskerstrand, T.; Garcia-Minaur, S.; Grix, A.; Green,
A.; Der Kaloustian, V.; Lewkonia, R.; and 16 others: Frontometaphyseal
dysplasia: mutations in FLNA and phenotypic diversity. Am. J. Med.
Genet. 140A: 1726-1736, 2006. Note: Erratum: Am. J. Med. Genet. 140A:
2840 only, 2006.

16. Robertson, S. P.; Twigg, S. R. F.; Sutherland-Smith, A. J.; Biancalana,
V.; Gorlin, R. J.; Horn, D.; Kenwrick, S. J.; Kim, C. A.; Morava,
E.; Newbury-Ecob, R.; Orstavik, K. H.; Quarrell, O. W. J.; Schwartz,
C. E.; Shears, D. J.; Suri, M.; Kendrick-Jones, J.; OPD-spectrum
Disorders Clinical Collaborative Group; Wilkie, A. O. M.: Localized
mutations in the gene encoding the cytoskeletal protein filamin A
cause diverse malformations in humans. Nature Genet. 33: 487-491,
2003.

17. Sauvegrain, J.; Lombard, M.; Garel, L.; Truscelli, D.: Dysplasie
fronto-metaphysaire. Ann. Radiol. 18: 155-162, 1975.

18. Stern, S. D.; Arenberg, I. K.; Ongal, R. M.; Sandall, G. S.; Holt,
J. F.: The ocular and cosmetic problems in frontometaphyseal dysplasia. J.
Pediat. Ophthal. 9: 151-161, 1972.

19. Superti-Furga, A.; Gimelli, F.: Fronto-metaphyseal dysplasia
and the oto-palato-digital syndrome. Dysmorph. Clin. Genet. 1: 2-5,
1987.

20. Ullrich, E.; Witkowski, R.; Kozlowski, R.: Fronto-metaphyseal
dysplasia (report of two familial cases). Aust. Radiol. 23: 265-271,
1979.

21. Verloes, A.; Lesenfants, S.; Barr, M.; Grange, D. K.; Journel,
H.; Lombet, J.; Mortier, G.; Roeder, E.: Fronto-otopalatodigital
osteodysplasia: clinical evidence for a single entity encompassing
Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2,
and frontometaphyseal dysplasia. Am. J. Med. Genet. 90: 407-422,
2000.

22. Walker, B. A.: A craniodiaphyseal dysplasia or craniometaphyseal
dysplasia? Birth Defects Orig. Art. Ser. V(4): 298-300, 1969.

23. Weiss, L.; Reynolds, W. A.; Szymanowski, R. T.: Frontometaphyseal
dysplasia: evidence for dominant inheritance. Am. J. Dis. Child. 130:
259-264, 1976.

*FIELD* CS
INHERITANCE:
X-linked recessive

HEAD AND NECK:
[Face];
Coarse facies;
Prominent supraorbital ridges;
Small pointed chin;
[Ears];
Progressive mixed conductive and sensorineural hearing loss;
[Eyes];
Hypertelorism;
Downslanting palpebral fissures;
[Nose];
Wide nasal bridge;
[Mouth];
High palate;
[Teeth];
Selective tooth agenesis;
Delayed tooth eruption;
Retained deciduous teeth;
Malocclusion

CARDIOVASCULAR:
[Heart];
Mitral valve prolapse

RESPIRATORY:
[Airways];
Subglottic tracheal narrowing;
Congenital stridor;
[Lung];
Cor pulmonale

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Winged scapulae;
Irregular rib contours;
"Coat hanger" deformity of lower ribs

GENITOURINARY:
[Kidneys];
Hydronephrosis;
[Ureters];
Hydroureter

SKELETAL:
[Skull];
Incomplete sinus development;
Wide foramen magnum;
Antegonial notching of mandible;
Hypoplastic condyloid process;
[Spine];
Wide interpedicular distance;
Scoliosis;
Cervical vertebral fusion;
Anteriorly placed odontoid process;
[Pelvis];
Flared pelvis;
Coxa valga;
[Limbs];
Elbow contractures;
Knee and ankle contractures;
Erlenmeyer-flask appearance of femur and tibia;
Genu valgum;
Increased density of long bone diaphyses;
[Hands];
Finger and wrist contractures;
Arachnodactyly;
Wide and elongated phalanges;
Partial fusion of carpals;
[Feet];
Large feet;
Partial fusion of tarsals

SKIN, NAILS, HAIR:
[Hair];
Hirsutism of buttocks and thighs

MUSCLE, SOFT TISSUE:
Muscle wasting (especially legs and arms)

NEUROLOGIC:
[Central nervous system];
Mental retardation

MISCELLANEOUS:
Variable expression in females Otopalatodigital syndrome type I (OPD1,
311300) is an allelic disorder;
Otopalatodigital syndrome type II (OPD2, 304120) is an allelic disorder;
Melnick-Needles syndrome (MNS, 309350) is an allelic disorder;
Periventricular heterotopia (300049) is an allelic disorder

MOLECULAR BASIS:
Caused by mutation in the filamin A gene (FLNA, 300017.0011)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/25/2004
Kelly A. Przylepa - revised: 9/9/2002

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

*FIELD* ED
joanna: 07/02/2013
ckniffin: 4/13/2007
joanna: 11/1/2004
ckniffin: 10/25/2004
joanna: 9/9/2002

*FIELD* CN
Carol A. Bocchini - updated: 7/28/2009
Marla J. F. O'Neill - updated: 10/9/2006
Marla J. F. O'Neill - updated: 3/1/2005
Marla J. F. O'Neill - updated: 1/28/2005
Victor A. McKusick - updated: 3/19/2003
Victor A. McKusick - updated: 2/4/2003
Victor A. McKusick - updated: 12/1/1997

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

*FIELD* ED
terry: 01/13/2011
carol: 7/28/2009
carol: 7/24/2009
carol: 1/5/2007
ckniffin: 1/2/2007
carol: 10/9/2006
wwang: 3/7/2005
terry: 3/1/2005
carol: 2/3/2005
terry: 1/28/2005
terry: 6/3/2004
alopez: 4/2/2003
alopez: 3/21/2003
terry: 3/19/2003
carol: 2/28/2003
tkritzer: 2/20/2003
terry: 2/4/2003
terry: 6/5/1998
mark: 12/8/1997
terry: 12/1/1997
mark: 6/20/1995
carol: 2/7/1995
terry: 4/21/1994
warfield: 4/20/1994
mimadm: 2/27/1994
carol: 11/10/1993

MIM 309350
*RECORD*
*FIELD* NO
309350
*FIELD* TI
#309350 MELNICK-NEEDLES SYNDROME; MNS
;;MELNICK-NEEDLES OSTEODYSPLASTY;;
OSTEODYSPLASTY OF MELNICK AND NEEDLES
read more*FIELD* TX
A number sign (#) is used with this entry because Melnick-Needles
syndrome is caused by mutations in the gene encoding filamin A (FLNA;
300017).

DESCRIPTION

Melnick-Needles syndrome is 1 of 4 otopalatodigital syndromes caused by
mutations in the FLNA gene. These disorders, including frontometaphyseal
dysplasia (FMD; 305620), otopalatodigital syndrome-1 (OPD1; 311300), and
otopalatodigital syndrome-2 (OPD2; 304120), constitute a phenotypic
spectrum. At the mild end of the spectrum, males with OPD1 have cleft
palate and mild skeletal anomalies with conductive deafness caused by
ossicular anomalies. FMD is characterized by a generalized skeletal
dysplasia, deafness and urogenital defects. Males with OPD2 have
disabling skeletal anomalies in addition to variable malformations in
the hindbrain, heart, intestines, and kidneys that frequently lead to
perinatal death. The most severe phenotype, MNS, is characterized by a
skeletal dysplasia in the heterozygote. Affected males exhibit severe
malformations similar to those observed in individuals with OPD2,
resulting in prenatal lethality or death in the first few months of life
(review by Robertson, 2005). Verloes et al. (2000) suggested that these
disorders constitute a single entity, which they called
'fronto-otopalatodigital osteodysplasia.'

CLINICAL FEATURES

Melnick and Needles (1966) described families that contained multiple
cases in multiple generations of a severe congenital bone disorder
characterized by typical facies (exophthalmos, full cheeks, micrognathia
and malalignment of teeth), flaring of the metaphyses of long bones,
s-like curvature of bones of legs, irregular constrictions in the ribs,
and sclerosis of base of skull. Male-to-male transmission was thought to
have occurred in 1 instance. Ureteral obstruction was observed in the
original case (Melnick and Needles, 1966) and in several others
reported.

'Osteodysplasty' was the term suggested by Coste et al. (1968), who
described an affected 58-year-old woman. Bone disease was recognized in
infancy when she began to walk. Normal childbirth was impossible because
of contracted pelvis. Osteoarthritis of the lumbar spine and hips gave
much pain. Her height was normal. Striking facies comprised frog-like
eyes, high forehead, full red cheeks, and receding chin. X-rays showed
curved long bones, tortuous ribboned ribs, and deformed clavicles,
scapula, and pelvis.

Beighton and Hamersma (1980) speculated that frontometaphyseal dysplasia
and osteodysplasty (MNS) may be due to the same gene. They suggested
that the gene may be X-linked and that the former condition is the usual
phenotype in hemizygous males and the latter condition the usual
phenotype in heterozygous females. They pointed out that the
manifestations in Melnick and Needles' 2 kindreds (13 affected persons;
9 females, 4 males) were highly variable. Apart from one doubtful
instance, no male-to-male transmission was reported.

Features emphasized by Kozlowski (1993) on the basis of 9 cases included
small, deformed chest, large anterior fontanel associated with prominent
forehead, and high vertebrae. One of his patients was diagnosed at the
age of 37 years. All were female.

Kristiansen et al. (2002) reported 2 severely affected girls with
Melnick-Needles syndrome and their mildly affected mother. They analyzed
the X-chromosome inactivation pattern in this family to determine if it
was related to the variable phenotype. A very skewed inactivation
pattern was observed in the blood from both the mildly affected mother
and one of her daughters, whereas a highly skewed inactivation pattern
in buccal smear DNA was observed in the mother only. X inactivation,
therefore, did not explain the variable phenotype in this family.

- Males Born to Affected Mothers

Von Oeyen et al. (1981) observed an affected woman whose son, who died
soon after birth, was also affected. The son had omphalocele and
hypoplastic kidneys. Von Oeyen et al. (1982) reported a severely
affected male with multiple congenital anomalies who was born of an
affected mother and died soon after birth. A similar case was reported
by Theander and Ekberg (1981). Zackai et al. (1986) and Donnenfeld et
al. (1987) described a lethally affected male fetus identified
prenatally in a woman with oligohydramnios and MNS. The condition was
detected sonographically at 16 weeks' gestation. Autopsy on the
electively aborted fetus showed exophthalmos, prune belly sequence with
urethral atresia and megacystis, tetralogy of Fallot, atrioventricular
canal defect, and complete malrotation of the gut. Krajewska-Walasek et
al. (1987) found 6 examples of this syndrome in males: there were 3
well-documented lethal examples of the disorder among the offspring of
affected females and 3 examples in males born to normal parents and
presumably representing new mutations. One of the patients described in
detail died of pneumonia at age 3 after having repeated bouts of
pneumonia.

Van der Lely et al. (1991) described typical features in an 11-year-old
black male who was the sixth of 8 children of healthy, unrelated
parents. He may be the oldest surviving male with this disorder.

Neou et al. (1996) described a mother with Melnick-Needles syndrome
whose son had partial manifestations of the syndrome. His facial
features were similar to those of his mother. He was not short, but was
mentally retarded. His radiologic examination showed sclerotic skull
base, ribbon-like flaring of ribs, short bowed clavicles, small pelvis
with thin iliac crest, and moderate flaring of the distal part of the
long bones. In addition, he had atrial septal defect, pulmonic stenosis,
intestinal malrotation, and ectopic kidney. Neou et al. (1996) proposed
that Melnick-Needles syndrome is not always lethal in males born to
affected mothers.

Verloes et al. (2000) reported a mild case of OPD2, a severe case of
OPD2 with anomalies of the central nervous system and some
manifestations of frontometaphyseal dysplasia, a lethal case of OPD2
with similarities to Melnick-Needles syndrome, and 3 unrelated boys born
to mothers with MNS (1 with a severe form, 1 with a lethal form, and an
aborted fetus). They reviewed the features in these disorders and in
OPD1 and suggested that these disorders constitute a single entity.

INHERITANCE

Melnick-Needles syndrome is an X-linked dominant disorder. Most cases
described are in females. Nyhan and Sakati (1976) described a family
with 4 affected females in 3 successive generations. Von Oeyen et al.
(1982) found a sex ratio of 21 females and 3 males in reported cases.
Melnick (1982) studied 4 additional families in the United States; in
two, 3 generations were affected and in the other two, 2 generations.
The Melnick-Needles syndrome had been assumed to be an autosomal
dominant disorder. However, Gorlin and Knier (1982) analyzed reported
families with restudy of some. Melnick had reexamined the male 'cases'
in the kindred he reported in 1966 and found them in fact to be normal.
In all, Gorlin and Knier (1982) found 23 patients in 15 pedigrees. Most
cases were sporadic and may represent new mutations. In only 3 pedigrees
was there transmission from one generation to the next, always female to
female.

Ter Haar et al. (1982) suggested autosomal recessive inheritance on the
basis of a kindred with an affected brother and sister and their
affected fourth cousin. This disorder was later characterized as a
distinct entity and named ter Haar syndrome; see 249420.

See also review by Wettke-Schafer and Kantner (1983).

PATHOGENESIS

Svejcar (1983) found an increased content of collagen; the sclerosing
bone process may be an expression thereof. Fryns et al. (1988)
emphasized hyperlaxity of skin and joints as suggesting that this
condition is a generalized connective tissue disorder.

MOLECULAR GENETICS

X-linked inheritance is established by the demonstration of Robertson et
al. (2003) that Melnick-Needles syndrome is caused by gain-of-function
mutations in the gene encoding filamin A (FLNA; 300017). Mutations in
the FLNA gene were found in 12 presumably unrelated patients with
Melnick-Needles syndrome, all female. All had mutations in exon 22 of
the gene. One mutation was found in 6 individuals, a second mutation in
5, and a third mutation in a single case.

Robertson et al. (2006) identified a mutation in the FLNA gene
(300017.0013) in a girl with Melnick-Needles syndrome. The girl had an
unaffected twin sister who did not carry the mutation; the unaffected
mother also did not carry the mutation. The twins were born with
separate amniotic sacs within a single chorion, and zygosity analysis
indicated a high probability that the girls were monozygotic twins.
Robertson et al. (2006) concluded that the FLNA mutation occurred
postzygotically in the affected twin and emphasized the importance of
the finding for genetic counseling.

*FIELD* SA
Gorlin and Langer (1978); Maroteaux et al. (1968); Robertson (2007);
Sellars and Beighton (1978); Theodorou et al. (1982)
*FIELD* RF
1. Beighton, P.; Hamersma, H.: Frontometaphyseal dysplasia: autosomal
dominant or X-linked? J. Med. Genet. 17: 53-56, 1980.

2. Coste, F.; Maroteaux, P.; Chouraki, L.: Osteodysplasty (Melnick
and Needles' syndrome): report of a case. Ann. Rheum. Dis. 27: 360-366,
1968.

3. Donnenfeld, A. E.; Conard, K. A.; Roberts, N. S.; Borns, P. F.;
Zackai, E. H.: Melnick-Needles syndrome in males: a lethal multiple
congenital anomalies syndrome. Am. J. Med. Genet. 27: 159-173, 1987.

4. Fryns, J. P.; Schinzel, A.; Van den Berghe, H.: Hyperlaxity in
males with Melnick-Needles syndrome. Am. J. Med. Genet. 29: 607-611,
1988.

5. Gorlin, R. J.; Knier, J.: X-linked or autosomal dominant, lethal
in the male, inheritance of the Melnick-Needles (osteodysplasty) syndrome?
A reappraisal. (Letter) Am. J. Med. Genet. 13: 465-467, 1982.

6. Gorlin, R. J.; Langer, L. O., Jr.: Melnick-Needles syndrome: radiographic
alterations in the mandible. Radiology 128: 351-353, 1978.

7. Kozlowski, K.: Personal Communication. Sydney, Australia 5/29/1993.

8. Krajewska-Walasek, M.; Winkielman, J.; Gorlin, R. J.: Melnick-Needles
syndrome in males. Am. J. Med. Genet. 27: 153-158, 1987.

9. Kristiansen, M.; Knudsen, G. P.; Soyland, A.; Westvik, J.; Orstavik,
K. H.: Phenotypic variation in Melnick-Needles syndrome is not reflected
in X inactivation patterns from blood or buccal smear. Am. J. Med.
Genet. 108: 120-127, 2002.

10. Maroteaux, P.; Chouraki, L.; Coste, F.: L'osteodysplastie (syndrome
de Melnick et de Needles). Presse Med. 76: 715-718, 1968.

11. Melnick, J. C.: Osteodysplasty (Melnick and Needles syndrome).In:
Papadatos, C. J.; Bartsocas, C. S. (eds.): Skeletal Dysplasias.
New York: Alan R. Liss (pub.) 1982. Pp. 133-137.

12. Melnick, J. C.; Needles, C. F.: An undiagnosed bone dysplasia:
a two family study of 4 generations and 3 generations. Am. J. Roentgen. 97:
39-48, 1966.

13. Neou, P.; Kyrkanides, S.; Gioureli, E.; Bartsocas, C. S.: Melnick-Needles
syndrome in a mother and her son. Genet. Counsel. 7: 123-129, 1996.

14. Nyhan, W. L.; Sakati, N. O.: Genetic and Malformation Syndromes
in Clinical Medicine. Chicago: Year Book Med. Publ. (pub.) 1976.
Pp. 427-429.

15. Robertson, S. P.: Otopalatodigital syndrome spectrum disorders:
otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia
and Melnick-Needles syndrome. Europ. J. Hum. Genet. 15: 3-9, 2007.

16. Robertson, S. P.: Filamin A: phenotypic diversity. Curr. Opinion
Genet. Dev. 15: 301-307, 2005.

17. Robertson, S. P.; Thompson, S.; Morgan, T.; Holder-Espinasse,
M.; Martinot-Duquenoy, V.; Wilkie, A. O. M.; Manouvrier-Hanu, S.:
Postzygotic mutation and germline mosaicism in the otopalatodigital
syndrome spectrum disorders. Europ. J. Hum. Genet. 14: 549-554,
2006.

18. Robertson, S. P.; Twigg, S. R. F.; Sutherland-Smith, A. J.; Biancalana,
V.; Gorlin, R. J.; Horn, D.; Kenwrick, S. J.; Kim, C. A.; Morava,
E.; Newbury-Ecob, R.; Orstavik, K. H.; Quarrell, O. W. J.; Schwartz,
C. E.; Shears, D. J.; Suri, M.; Kendrick-Jones, J.; OPD-spectrum
Disorders Clinical Collaborative Group; Wilkie, A. O. M.: Localized
mutations in the gene encoding the cytoskeletal protein filamin A
cause diverse malformations in humans. Nature Genet. 33: 487-491,
2003.

19. Sellars, S. L.; Beighton, P. H.: Deafness in osteodysplasty of
Melnick and Needles. Arch. Otolaryng. 104: 225-227, 1978.

20. Svejcar, J.: Biochemical abnormalities in connective tissue of
osteodysplasty of Melnick-Needles and dyssegmental dwarfism. Clin.
Genet. 23: 369-375, 1983.

21. ter Haar, B.; Hamel, B.; Hendriks, J.; de Jager, J.: Melnick-Needles
syndrome: indication for an autosomal recessive form. Am. J. Med.
Genet. 13: 469-477, 1982.

22. Theander, G.; Ekberg, O.: Congenital malformations associated
with maternal osteodysplasty. Acta Radiol. 22: 369-377, 1981.

23. Theodorou, S. D.; Ierodiaconou, M. N.; Gerostathopoulos, N.; Grivas,
T.: Osteodysplasty (Melnick-Needles syndrome) in a male.In: Papadatos,
C. J.; Bartsocas, C. S.: Skeletal Dysplasias. New York: Alan R.
Liss (pub.) 1982. Pp. 139-142.

24. van der Lely, H.; Robben, S. G. F.; Meradji, M.; Derksen-Lubsen,
G.: Melnick-Needles syndrome (osteodysplasty) in an older male--report
of a case and a review of the literature. Brit. J. Radiol. 64: 852-854,
1991.

25. Verloes, A.; Lesenfants, S.; Barr, M.; Grange, D. K.; Journel,
H.; Lombet, J.; Mortier, G.; Roeder, E.: Fronto-otopalatodigital
osteodysplasia: clinical evidence for a single entity encompassing
Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2,
and frontometaphyseal dysplasia. Am. J. Med. Genet. 90: 407-422,
2000.

26. von Oeyen, P.; Holmes, L. B.; Trelstad, R. L.; Griscom, N. T.
H.: Omphalocele and multiple severe congenital anomalies associated
with osteodysplasty (Melnick-Needles syndrome). Am. J. Med. Genet. 13:
453-463, 1982.

27. von Oeyen, P. T.; Holmes, L. B.; Trelstad, R. L.; Griscom, N.
T.: Melnick-Needles syndrome with omphalocele and renal hypoplasia.
(Abstract) Am. J. Hum. Genet. 33: 92A only, 1981.

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

29. Zackai, E. H.; Donnenfeld, A. E.; Conard, K. A.; Roberts, N. S.;
Borns, P. F.: The male Melnick-Needles syndrome phenotype. (Abstract) Am.
J. Hum. Genet. 39: A88 only, 1986.

*FIELD* CS
INHERITANCE:
X-linked dominant

GROWTH:
[Height];
Short to normal stature;
[Other];
Failure to thrive

HEAD AND NECK:
[Head];
Delayed closure of fontanel;
[Face];
Small face;
Prominent hirsute forehead;
Full cheek;
Micrognathia;
Prominent supraorbital ridge;
[Ears];
Large ears;
Recurrent otitis media;
[Eyes];
Exophthalmos;
Hypertelorism;
Strabismus;
[Mouth];
Cleft palate;
[Teeth];
Malaligned teeth;
Delayed tooth eruption;
[Neck];
Long neck

CARDIOVASCULAR:
[Heart];
Mitral valve prolapse;
Tricuspid valve prolapse;
Noncompaction of ventricular myocardium

RESPIRATORY:
Recurrent respiratory infections;
[Lung];
Pulmonary hypertension

CHEST:
[External features];
Narrow shoulders;
[Ribs, sternum, clavicles, and scapulae];
Pectus excavatum;
Irregular ribbon-like ribs;
Short clavicles;
Short scapulae

ABDOMEN:
[Gastrointestinal];
Omphalocele (males)

GENITOURINARY:
[Kidneys];
Hydronephrosis;
[Ureters];
Ureteral stenosis

SKELETAL:
[Skull];
Small mandible with obtuse angle;
Hypoplastic coronoid process;
Dense skull base;
Delayed paranasal sinus development;
[Spine];
Tall vertebrae;
Kyphoscoliosis;
Anterior concavity of thoracic vertebrae;
[Pelvis];
Coxa valga;
Iliac flaring;
Hip dislocation;
[Limbs];
Short upper arms;
Bowing of humerus;
Bowing of radius;
Bowing of ulna;
Bowing of tibia;
Metaphyseal flaring of long bones;
Genu valgum;
Limited elbow extension;
[Hands];
Short distal phalanges;
Cone-shaped epiphyses;
Acroosteolysis;
[Feet];
Club feet;
Pes planus

SKIN, NAILS, HAIR:
[Skin];
Hirsute forehead;
Skin hyperlaxity (males);
[Hair];
Coarse hair

NEUROLOGIC:
[Central nervous system];
Delayed motor development;
Abnormal gait

VOICE:
Hoarse voice

MISCELLANEOUS:
Fifty percent of cases secondary to new mutations;
Males born to affected females are stillborn with exophthalmos, omphalocele,
thin calvaria, curved long bones, and hypoplastic/absence thumbs and
halluces;
Affected males who survive are secondary to new mutations;
Otopalatodigital syndrome type I (OPD1, 311300) is an allelic disorder;
Otopalatodigital syndrome type II (OPD2, 304120) is an allelic disorder;
Frontometaphyseal dysplasia (FMD, 305620) is an allelic disorder;
Periventricular heterotopia (300049) is an allelic disorder

MOLECULAR BASIS:
Caused by mutations in the filamin A gene (FLNA, 300017.0012)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/25/2004
Kelly A. Przylepa - revised: 12/9/2003

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

*FIELD* ED
joanna: 12/05/2008
ckniffin: 10/25/2004
joanna: 12/9/2003

*FIELD* CN
Carol A. Bocchini - updated: 07/28/2009
Cassandra L. Kniffin - updated: 6/2/2006
Victor A. McKusick - updated: 3/19/2003
Cassandra L. Kniffin - reorganized: 5/1/2002
Sonja A. Rasmussen - updated: 4/18/2002
Iosif W. Lurie - updated: 9/22/1996

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

*FIELD* ED
carol: 07/28/2009
wwang: 6/5/2006
ckniffin: 6/2/2006
alopez: 5/12/2004
carol: 4/6/2004
alopez: 4/2/2003
alopez: 3/21/2003
terry: 3/19/2003
carol: 5/1/2002
ckniffin: 4/30/2002
carol: 4/19/2002
terry: 4/18/2002
carol: 9/22/1996
terry: 4/20/1994
mimadm: 2/27/1994
carol: 6/3/1993
supermim: 3/17/1992
carol: 3/7/1992
carol: 10/28/1991

MIM 311300
*RECORD*
*FIELD* NO
311300
*FIELD* TI
#311300 OTOPALATODIGITAL SYNDROME, TYPE I; OPD1
;;OPD I SYNDROME;;
OPD SYNDROME 1
OTOPALATODIGITAL SPECTRUM DISORDER, INCLUDED;;
read moreFRONTOOTOPALATODIGITAL OSTEODYSPLASIA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because otopalatodigital
syndrome type I (OPD1) is caused by gain-of-function mutations in the
gene encoding filamin A (FLNA; 300017).

DESCRIPTION

Otopalatodigital syndrome-1 is 1 of 4 otopalatodigital syndromes caused
by mutations in the FLNA gene. The disorders, which include
frontometaphyseal dysplasia (FMD; 305620), otopalatodigital syndrome-2
(OPD2; 304120), and Melnick-Needles syndrome (MNS; 309350), constitute a
phenotypic spectrum. At the mild end of the spectrum, males with OPD1
have cleft palate and mild skeletal anomalies with conductive deafness
caused by ossicular anomalies. FMD is characterized by a generalized
skeletal dysplasia, deafness and urogenital defects. Males with OPD2
have disabling skeletal anomalies in addition to variable malformations
in the hindbrain, heart, intestines, and kidneys that frequently lead to
perinatal death. The most severe phenotype, MNS, is characterized by a
skeletal dysplasia in the heterozygote. Affected males exhibit severe
malformations similar to those observed in individuals with OPD2,
resulting in prenatal lethality or death in the first few months of life
(review by Robertson, 2005). Verloes et al. (2000) suggested that these
disorders constitute a single entity, which they termed
'frontootopalatodigital osteodysplasia.'

CLINICAL FEATURES

Dudding et al. (1967) described 3 male sibs with conduction deafness,
cleft palate, characteristic facies, and a generalized bone dysplasia. A
broad nasal root gives the patient a pugilistic appearance. Wide-spacing
of the toes creates a resemblance to the foot of a tree frog. X-linkage
and autosomal inheritance could not be distinguished. Roentgenologic
features were reviewed in the same patients by Langer (1967). (The male
patient reported by Taybi (1962) may have had this condition.)
Conductive hearing loss, somewhat broad thumbs and great toes, short
fingernails, fifth finger clinodactyly, dislocation of the head of the
radius, pectus excavatum, and mild dwarfism were also features. A
secondary ossification center at the base of the second metacarpal and
metatarsal is characteristic.

Turner (1970) observed affected half brothers who had different fathers,
thus supporting X-linked inheritance. Weinstein and Cohen (1966)
suggested that an X-linked form of cleft palate exists. Affected males
and carrier females showed hypertelorism and median frontal prominence.
Four males in 3 sibships connected through 5 presumably heterozygous
females were affected. Gorlin (1967) suggested that the condition in
this family was the OPD syndrome. The x-ray changes in the hands and
feet were consistent (Gorlin, 1971). Gall et al. (1972) and Poznanski et
al. (1974) demonstrated heterozygote changes in radiographs of the hands
and feet.

Pazzaglia and Beluffi (1986) described a family with affected persons in
4 generations. Severe scoliosis was present in 1 patient, a feature that
apparently had not previously been reported in the OPD syndrome. Also in
this family, there was no deafness or cleft palate. On the other hand,
many of the skeletal findings were thought to be characteristic. The
pedigree was consistent with X-linked inheritance with variable and
intermediate expression in the female.

Rosenbaum et al. (1986) described a family with affected mother, son,
and daughter; in only the male was the expression complete. The mother
was related to her husband as a first cousin. Another couple, both of
whom were related to this man and his wife as first cousins, had 3
children thought to have Larsen syndrome (245600), manifest by
congenital dislocation of the hips and knees associated with flattened
facies.

Le Marec et al. (1988) described a family with affected persons in 5
generations. They suggested that the disorder called OPD II (304120) by
Fitch et al. (1983) might be allelic.

Kozlowski (1993) pointed out that long second metacarpal and fifth
metatarsal are typical in OPD I. Extracarpal bones occur as in Larsen
syndrome, particularly typical changes at the elbow and especially a
deepened fossa at the proximal ulna. Kozlowski (1993) emphasized that
OPD I, a relatively common bone dysplasia, can have very subtle clinical
and radiologic expression that may go unnoticed until the disorder is
recognized in a more severely affected member of the family. OPD II, on
the other hand, is a severe disorder. Gorlin (1993) indicated that
mental retardation is not a feature of OPD I.

Verloes et al. (2000) reported a mild case of OPD2, a severe case of
OPD2 with anomalies of the central nervous system and some
manifestations of frontometaphyseal dysplasia, a lethal case of OPD2
with similarities to Melnick-Needles syndrome, and 3 unrelated boys born
to mothers with MNS (1 with a severe form, 1 with a lethal form, and an
aborted fetus). They reviewed the features in these disorders and in
OPD1 and suggested that these disorders constitute a single entity,
which they called 'fronto-otopalatodigital osteodysplasia.' Verloes et
al. (2000) also discussed the relationship to similar syndromes, such as
Yunis-Varon syndrome (216340), type III atelosteogenesis (108721), and
boomerang dysplasia (112310).

Morava et al. (2003) described 2 families in which both males and
females showed the facial and skeletal characteristics of FMD in
association with severe progressive scoliosis. Some also had hearing
loss and urogenital anomalies, leading Morava et al. (2003) to suggest
that these were examples of frontootopalatodigital osteodysplasia as
described by Verloes et al. (2000).

MAPPING

In studies of a 3-generation family with OPD1, Hoo et al. (1991) and
Hoar et al. (1992) found a suggestion of linkage to DNA markers on the
distal long arm of the X chromosome. Studies of another family by
Biancalana et al. (1991) excluded linkage to the Xq26 region and
provided further support for mapping of the OPD1 gene to Xq28. A
combined lod score of 3.19 was reported.

Robertson et al. (2001) found linkage of the more severe, frequently
lethal phenotype, termed OPD2, to the same region of distal Xq28 to
which the OPD1 locus had been mapped. This provided support for allelism
between OPD1 and OPD2. Furthermore, it was possible to reduce the size
of the disease interval to 1.8 to 2.1 Mb. They demonstrated that female
carriers of OPD2 exhibited skewed inactivation that segregated with the
high-risk haplotype and may be inversely related to the severity with
which they manifest features of the disorder.

MOLECULAR GENETICS

Robertson et al. (2003) demonstrated that OPD1 is caused by
gain-of-function mutations in the gene encoding filamin A (FLNA;
300017). They also demonstrated FLNA mutations in OPD2.

In a 26-year-old Mexican female with OPD1, Hidalgo-Bravo et al. (2005)
identified a heterozygous missense mutation in the FLNA gene
(300017.0020). The patient had prominent features of OPD1, including
cleft palate; an extremely skewed pattern of X inactivation toward the
maternal allele was noted.

Robertson et al. (2006) identified a mutation in the FLNA gene
(300017.0009) in 2 brothers with OPD1. The mutation was not identified
in leukocytes of the mother, suggesting germline mosaicism. The authors
emphasized the importance of the finding for genetic counseling.

In 6 females with cranial hyperostosis and various skeletal
abnormalities from a 4-generation pedigree, Stefanova et al. (2005)
identified heterozygosity for a deletion in the FLNA gene (300017.0016).
The phenotype of affected females resembled FMD with some overlap to
OPD1 and OPD2, but no signs specific for MNS. However, males had severe
extraskeletal malformations and died early, thus constituting an overlap
with OPD2 and MNS. Stefanova et al. (2005) concluded that the disorder
in this family is best described as an intermediate OPD-spectrum
phenotype that bridges the FMD and OPD2 phenotypes.

Zenker et al. (2006) described a de novo mutation in the FLNA gene
(300017.0022) in a girl with manifestations of FMN and OPD1.

*FIELD* SA
Robertson (2007)
*FIELD* RF
1. Biancalana, V.; Le Marec, B.; Odent, S.; van den Hurk, J. A. M.
J.; Hanauer, A.: Oto-palato-digital syndrome type I: further evidence
for assignment of the locus to Xq28. Hum. Genet. 88: 228-230, 1991.

2. Dudding, B. A.; Gorlin, R. J.; Langer, L. O., Jr.: The oto-palato-digital
syndrome: a new symptom-complex consisting of deafness, dwarfism,
cleft palate, characteristic facies, and a generalized bone dysplasia. Am.
J. Dis. Child. 113: 214-221, 1967.

3. Fitch, N.; Jequier, S.; Gorlin, R.: The oto-palato-digital syndrome,
proposed type II. Am. J. Med. Genet. 15: 655-664, 1983.

4. Gall, J. C., Jr.; Stern, A. M.; Poznanski, A. K.; Garn, S. M.;
Weinstein, E. D.; Hayward, J. R.: Oto-palato-digital syndrome: comparison
of clinical and radiographic manifestations in males and females. Am.
J. Hum. Genet. 24: 24-36, 1972.

5. Gorlin, R. J.: Personal Communication. Minneapolis, Minn. 5/30/1993.

6. Gorlin, R. J.: Personal Communication. Minneapolis, Minn. 1967.

7. Gorlin, R. J.: Personal Communication. Minneapolis, Minn. 1971.

8. Hidalgo-Bravo, A.; Pompa-Mera, E. N.; Kofman-Alfaro, S.; Gonzalez-Bonilla,
C. R.; Zenteno, J. C.: A novel filamin A D203Y mutation in a female
patient with otopalatodigital type 1 syndrome and extremely skewed
X chromosome inactivation. Am. J. Med. Genet. 136A: 190-193, 2005.

9. Hoar, D. I.; Field, L. L.; Beards, F.; Hoganson, G.; Rollnick,
B.; Hoo, J. J.: Tentative assignment of gene for oto-palato-digital
syndrome to distal Xq (Xq26-q28). Am. J. Med. Genet. 42: 170-172,
1992.

10. Hoo, J. J.; Hoar, D. I.; Field, L. L.; Beards, F.; Hoganson, G.;
Rollnick, B.: Tentative assignment of oto-palato-digital syndrome
gene to distal Xq (Xq26-q28) New York: IRL Press (pub.) 1991.
P. 11.

11. Kozlowski, K.: Personal Communication. Sydney, Australia 5/30/1993.

12. Langer, L. O., Jr.: The roentgenographic features of the oto-palato-digital
(OPD) syndrome. Am. J. Roentgen. 100: 63-70, 1967.

13. Le Marec, B.; Odent, S.; Bracq, E.; Bulard, M. B.; Bourdiniere,
J.; Babut, J. M.: Syndrome oto-palato-digital de type I atteignant
cinq generations: relations avec la forme de type II. Ann. Genet. 31:
155-161, 1988.

14. Morava, E.; Illes, T.; Weisenbach, J.; Karteszi, J.; Kosztolanyi,
G.: Clinical and genetic heterogeneity in frontometaphyseal dysplasia:
severe progressive scoliosis in two families. Am. J. Med. Genet. 116A:
272-277, 2003.

15. Pazzaglia, U. E.; Beluffi, G.: Oto-palato-digital syndrome in
four generations of a large family. Clin. Genet. 30: 338-344, 1986.

16. Poznanski, A. K.; Macpherson, R. I.; Dijkman, D. J.; Gorlin, R.
J.; Gall, J. C., Jr.; Stern, A. M.; Garn, S. M.; Nagy, J. M.: Otopalatodigital
syndrome: radiologic findings in the hand and foot. Birth Defects
Orig. Art. Ser. 10(5): 125-139, 1974.

17. Robertson, S. P.: Filamin A: phenotypic diversity. Curr. Opinion
Genet. Dev. 15: 301-307, 2005.

18. Robertson, S. P.: Otopalatodigital syndrome spectrum disorders:
otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia
and Melnick-Needles syndrome. Europ. J. Hum. Genet. 15: 3-9, 2007.

19. Robertson, S. P.; Thompson, S.; Morgan, T.; Holder-Espinasse,
M.; Martinot-Duquenoy, V.; Wilkie, A. O. M.; Manouvrier-Hanu, S.:
Postzygotic mutation and germline mosaicism in the otopalatodigital
syndrome spectrum disorders. Europ. J. Hum. Genet. 14: 549-554,
2006.

20. Robertson, S. P.; Twigg, S. R. F.; Sutherland-Smith, A. J.; Biancalana,
V.; Gorlin, R. J.; Horn, D.; Kenwrick, S. J.; Kim, C. A.; Morava,
E.; Newbury-Ecob, R.; Orstavik, K. H.; Quarrell, O. W. J.; Schwartz,
C. E.; Shears, D. J.; Suri, M.; Kendrick-Jones, J.; OPD-spectrum
Disorders Clinical Collaborative Group; Wilkie, A. O. M.: Localized
mutations in the gene encoding the cytoskeletal protein filamin A
cause diverse malformations in humans. Nature Genet. 33: 487-491,
2003.

21. Robertson, S. P.; Walsh, S.; Oldridge, M.; Gunn, T.; Becroft,
D.; Wilkie, A. O. M.: Linkage of otopalatodigital syndrome type 2
(OPD2) to distal Xq28: evidence for allelism with OPD1. Am. J. Hum.
Genet. 69: 223-227, 2001.

22. Rosenbaum, S.; Carakushazky, G.; Gleiser, S.: The oto-palatal-digital
syndrome. Rev. Brasil. Genet. 9: 341-347, 1986.

23. Stefanova, M.; Meinecke, P.; Gal, A.; Bolz, H.: A novel 9 bp
deletion in the filamin A gene causes an otopalatodigital-spectrum
disorder with a variable, intermediate phenotype. Am. J. Med. Genet. 132A:
386-390, 2005.

24. Taybi, H.: Generalized skeletal dysplasia with multiple anomalies:
a note on Pyle's disease. Am. J. Roentgen. 88: 450-457, 1962.

25. Turner, G.: Personal Communication. Sydney, Australia 1970.

26. Verloes, A.; Lesenfants, S.; Barr, M.; Grange, D. K.; Journel,
H.; Lombet, J.; Mortier, G.; Roeder, E.: Fronto-otopalatodigital
osteodysplasia: clinical evidence for a single entity encompassing
Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2,
and frontometaphyseal dysplasia. Am. J. Med. Genet. 90: 407-422,
2000.

27. Weinstein, E. D.; Cohen, M. M.: Sex-linked cleft palate: report
of a family and review of 77 kindreds. J. Med. Genet. 3: 17-22,
1966.

28. Zenker, M.; Nahrlich, L.; Sticht, H.; Reis, A.; Horn, D.: Genotype-epigenot
ype-phenotype correlations in females with frontometaphyseal dysplasia. Am.
J. Med. Genet. 140A: 1069-1073, 2006.

*FIELD* CS
INHERITANCE:
X-linked dominant

GROWTH:
[Height];
Short stature (<10th percentile for age)

HEAD AND NECK:
[Head];
Prominent occiput;
Prominent supraorbital ridges;
[Face];
Frontal bossing;
Flat face;
[Ears];
Conductive hearing loss;
[Eyes];
Hypertelorism;
Downslanting palpebral fissures;
[Nose];
Small nose;
Broad nasal root;
[Mouth];
Microstomia;
Cleft palate;
[Teeth];
Selective tooth agenesis;
Impacted teeth

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Pectus excavatum

ABDOMEN:
[External features];
Omphalocele

SKELETAL:
[Skull];
Absent frontal sinuses;
Absent sphenoid sinuses;
Thick frontal bone;
Thick skull base;
Delayed closure of anterior fontanel;
Steep clivus;
Dense middle-ear ossicles;
[Spine];
Scoliosis;
Small pedicles;
[Pelvis];
Small iliac crests;
Hip dislocation;
Flat acetabulum;
Coxa valga;
[Limbs];
Limited elbow extension;
Limited knee flexion;
Radial head dislocation;
Mild, lateral femoral bowing;
[Hands];
Short, broad distal phalanges, especially thumbs;
Short square nails;
Short third, fourth, fifth metacarpals;
Supernumerary carpal bones;
Fusion of hamate and capitate;
[Feet];
Short, broad halluces;
Toe syndactyly;
Anomalous fifth metatarsal;
Extra calcaneal ossification center;
Gap between first and second toes;
'Tree-frog' feet

SKIN, NAILS, HAIR:
[Nails];
Nail dystrophy;
Short square fingernails

NEUROLOGIC:
[Central nervous system];
Mild mental retardation

MISCELLANEOUS:
Intermediate expression in females;
Complete manifestation in males;
Otopalatodigital syndrome type II (OPD2, 304120) is an allelic disorder
with a more severe, frequently lethal phenotype;
Frontometaphyseal dysplasia (FMD, 305620) is an allelic disorder;
Melnick-Needles syndrome (MNS, 309350) is an allelic disorder;
Periventricular heterotopia (300049) is an allelic disorder

MOLECULAR BASIS:
Caused by mutation in the filamin A gene (300017.0009)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/25/2004
Kelly A. Przylepa - revised: 4/25/2002

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

*FIELD* ED
joanna: 05/25/2012
ckniffin: 4/13/2007
ckniffin: 10/25/2004
joanna: 4/25/2002

*FIELD* CN
Carol A. Bocchini - updated: 7/28/2009
Marla J. F. O'Neill - updated: 2/1/2008
Cassandra L. Kniffin - updated: 6/5/2006
Marla J. F. O'Neill - updated: 12/29/2005
Victor A. McKusick - updated: 3/19/2003
Victor A. McKusick - updated: 8/16/2001

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

*FIELD* ED
carol: 09/16/2010
carol: 7/28/2009
carol: 7/24/2009
carol: 7/23/2009
wwang: 2/4/2008
terry: 2/1/2008
wwang: 6/5/2006
wwang: 12/29/2005
terry: 6/3/2004
alopez: 4/2/2003
alopez: 3/21/2003
terry: 3/19/2003
cwells: 9/7/2001
cwells: 8/28/2001
terry: 8/16/2001
terry: 7/9/1997
davew: 8/17/1994
jason: 7/13/1994
mimadm: 4/29/1994
warfield: 3/16/1994
carol: 6/28/1993
carol: 6/3/1993

MIM 314400
*RECORD*
*FIELD* NO
314400
*FIELD* TI
#314400 CARDIAC VALVULAR DYSPLASIA, X-LINKED; CVD1
;;VALVULAR HEART DISEASE, CONGENITAL;;
read moreMYXOMATOUS VALVULAR DYSTROPHY, X-LINKED; XMVD
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
X-linked cardiac valvular dysplasia is caused by mutation in the FLNA
gene (300017).

DESCRIPTION

X-linked cardiac valvular dysplasia is a rare X-linked form of heart
disease characterized by mitral and/or aortic valve regurgitation. Only
males have been diagnosed as affected, while carrier females are
asymptomatic. The histologic features do not differ from the common
severe and idiopathic mitral valve prolapse.

CLINICAL FEATURES

Monteleone and Fagan (1969) described 6 definite and 1 probable case of
congenital heart disease in males in 4 sibships of 3 generations of a
black kindred in a pattern suggesting X-linked recessive inheritance.
Four had mitral and aortic regurgitation, of whom 2 also had tricuspid
regurgitation. The fifth definite case had only mitral regurgitation.
Histologically, changes in the mitral valve of 1 case resembled those
seen in the 'floppy valve syndrome' (Read et al., 1965) or in Marfan
syndrome (which was suggested by no other feature of the cases).

Newbury-Ecob et al. (1993) described a British family in which 2
brothers and the son of a daughter of one of them had valvular
dysplasia. The grandson died in severe heart failure in the first day of
life. All 4 heart valves were abnormal. The tricuspid and mitral valves
had edematous and irregular cusps with short and irregular chordae. The
aortic and pulmonary valves were bicuspid but also showed thickening and
edema of the cusps. The aortic ring was stenotic. The maternal
grandfather was asymptomatic until the age of 25 years when he developed
progressive breathlessness; at the age of 41 years, he underwent
surgical replacement of the aortic mitral and tricuspid valves, which
were the site of myxomatous degeneration with secondary calcification
and regurgitation. His brother had severe mitral valve prolapse.

Kyndt et al. (2007) studied a large French pedigree segregating X-linked
cardiac valvular disease, originally reported by Benichou et al. (1997)
and Kyndt et al. (1998), and identified a new branch of the family with
a common ancestor born in the eighteenth century. The extended family
included 14 affected males, all of whom had mitral valve disease and all
but 1 of whom also had aortic valve regurgitation. Twelve male patients
had progressive mitral valve prolapse, found on the anterior valve in 4
and on both valves in 8. Five male patients underwent valve surgery, 3
for replacement of the aortic valve, 1 for both aortic and mitral valve
replacement, and 1 for mitral valvuloplasty. Mild to moderate tricuspid
valve regurgitation was found in 11 affected males, and mild pulmonary
regurgitation in 4, but none had surgery of the tricuspid or pulmonary
valves. In all affected males, the valvular disease was associated with
mild hemophilia A (306700), with factor VIII (300841) activity between
15% and 50%. There were 30 carrier females in the family, all of whom
were asymptomatic; upon examination, however, 14 of the carrier females
were considered affected, 12 had minor valve disease and were designated
'undetermined,' and only 4 were considered unaffected. Among carrier
females, 4 had mitral valve prolapse, involving the anterior valve in 3
cases and the posterior valve in 1 case; mitral valve regurgitation was
mild in 19 and moderate in 4; aortic valve regurgitation was mild in 8,
moderate in 3, and severe in 1; tricuspid valve regurgitation was mild
in 9 and moderate in 1; and pulmonary valve regurgitation was mild in 2
and moderate in 1. None of the carrier females had undergone valvular
surgery.

MAPPING

Benichou et al. (1997) did linkage studies of a large 5-generation
French pedigree in which males were severely affected and carrier
females were also affected but to a milder extent, consistent with
X-linked inheritance. Using dinucleotide repeat markers, they assigned
the gene for CVD to an 8-cM region of Xq28. A 5.91 lod score was
obtained for 2 distal markers, including an intronic microsatellite of
the factor VIII gene. In the full report of this study, Kyndt et al.
(1998) reported a maximum lod score of 6.54 at theta = 0.0 for 2
polymorphic microsatellite markers, INT3 and DXS1008, the first being
intronic to the factor VIII gene. Kyndt et al. (1998) referred to
X-linked CVD as X-linked myxomatous valvular dystrophy (XMVD). Haplotype
analysis of this chromosomal region allowed definition of an 8-cM
minimal interval containing the gene for XMVD, between DXS8011 and
Xqter. Kyndt et al. (2007) performed additional linkage analysis in the
large French pedigree with valvular dysplasia, including a new branch of
the family with a common ancestor born in the eighteenth century, and
refined the critical region to a 2.5-Mb interval between DXS10049 and
the GAB3 gene (300482) that excluded the factor VIII gene (300841).

MOLECULAR GENETICS

Kyndt et al. (2007) analyzed candidate genes in the large French
pedigree with X-linked cardiac valvular disease and identified a
hemizygous mutation (P637Q; 300017.0030) that segregated with disease.
In the British family originally studied by Newbury-Ecob et al. (1993)
and in 2 additional families with cardiac valvular disease, Kyndt et al.
(2007) identified respective mutations in the FLNA gene
(300017.0031-300017.0033). The mutations segregated with disease in the
families and were not found in control chromosomes. All 4 families
presented no clinically apparent extracardiac abnormalities, no
dysmorphic features, and no epileptic seizures.

*FIELD* RF
1. Benichou, B.; Kyndt, F.; Schott, J.-J.; Trochu, J.-N.; Baranger,
F.; Herbert, O.; Scott, V.; Fressinaud, E.; David, A.; Moisan, J.-P.;
Bouhour, J.-B.; Le Marec, H.: Mapping of X-linked valvular dysplasia
to chromosome Xq28. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A268
only, 1997.

2. Kyndt, F.; Gueffet, J.-P.; Probst, V.; Jaafar, P.; Legendre, A.;
Le Bouffant, F.; Toquet, C.; Roy, E.; McGregor, L.; Lynch, S. A.;
Newbury-Ecob, R.; Tran, V.; Young, I.; Trochu, J.-N.; Le Marec, H.;
Schott, J.-J.: Mutations in the gene encoding filamin A as a cause
for familial cardiac valvular dystrophy. Circulation 115: 40-49,
2007.

3. Kyndt, F.; Schott, J.-J.; Trochu, J.-N.; Baranger, F.; Herbert,
O.; Scott, V.; Fressinaud, E.; David, A.; Moisan, J.-P.; Bouhour,
J.-B.; Le Marec, H.; Benichou, B.: Mapping of X-linked myxomatous
valvular dystrophy to chromosome Xq28. Am. J. Hum. Genet. 62: 627-632,
1998.

4. Monteleone, P. L.; Fagan, L. F.: Possible X-linked congenital
heart disease. Circulation 39: 611-614, 1969.

5. Newbury-Ecob, R. A.; Zuccollo, J. M.; Rutter, N.; Young, I. D.
: Sex linked valvular dysplasia. J. Med. Genet. 30: 873-874, 1993.

6. Read, R. C.; Thal, A. P.; Wendt, V. E.: Symptomatic valvular myxomatous
transformation (the floppy valve syndrome). A possible forme fruste
of the Marfan syndrome. Circulation 32: 897-910, 1965.

*FIELD* CS

Cardiac:
Congenital heart defect;
Mitral regurgitation;
Aortic regurgitation;
Tricuspid regurgitation;
Mitral valve prolapse;
Valvular dysplasia;
Congestive heart failure;
Thickened valve cusps;
Irregular valve cusps;
Short and irregular chordae;
Stenotic aortic ring

Lab:
Myxomatous cardiac valvular degeneration with secondary calcification

Inheritance:
X-linked recessive

*FIELD* CN
Marla J. F. O'Neill - updated: 10/28/2010
Victor A. McKusick - updated: 3/10/1998
Victor A. McKusick - updated: 10/22/1997

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

*FIELD* ED
carol: 04/07/2011
wwang: 10/28/2010
terry: 10/28/2010
alopez: 3/17/2004
carol: 11/7/2002
dholmes: 3/30/1998
alopez: 3/10/1998
terry: 3/9/1998
terry: 10/28/1997
jenny: 10/24/1997
terry: 10/22/1997
mimadm: 2/28/1994
carol: 11/5/1993
supermim: 3/17/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

RBCC Red Blood Cell Collection

Full text data of FLNA