RBCC Red Blood Cell Collection

FLNB (FLN1L, FLN3, TABP, TAP) [Confidence: low (only semi-automatic identification from reviews)]
Filamin-B; FLN-B (ABP-278; ABP-280 homolog; Actin-binding-like protein; Beta-filamin; Filamin homolog 1; Fh1; Filamin-3; Thyroid autoantigen; Truncated actin-binding protein; Truncated ABP)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt O75369
ID FLNB_HUMAN Reviewed; 2602 AA.
AC O75369; B2ZZ83; B2ZZ84; B2ZZ85; C9JKE6; C9JMC4; Q13706; Q59EC2;
read moreAC Q60FE7; Q6MZJ1; Q8WXS9; Q8WXT0; Q8WXT1; Q8WXT2; Q9NRB5; Q9NT26;
AC Q9UEV9;
DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Filamin-B;
DE Short=FLN-B;
DE AltName: Full=ABP-278;
DE AltName: Full=ABP-280 homolog;
DE AltName: Full=Actin-binding-like protein;
DE AltName: Full=Beta-filamin;
DE AltName: Full=Filamin homolog 1;
DE Short=Fh1;
DE AltName: Full=Filamin-3;
DE AltName: Full=Thyroid autoantigen;
DE AltName: Full=Truncated actin-binding protein;
DE Short=Truncated ABP;
GN Name=FLNB; Synonyms=FLN1L, FLN3, TABP, TAP;
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), TISSUE SPECIFICITY,
RP SUBCELLULAR LOCATION, INTERACTION WITH GP1BA, AND VARIANTS ASN-1157
RP AND MET-1471.
RC TISSUE=Endothelial cell, and Placenta;
RX PubMed=9651345; DOI=10.1074/jbc.273.28.17531;
RA Takafuta T., Wu G., Murphy G.F., Shapiro S.S.;
RT "Human beta-filamin is a new protein that interacts with the
RT cytoplasmic tail of glycoprotein Ibalpha.";
RL J. Biol. Chem. 273:17531-17538(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING, TISSUE
RP SPECIFICITY, AND INTERACTION WITH GP1BA.
RC TISSUE=Placenta;
RX PubMed=9694715;
RA Xu W.-F., Xie Z.-W., Chung D.W., Davie E.W.;
RT "A novel human actin-binding protein homologue that binds to platelet
RT glycoprotein Ibalpha.";
RL Blood 92:1268-1276(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 3; 4 AND 5), TISSUE
RP SPECIFICITY, SUBCELLULAR LOCATION, AND INTERACTION WITH ISOFORMS OF
RP ITGB1.
RC TISSUE=Keratinocyte, and Skeletal muscle;
RX PubMed=11807098; DOI=10.1083/jcb.200103037;
RA van Der Flier A., Kuikman I., Kramer D., Geerts D., Kreft M.,
RA Takafuta T., Shapiro S.S., Sonnenberg A.;
RT "Different splice variants of filamin-B affect myogenesis, subcellular
RT distribution, and determine binding to integrin (beta) subunits.";
RL J. Cell Biol. 156:361-376(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), GENE
RP ORGANIZATION, SIMILARITY TO OTHER MEMBERS OF THE FAMILY, AND VARIANTS
RP ASN-1157 AND MET-1471.
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 8 AND 9), AND VARIANTS
RP ASN-1157 AND MET-1471.
RX PubMed=18487259; DOI=10.1093/dnares/dsn010;
RA Oshikawa M., Sugai Y., Usami R., Ohtoko K., Toyama S., Kato S.;
RT "Fine expression profiling of full-length transcripts using a size-
RT unbiased cDNA library prepared with the vector-capping method.";
RL DNA Res. 15:123-136(2008).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 8 AND 9).
RX PubMed=16106752; DOI=10.1093/dnares/12.1.53;
RA Kato S., Ohtoko K., Ohtake H., Kimura T.;
RT "Vector-capping: a simple method for preparing a high-quality full-
RT length cDNA library.";
RL DNA Res. 12:53-62(2005).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7).
RC TISSUE=Endometrial tumor, and Fetal brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 990-2602.
RC TISSUE=Aortic endothelium;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2130-2602, AND INTERACTION WITH INPPL1.
RC TISSUE=Skeletal muscle;
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 [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1874-2602.
RC TISSUE=Fetal brain;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2311-2602, AND INTERACTION WITH PSEN1
RP AND PSEN2.
RC TISSUE=Fetal brain;
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 [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2404-2602, AND TISSUE SPECIFICITY.
RC TISSUE=Thyroid;
RX PubMed=8327473; DOI=10.1073/pnas.90.13.5994;
RA Leedman P.J., Faulkner-Jones B., Cram D.C., Harrison P.J., West J.,
RA O'Brien E.J., Simpson R., Coppel R.L., Harrison L.C.;
RT "Cloning from the thyroid of a protein related to actin binding
RT protein that is recognized by Graves disease immunoglobulins.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:5994-5998(1993).
RN [14]
RP INTERACTION WITH HBV CAPSID PROTEIN.
RX PubMed=10754391; DOI=10.1159/000025442;
RA Huang C.J., Chen Y.H., Ting L.P.;
RT "Hepatitis B virus core protein interacts with the C-terminal region
RT of actin-binding protein.";
RL J. Biomed. Sci. 7:160-168(2000).
RN [15]
RP INTERACTION WITH FLNA.
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 [16]
RP INTERACTION WITH FBLP1.
RC TISSUE=Placenta;
RX PubMed=12496242; DOI=10.1074/jbc.M209339200;
RA Takafuta T., Saeki M., Fujimoto T.-T., Fujimura K., Shapiro S.S.;
RT "A new member of the LIM protein family binds to filamin B and
RT localizes at stress fibers.";
RL J. Biol. Chem. 278:12175-12181(2003).
RN [17]
RP DIMERIZATION, AND INTERACTION WITH FLNC.
RX PubMed=12525170; DOI=10.1021/bi026501+;
RA Himmel M., van der Ven P.F.M., Stoecklein W., Fuerst D.O.;
RT "The limits of promiscuity: isoform-specific dimerization of
RT filamins.";
RL Biochemistry 42:430-439(2003).
RN [18]
RP INTERACTION WITH ITGB1; 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 [19]
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 [20]
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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-983, AND MASS
RP 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 [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-519; SER-983; SER-1028;
RP SER-1316; SER-1505; SER-1602; SER-2083; SER-2107; SER-2478 AND
RP SER-2481, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [24]
RP ISGYLATION AT LYS-2468, AND MUTAGENESIS OF LYS-2468.
RX PubMed=19270716; DOI=10.1038/embor.2009.23;
RA Jeon Y.J., Choi J.S., Lee J.Y., Yu K.R., Kim S.M., Ka S.H., Oh K.H.,
RA Kim K.I., Zhang D.E., Bang O.S., Chung C.H.;
RT "ISG15 modification of filamin B negatively regulates the type I
RT interferon-induced JNK signalling pathway.";
RL EMBO Rep. 10:374-380(2009).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-983 AND SER-2478, AND
RP MASS 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 [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-681 AND LYS-2576, AND MASS
RP 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 [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-519; SER-730; SER-886;
RP SER-932; SER-983; SER-1316; SER-1433; SER-2369; SER-2465 AND SER-2478,
RP 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 [28]
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 [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [30]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 2-242.
RX PubMed=19505475; DOI=10.1016/j.jmb.2009.06.009;
RA Sawyer G.M., Clark A.R., Robertson S.P., Sutherland-Smith A.J.;
RT "Disease-associated substitutions in the filamin B actin binding
RT domain confer enhanced actin binding affinity in the absence of major
RT structural disturbance: Insights from the crystal structures of
RT filamin B actin binding domains.";
RL J. Mol. Biol. 390:1030-1047(2009).
RN [32]
RP STRUCTURE BY NMR OF 1017-1721; 1736-2488 AND 2509-2602.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the 9th through 24th filamin domains from human
RT filamin-B.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [33]
RP INVOLVEMENT IN SCT, VARIANTS LRS CYS-161; LYS-227; ASN-1571 DEL;
RP ARG-1586 AND SER-1691, VARIANTS AO1 VAL-173 AND PRO-188, VARIANT AO3
RP ARG-751, AND VARIANT AO1/AO3 VAL-202.
RX PubMed=14991055; DOI=10.1038/ng1319;
RA Krakow D., Robertson S.P., King L.M., Morgan T., Sebald E.T.,
RA Bertolotto C., Wachsmann-Hogiu S., Acuna D., Shapiro S.S.,
RA Takafuta T., Aftimos S., Kim C.A., Firth H., Steiner C.E.,
RA Cormier-Daire V., Superti-Furga A., Bonafe L., Graham J.M. Jr.,
RA Grix A., Bacino C.A., Allanson J., Bialer M.G., Lachman R.S.,
RA Rimoin D.L., Cohn D.H.;
RT "Mutations in the gene encoding filamin B disrupt vertebral
RT segmentation, joint formation and skeletogenesis.";
RL Nat. Genet. 36:405-410(2004).
RN [34]
RP STRUCTURE BY NMR OF 1017-2602.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of filamin domains from human filamin-B.";
RL Submitted (AUG-2007) to the PDB data bank.
RN [35]
RP VARIANTS BOOMD ARG-171 AND PRO-235.
RX PubMed=15994868; DOI=10.1136/jmg.2004.029967;
RA Bicknell L.S., Morgan T., Bonafe L., Wessels M.W., Bialer M.G.,
RA Willems P.J., Cohn D.H., Krakow D., Robertson S.P.;
RT "Mutations in FLNB cause boomerang dysplasia.";
RL J. Med. Genet. 42:E43-E43(2005).
RN [36]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-566; LYS-663; LYS-703 AND
RP GLY-1534.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [37]
RP VARIANTS LRS CYS-161; SER-168; LYS-227; VAL-234; SER-361; GLU-363;
RP ARG-1431; ASN-1571 DEL; ARG-1586; ASP-1592; LEU-1603; SER-1691 AND
RP ARG-1834.
RX PubMed=16801345; DOI=10.1136/jmg.2006.043687;
RA Bicknell L.S., Farrington-Rock C., Shafeghati Y., Rump P., Alanay Y.,
RA Alembik Y., Al-Madani N., Firth H., Karimi-Nejad M.H., Kim C.A.,
RA Leask K., Maisenbacher M., Moran E., Pappas J.G., Prontera P.,
RA de Ravel T., Fryns J.-P., Sweeney E., Fryer A., Unger S., Wilson L.C.,
RA Lachman R.S., Rimoin D.L., Cohn D.H., Krakow D., Robertson S.P.;
RT "A molecular and clinical study of Larsen syndrome caused by mutations
RT in FLNB.";
RL J. Med. Genet. 44:89-98(2007).
CC -!- FUNCTION: Connects cell membrane constituents to the actin
CC cytoskeleton. May promote orthogonal branching of actin filaments
CC and links actin filaments to membrane glycoproteins. Anchors
CC various transmembrane proteins to the actin cytoskeleton.
CC Interaction with FLNA may allow neuroblast migration from the
CC ventricular zone into the cortical plate. Various interactions and
CC localizations of isoforms affect myotube morphology and
CC myogenesis. Isoform 6 accelerates muscle differentiation in vitro.
CC -!- SUBUNIT: Homodimer. Interacts with MICALL2 (By similarity).
CC Isoform 1 interacts with FBLP1, FLNA, FLNC, GP1BA, INPPL1, ITGB1A,
CC PSEN1 and PSEN2. Isoform 3 interacts with ITGB1A, ITGB1D, ITGB3
CC and ITGB6. Interacts with MYOT and MYOZ1. Interacts with HBV
CC capsid protein.
CC -!- INTERACTION:
CC Self; NbExp=4; IntAct=EBI-352089, EBI-352089;
CC P21333:FLNA; NbExp=5; IntAct=EBI-352089, EBI-350432;
CC P62993:GRB2; NbExp=2; IntAct=EBI-352089, EBI-401755;
CC P05161:ISG15; NbExp=4; IntAct=EBI-352089, EBI-746466;
CC Q13233:MAP3K1; NbExp=2; IntAct=EBI-352089, EBI-49776;
CC Q9Y6R4:MAP3K4; NbExp=2; IntAct=EBI-352089, EBI-448104;
CC P16333:NCK1; NbExp=3; IntAct=EBI-352089, EBI-389883;
CC P63000:RAC1; NbExp=2; IntAct=EBI-352089, EBI-413628;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cytoplasm, cell cortex.
CC Cytoplasm, cytoskeleton. Cytoplasm, myofibril, sarcomere, Z line.
CC Note=In differentiating myotubes, isoform 1, isoform 2 and isoform
CC 3 are localized diffusely throughout the cytoplasm with regions of
CC enrichment at the longitudinal actin stress fiber. In
CC differentiated tubes, isoform 1 is also detected within the Z-
CC lines.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm, cytoskeleton.
CC Note=Predominantly localized at actin stress fibers.
CC -!- SUBCELLULAR LOCATION: Isoform 3: Cytoplasm, cytoskeleton.
CC Note=Predominantly localized at actin stress fibers.
CC -!- SUBCELLULAR LOCATION: Isoform 6: Cytoplasm, cytoskeleton.
CC Note=Polarized at the periphery of myotubes.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=9;
CC Name=1; Synonyms=ABP-278;
CC IsoId=O75369-1; Sequence=Displayed;
CC Name=2; Synonyms=ABP-276;
CC IsoId=O75369-2; Sequence=VSP_008773;
CC Note=May be due to exon skipping;
CC Name=3; Synonyms=Var-1;
CC IsoId=O75369-3; Sequence=VSP_008774;
CC Note=May be due to exon skipping;
CC Name=7;
CC IsoId=O75369-7; Sequence=VSP_024113, VSP_024114, VSP_024115;
CC Name=4; Synonyms=Var-3;
CC IsoId=O75369-4; Sequence=VSP_008775, VSP_008776;
CC Name=5; Synonyms=Var-2;
CC IsoId=O75369-5; Sequence=VSP_008777, VSP_008778;
CC Note=May be due to competing donor splice sites;
CC Name=6; Synonyms=Var-1-DeltaH1;
CC IsoId=O75369-6; Sequence=VSP_008773, VSP_008774;
CC Note=May be due to exon skipping;
CC Name=8;
CC IsoId=O75369-8; Sequence=VSP_043446;
CC Name=9;
CC IsoId=O75369-9; Sequence=VSP_024115;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Isoform 1 and isoform 2 are
CC expressed in placenta, bone marrow, brain, umbilical vein
CC endothelial cells (HUVEC), retina and skeletal muscle. Isoform 1
CC is predominantly expressed in prostate, uterus, liver, thyroid,
CC stomach, lymph node, small intestine, spleen, skeletal muscle,
CC kidney, placenta, pancreas, heart, lung, platelets, endothelial
CC cells, megakaryocytic and erythroleukemic cell lines. Isoform 2 is
CC predominantly expressed in spinal cord, platelet and Daudi cells.
CC Also expressed in thyroid adenoma, neurofibrillary tangles (NFT),
CC senile plaques in the hippocampus and cerebral cortex in Alzheimer
CC disease (AD). Isoform 3 and isoform 6 are expressed predominantly
CC in lung, heart, skeletal muscle, testis, spleen, thymus and
CC leukocytes. Isoform 4 and isoform 5 are expressed in heart.
CC -!- DOMAIN: Comprised of a NH2-terminal actin-binding domain, 24
CC internally homologous repeats and two hinge regions. Repeat 24 and
CC the second hinge domain are important for dimer formation. The
CC first hinge region prevents binding to ITGA and ITGB subunits.
CC -!- PTM: ISGylation prevents ability to interact with the upstream
CC activators of the JNK cascade and inhibits IFNA-induced JNK
CC signaling.
CC -!- DISEASE: Note=Interaction with FLNA may compensate for
CC dysfunctional FLNA homodimer in the periventricular nodular
CC heterotopia (PVNH) disorder.
CC -!- DISEASE: Atelosteogenesis 1 (AO1) [MIM:108720]: A lethal
CC chondrodysplasia characterized by distal hypoplasia of the humeri
CC and femurs, hypoplasia of the mid-thoracic spine, occasionally
CC complete lack of ossification of single hand bones, and the
CC finding in cartilage of multiple degenerated chondrocytes which
CC are encapsulated in fibrous tissue. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Atelosteogenesis 3 (AO3) [MIM:108721]: A short-limb
CC lethal skeletal dysplasia with vertebral abnormalities,
CC disharmonious skeletal maturation, poorly modeled long bones and
CC joint dislocations. Recurrent respiratory insufficiency and/or
CC infections usually result in early death. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Boomerang dysplasia (BOOMD) [MIM:112310]: A perinatal
CC lethal osteochondrodysplasia characterized by absence or
CC underossification of the limb bones and vertebrae. Patients
CC manifest dwarfism with short, bowed, rigid limbs and
CC characteristic facies. Boomerang dysplasia is distinguished from
CC atelosteogenesis on the basis of a more severe defect in
CC mineralization, with complete absence of ossification in some limb
CC elements and vertebral segments. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Larsen syndrome (LRS) [MIM:150250]: An
CC osteochondrodysplasia characterized by large-joint dislocations
CC and characteristic craniofacial abnormalities. The cardinal
CC features of the condition are dislocations of the hip, knee and
CC elbow joints, with equinovarus or equinovalgus foot deformities.
CC Spatula-shaped fingers, most marked in the thumb, are also
CC present. Craniofacial anomalies include hypertelorism, prominence
CC of the forehead, a depressed nasal bridge, and a flattened
CC midface. Cleft palate and short stature are often associated
CC features. Spinal anomalies include scoliosis and cervical
CC kyphosis. Hearing loss is a well-recognized complication. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Spondylocarpotarsal synostosis syndrome (SCT)
CC [MIM:272460]: Disorder characterized by short stature and
CC vertebral, carpal and tarsal fusions. Note=The disease is caused
CC by mutations affecting the gene represented in 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 -!- SEQUENCE CAUTION:
CC Sequence=AAA35505.1; Type=Frameshift; Positions=2432, 2589;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FLNB";
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DR EMBL; AF042166; AAC39842.1; -; mRNA.
DR EMBL; AF043045; AAC33845.1; -; mRNA.
DR EMBL; AF353667; AAL68440.1; -; Genomic_DNA.
DR EMBL; AF353667; AAL68441.1; -; Genomic_DNA.
DR EMBL; AF353667; AAL68442.1; -; Genomic_DNA.
DR EMBL; AF353667; AAL68443.1; -; Genomic_DNA.
DR EMBL; AF191633; AAF72339.1; -; Genomic_DNA.
DR EMBL; AF191594; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191595; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191596; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191597; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191598; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191599; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191600; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191601; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191602; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191603; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191604; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191605; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191606; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191607; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191608; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191609; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191611; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191610; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191613; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191612; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191614; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191615; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191617; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191616; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191618; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191619; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191620; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191621; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191622; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191623; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191624; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191625; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191627; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191626; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191628; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191629; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191630; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191631; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF191632; AAF72339.1; JOINED; Genomic_DNA.
DR EMBL; AF238609; AAF97046.1; -; mRNA.
DR EMBL; AB371580; BAG48309.1; -; mRNA.
DR EMBL; AB371581; BAG48310.1; -; mRNA.
DR EMBL; AB371582; BAG48311.1; -; mRNA.
DR EMBL; AB191258; BAD52434.1; -; mRNA.
DR EMBL; BX641085; CAE46040.1; -; mRNA.
DR EMBL; AC114399; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC137936; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL137574; CAB70818.1; -; mRNA.
DR EMBL; AB209889; BAD93126.1; -; mRNA.
DR EMBL; M62994; AAA35505.1; ALT_FRAME; mRNA.
DR PIR; T46270; T46270.
DR RefSeq; NP_001157789.1; NM_001164317.1.
DR RefSeq; NP_001157790.1; NM_001164318.1.
DR RefSeq; NP_001157791.1; NM_001164319.1.
DR RefSeq; NP_001448.2; NM_001457.3.
DR RefSeq; XP_005265036.1; XM_005264979.1.
DR UniGene; Hs.476448; -.
DR PDB; 2DI8; NMR; -; A=1999-2096.
DR PDB; 2DI9; NMR; -; A=1017-1134.
DR PDB; 2DIA; NMR; -; A=1130-1229.
DR PDB; 2DIB; NMR; -; A=1215-1329.
DR PDB; 2DIC; NMR; -; A=1325-1422.
DR PDB; 2DJ4; NMR; -; A=1418-1518.
DR PDB; 2DLG; NMR; -; A=2104-2192.
DR PDB; 2DMB; NMR; -; A=1611-1721.
DR PDB; 2DMC; NMR; -; A=1899-2001.
DR PDB; 2E9I; NMR; -; A=2094-2192.
DR PDB; 2E9J; NMR; -; A=1504-1615.
DR PDB; 2EE6; NMR; -; A=2190-2287.
DR PDB; 2EE9; NMR; -; A=1736-1823.
DR PDB; 2EEA; NMR; -; A=1808-1915.
DR PDB; 2EEB; NMR; -; A=2284-2382.
DR PDB; 2EEC; NMR; -; A=2371-2488.
DR PDB; 2EED; NMR; -; A=2509-2602.
DR PDB; 2WA5; X-ray; 1.90 A; A=2-242.
DR PDB; 2WA6; X-ray; 1.95 A; A=2-242.
DR PDB; 2WA7; X-ray; 1.85 A; A=2-242.
DR PDB; 3FER; X-ray; 2.40 A; A/B/C/D=1-252.
DR PDB; 4B7L; X-ray; 2.05 A; A/B=1-347.
DR PDBsum; 2DI8; -.
DR PDBsum; 2DI9; -.
DR PDBsum; 2DIA; -.
DR PDBsum; 2DIB; -.
DR PDBsum; 2DIC; -.
DR PDBsum; 2DJ4; -.
DR PDBsum; 2DLG; -.
DR PDBsum; 2DMB; -.
DR PDBsum; 2DMC; -.
DR PDBsum; 2E9I; -.
DR PDBsum; 2E9J; -.
DR PDBsum; 2EE6; -.
DR PDBsum; 2EE9; -.
DR PDBsum; 2EEA; -.
DR PDBsum; 2EEB; -.
DR PDBsum; 2EEC; -.
DR PDBsum; 2EED; -.
DR PDBsum; 2WA5; -.
DR PDBsum; 2WA6; -.
DR PDBsum; 2WA7; -.
DR PDBsum; 3FER; -.
DR PDBsum; 4B7L; -.
DR ProteinModelPortal; O75369; -.
DR SMR; O75369; 13-347, 1017-1723, 1735-2488, 2511-2602.
DR IntAct; O75369; 29.
DR MINT; MINT-4998813; -.
DR PhosphoSite; O75369; -.
DR PaxDb; O75369; -.
DR PRIDE; O75369; -.
DR DNASU; 2317; -.
DR Ensembl; ENST00000295956; ENSP00000295956; ENSG00000136068.
DR Ensembl; ENST00000348383; ENSP00000232447; ENSG00000136068.
DR Ensembl; ENST00000357272; ENSP00000349819; ENSG00000136068.
DR Ensembl; ENST00000358537; ENSP00000351339; ENSG00000136068.
DR Ensembl; ENST00000419752; ENSP00000414532; ENSG00000136068.
DR Ensembl; ENST00000429972; ENSP00000415599; ENSG00000136068.
DR Ensembl; ENST00000490882; ENSP00000420213; ENSG00000136068.
DR GeneID; 2317; -.
DR KEGG; hsa:2317; -.
DR UCSC; uc003djj.2; human.
DR CTD; 2317; -.
DR GeneCards; GC03P057969; -.
DR H-InvDB; HIX0003397; -.
DR HGNC; HGNC:3755; FLNB.
DR HPA; CAB019322; -.
DR HPA; HPA004747; -.
DR HPA; HPA004886; -.
DR MIM; 108720; phenotype.
DR MIM; 108721; phenotype.
DR MIM; 112310; phenotype.
DR MIM; 150250; phenotype.
DR MIM; 272460; phenotype.
DR MIM; 603381; gene.
DR neXtProt; NX_O75369; -.
DR Orphanet; 1190; Atelosteogenesis type I.
DR Orphanet; 56305; Atelosteogenesis type III.
DR Orphanet; 503; Autosomal dominant Larsen syndrome.
DR Orphanet; 1263; Boomerang dysplasia.
DR Orphanet; 3275; Spondylocarpotarsal synostosis.
DR PharmGKB; PA28173; -.
DR eggNOG; COG5069; -.
DR HOGENOM; HOG000044235; -.
DR HOVERGEN; HBG004163; -.
DR InParanoid; O75369; -.
DR KO; K04437; -.
DR OMA; IHNANDT; -.
DR OrthoDB; EOG76T9QC; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; O75369; -.
DR ChiTaRS; FLNB; human.
DR EvolutionaryTrace; O75369; -.
DR GeneWiki; FLNB; -.
DR GenomeRNAi; 2317; -.
DR NextBio; 9409; -.
DR PRO; PR:O75369; -.
DR ArrayExpress; O75369; -.
DR Bgee; O75369; -.
DR Genevestigator; O75369; -.
DR GO; GO:0015629; C:actin cytoskeleton; TAS:ProtInc.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005925; C:focal adhesion; IEA:Ensembl.
DR GO; GO:0016021; C:integral to membrane; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0001725; C:stress fiber; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IEA:UniProtKB-SubCell.
DR GO; GO:0003779; F:actin binding; NAS:UniProtKB.
DR GO; GO:0030036; P:actin cytoskeleton organization; TAS:ProtInc.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0007016; P:cytoskeletal anchoring at plasma membrane; TAS:ProtInc.
DR GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl.
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 Complete proteome; Cytoplasm; Cytoskeleton; Developmental protein;
KW Differentiation; Disease mutation; Dwarfism; Isopeptide bond;
KW Myogenesis; Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Ubl conjugation.
FT CHAIN 1 2602 Filamin-B.
FT /FTId=PRO_0000087298.
FT DOMAIN 1 239 Actin-binding.
FT DOMAIN 16 122 CH 1.
FT DOMAIN 139 239 CH 2.
FT REPEAT 249 347 Filamin 1.
FT REPEAT 349 446 Filamin 2.
FT REPEAT 447 543 Filamin 3.
FT REPEAT 544 636 Filamin 4.
FT REPEAT 640 736 Filamin 5.
FT REPEAT 737 839 Filamin 6.
FT REPEAT 840 938 Filamin 7.
FT REPEAT 939 1034 Filamin 8.
FT REPEAT 1035 1127 Filamin 9.
FT REPEAT 1128 1222 Filamin 10.
FT REPEAT 1223 1322 Filamin 11.
FT REPEAT 1323 1415 Filamin 12.
FT REPEAT 1416 1511 Filamin 13.
FT REPEAT 1512 1608 Filamin 14.
FT REPEAT 1609 1704 Filamin 15.
FT REPEAT 1729 1813 Filamin 16.
FT REPEAT 1816 1908 Filamin 17.
FT REPEAT 1919 1994 Filamin 18.
FT REPEAT 1997 2089 Filamin 19.
FT REPEAT 2091 2185 Filamin 20.
FT REPEAT 2188 2280 Filamin 21.
FT REPEAT 2282 2375 Filamin 22.
FT REPEAT 2379 2471 Filamin 23.
FT REPEAT 2507 2601 Filamin 24.
FT REGION 1128 1511 Interaction with FBLP1.
FT REGION 1705 1728 Hinge 1 (By similarity).
FT REGION 1862 2148 Interaction with the cytoplasmic tail of
FT GP1BA.
FT REGION 2060 2225 Interaction with FLNA 1.
FT REGION 2130 2602 Interaction with INPPL1.
FT REGION 2472 2602 Self-association site, tail (By
FT similarity).
FT REGION 2472 2506 Hinge 2 (By similarity).
FT REGION 2507 2602 Interaction with FLNA 2.
FT MOD_RES 519 519 Phosphothreonine.
FT MOD_RES 681 681 N6-acetyllysine.
FT MOD_RES 730 730 Phosphoserine.
FT MOD_RES 886 886 Phosphoserine.
FT MOD_RES 932 932 Phosphoserine.
FT MOD_RES 983 983 Phosphoserine.
FT MOD_RES 1028 1028 Phosphoserine.
FT MOD_RES 1316 1316 Phosphoserine.
FT MOD_RES 1433 1433 Phosphoserine.
FT MOD_RES 1505 1505 Phosphoserine.
FT MOD_RES 1602 1602 Phosphoserine.
FT MOD_RES 2083 2083 Phosphoserine.
FT MOD_RES 2107 2107 Phosphoserine.
FT MOD_RES 2369 2369 Phosphoserine.
FT MOD_RES 2465 2465 Phosphoserine.
FT MOD_RES 2478 2478 Phosphoserine.
FT MOD_RES 2481 2481 Phosphoserine.
FT MOD_RES 2576 2576 N6-acetyllysine.
FT CROSSLNK 2468 2468 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT VAR_SEQ 1 169 Missing (in isoform 7).
FT /FTId=VSP_024113.
FT VAR_SEQ 170 181 ALGALVDSCAPG -> MQEHSTRRRSLS (in isoform
FT 7).
FT /FTId=VSP_024114.
FT VAR_SEQ 1463 1463 R -> RADDTDSQSWRSPLKALSEFFKGDPKGDFNKT (in
FT isoform 8).
FT /FTId=VSP_043446.
FT VAR_SEQ 1704 1727 Missing (in isoform 2 and isoform 6).
FT /FTId=VSP_008773.
FT VAR_SEQ 1717 1727 Missing (in isoform 7 and isoform 9).
FT /FTId=VSP_024115.
FT VAR_SEQ 2081 2121 Missing (in isoform 3 and isoform 6).
FT /FTId=VSP_008774.
FT VAR_SEQ 2123 2150 EINSSDMSAHVTSPSGRVTEAEIVPMGK -> GVRVMNCSA
FT QILWGWRVQFHTGSRNQQQ (in isoform 4).
FT /FTId=VSP_008775.
FT VAR_SEQ 2123 2146 EINSSDMSAHVTSPSGRVTEAEIV -> GVRVMNCSAQILW
FT GWRVQFHTGSR (in isoform 5).
FT /FTId=VSP_008777.
FT VAR_SEQ 2147 2602 Missing (in isoform 5).
FT /FTId=VSP_008778.
FT VAR_SEQ 2151 2602 Missing (in isoform 4).
FT /FTId=VSP_008776.
FT VARIANT 161 161 F -> C (in LRS).
FT /FTId=VAR_033069.
FT VARIANT 168 168 G -> S (in LRS).
FT /FTId=VAR_033070.
FT VARIANT 171 171 L -> R (in BOOMD).
FT /FTId=VAR_033071.
FT VARIANT 173 173 A -> V (in AO1; dbSNP:rs28937586).
FT /FTId=VAR_033072.
FT VARIANT 188 188 S -> P (in AO1).
FT /FTId=VAR_033073.
FT VARIANT 202 202 M -> V (in AO1 and AO3;
FT dbSNP:rs28939707).
FT /FTId=VAR_033074.
FT VARIANT 227 227 E -> K (in LRS).
FT /FTId=VAR_033075.
FT VARIANT 234 234 L -> V (in LRS).
FT /FTId=VAR_033076.
FT VARIANT 235 235 S -> P (in BOOMD).
FT /FTId=VAR_033077.
FT VARIANT 361 361 G -> S (in LRS).
FT /FTId=VAR_033078.
FT VARIANT 363 363 G -> E (in LRS).
FT /FTId=VAR_033079.
FT VARIANT 566 566 R -> Q (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035917.
FT VARIANT 663 663 N -> K (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035918.
FT VARIANT 703 703 T -> K (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035919.
FT VARIANT 751 751 G -> R (in AO3; dbSNP:rs28937587).
FT /FTId=VAR_033080.
FT VARIANT 1018 1018 V -> M (in dbSNP:rs2276742).
FT /FTId=VAR_017182.
FT VARIANT 1157 1157 D -> N (in dbSNP:rs1131356).
FT /FTId=VAR_017183.
FT VARIANT 1179 1179 E -> K (in dbSNP:rs17058845).
FT /FTId=VAR_031392.
FT VARIANT 1431 1431 L -> R (in LRS).
FT /FTId=VAR_033081.
FT VARIANT 1471 1471 V -> M (in dbSNP:rs12632456).
FT /FTId=VAR_031393.
FT VARIANT 1534 1534 A -> G (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035920.
FT VARIANT 1571 1571 Missing (in LRS).
FT /FTId=VAR_033082.
FT VARIANT 1586 1586 G -> R (in LRS; dbSNP:rs28939706).
FT /FTId=VAR_033083.
FT VARIANT 1592 1592 V -> D (in LRS).
FT /FTId=VAR_033084.
FT VARIANT 1603 1603 P -> L (in LRS).
FT /FTId=VAR_033085.
FT VARIANT 1691 1691 G -> S (in LRS).
FT /FTId=VAR_033086.
FT VARIANT 1834 1834 G -> R (in LRS).
FT /FTId=VAR_033087.
FT MUTAGEN 2468 2468 K->R: Cytoplasmic localization.
FT CONFLICT 816 816 A -> T (in Ref. 7; CAE46040).
FT CONFLICT 924 924 Y -> H (in Ref. 7; CAE46040).
FT CONFLICT 1411 1411 F -> L (in Ref. 7; CAE46040).
FT CONFLICT 1560 1560 E -> G (in Ref. 7; CAE46040).
FT CONFLICT 1953 1953 L -> F (in Ref. 4; AAF97046).
FT CONFLICT 2006 2006 K -> R (in Ref. 2; AAC33845).
FT CONFLICT 2099 2099 I -> S (in Ref. 7; CAE46040).
FT CONFLICT 2170 2170 K -> N (in Ref. 4; AAF97046).
FT CONFLICT 2293 2293 M -> V (in Ref. 4; AAF97046 and 7;
FT CAE46040).
FT CONFLICT 2354 2354 V -> A (in Ref. 11; CAB70818).
FT CONFLICT 2487 2487 S -> C (in Ref. 13; AAA35505).
FT CONFLICT 2571 2571 V -> A (in Ref. 11; CAB70818).
FT HELIX 5 10
FT HELIX 13 16
FT HELIX 17 30
FT HELIX 31 33
FT TURN 40 46
FT HELIX 48 58
FT HELIX 73 89
FT HELIX 99 103
FT HELIX 107 122
FT HELIX 141 152
FT HELIX 163 165
FT HELIX 169 178
FT HELIX 186 188
FT HELIX 194 208
FT HELIX 217 220
FT HELIX 227 234
FT HELIX 236 239
FT HELIX 254 256
FT STRAND 258 261
FT HELIX 262 264
FT STRAND 265 267
FT STRAND 275 280
FT TURN 282 284
FT STRAND 289 294
FT STRAND 300 302
FT STRAND 304 309
FT STRAND 313 319
FT STRAND 323 333
FT STRAND 342 347
FT HELIX 1040 1042
FT STRAND 1044 1047
FT HELIX 1048 1051
FT STRAND 1052 1054
FT STRAND 1059 1064
FT TURN 1066 1068
FT STRAND 1073 1077
FT STRAND 1079 1081
FT STRAND 1084 1089
FT STRAND 1091 1100
FT STRAND 1102 1115
FT STRAND 1122 1128
FT HELIX 1133 1135
FT STRAND 1136 1140
FT HELIX 1141 1143
FT STRAND 1154 1160
FT STRAND 1166 1172
FT TURN 1173 1175
FT STRAND 1179 1184
FT STRAND 1188 1195
FT STRAND 1200 1208
FT STRAND 1217 1223
FT STRAND 1232 1235
FT HELIX 1236 1239
FT STRAND 1249 1254
FT STRAND 1256 1258
FT STRAND 1273 1275
FT STRAND 1281 1284
FT STRAND 1286 1294
FT STRAND 1300 1310
FT STRAND 1317 1321
FT STRAND 1332 1335
FT HELIX 1336 1339
FT STRAND 1347 1352
FT TURN 1354 1356
FT STRAND 1361 1369
FT STRAND 1374 1377
FT STRAND 1379 1381
FT STRAND 1383 1387
FT STRAND 1393 1401
FT STRAND 1410 1416
FT STRAND 1425 1428
FT TURN 1429 1431
FT STRAND 1441 1446
FT TURN 1448 1450
FT STRAND 1455 1460
FT STRAND 1462 1464
FT STRAND 1475 1483
FT STRAND 1489 1501
FT STRAND 1506 1512
FT HELIX 1517 1519
FT STRAND 1520 1524
FT HELIX 1525 1527
FT STRAND 1538 1546
FT STRAND 1566 1570
FT STRAND 1573 1580
FT STRAND 1586 1590
FT STRAND 1593 1596
FT STRAND 1603 1609
FT STRAND 1618 1621
FT HELIX 1622 1624
FT STRAND 1625 1639
FT STRAND 1641 1643
FT STRAND 1648 1653
FT STRAND 1663 1666
FT STRAND 1672 1677
FT STRAND 1682 1692
FT STRAND 1699 1705
FT STRAND 1748 1750
FT STRAND 1759 1765
FT STRAND 1775 1778
FT STRAND 1780 1782
FT STRAND 1784 1787
FT STRAND 1792 1804
FT STRAND 1811 1816
FT STRAND 1825 1828
FT HELIX 1829 1832
FT STRAND 1833 1835
FT STRAND 1840 1845
FT STRAND 1854 1862
FT STRAND 1872 1881
FT STRAND 1888 1898
FT STRAND 1903 1909
FT STRAND 1924 1927
FT STRAND 1941 1943
FT STRAND 1952 1957
FT TURN 1958 1960
FT STRAND 1961 1966
FT STRAND 1972 1977
FT STRAND 1979 1984
FT STRAND 1989 1994
FT STRAND 1997 1999
FT HELIX 2002 2004
FT STRAND 2006 2010
FT TURN 2011 2013
FT STRAND 2014 2016
FT STRAND 2021 2026
FT TURN 2028 2030
FT STRAND 2035 2043
FT STRAND 2057 2061
FT STRAND 2067 2077
FT STRAND 2084 2090
FT STRAND 2111 2113
FT STRAND 2118 2120
FT HELIX 2126 2128
FT STRAND 2130 2134
FT STRAND 2140 2142
FT STRAND 2144 2147
FT STRAND 2149 2157
FT STRAND 2164 2175
FT STRAND 2180 2185
FT HELIX 2193 2195
FT TURN 2201 2203
FT STRAND 2206 2208
FT STRAND 2210 2214
FT STRAND 2219 2221
FT STRAND 2226 2234
FT STRAND 2236 2240
FT STRAND 2250 2256
FT STRAND 2258 2266
FT STRAND 2275 2281
FT STRAND 2288 2294
FT STRAND 2306 2314
FT STRAND 2320 2324
FT STRAND 2330 2332
FT STRAND 2334 2337
FT STRAND 2340 2347
FT STRAND 2352 2365
FT STRAND 2370 2375
FT TURN 2384 2386
FT STRAND 2388 2392
FT TURN 2393 2395
FT STRAND 2403 2408
FT TURN 2410 2412
FT STRAND 2417 2425
FT STRAND 2430 2433
FT STRAND 2435 2442
FT STRAND 2448 2459
FT STRAND 2466 2473
FT TURN 2512 2514
FT STRAND 2516 2519
FT HELIX 2520 2523
FT STRAND 2531 2536
FT TURN 2538 2540
FT STRAND 2545 2547
FT STRAND 2557 2565
FT STRAND 2568 2574
FT STRAND 2579 2583
FT STRAND 2585 2591
FT STRAND 2596 2601
SQ SEQUENCE 2602 AA; 278164 MW; 1BF5C64C86360C6A CRC64;
MPVTEKDLAE DAPWKKIQQN TFTRWCNEHL KCVNKRIGNL QTDLSDGLRL IALLEVLSQK
RMYRKYHQRP TFRQMQLENV SVALEFLDRE SIKLVSIDSK AIVDGNLKLI LGLVWTLILH
YSISMPVWED EGDDDAKKQT PKQRLLGWIQ NKIPYLPITN FNQNWQDGKA LGALVDSCAP
GLCPDWESWD PQKPVDNARE AMQQADDWLG VPQVITPEEI IHPDVDEHSV MTYLSQFPKA
KLKPGAPLKP KLNPKKARAY GRGIEPTGNM VKQPAKFTVD TISAGQGDVM VFVEDPEGNK
EEAQVTPDSD KNKTYSVEYL PKVTGLHKVT VLFAGQHISK SPFEVSVDKA QGDASKVTAK
GPGLEAVGNI ANKPTYFDIY TAGAGVGDIG VEVEDPQGKN TVELLVEDKG NQVYRCVYKP
MQPGPHVVKI FFAGDTIPKS PFVVQVGEAC NPNACRASGR GLQPKGVRIR ETTDFKVDTK
AAGSGELGVT MKGPKGLEEL VKQKDFLDGV YAFEYYPSTP GRYSIAITWG GHHIPKSPFE
VQVGPEAGMQ KVRAWGPGLH GGIVGRSADF VVESIGSEVG SLGFAIEGPS QAKIEYNDQN
DGSCDVKYWP KEPGEYAVHI MCDDEDIKDS PYMAFIHPAT GGYNPDLVRA YGPGLEKSGC
IVNNLAEFTV DPKDAGKAPL KIFAQDGEGQ RIDIQMKNRM DGTYACSYTP VKAIKHTIAV
VWGGVNIPHS PYRVNIGQGS HPQKVKVFGP GVERSGLKAN EPTHFTVDCT EAGEGDVSVG
IKCDARVLSE DEEDVDFDII HNANDTFTVK YVPPAAGRYT IKVLFASQEI PASPFRVKVD
PSHDASKVKA EGPGLSKAGV ENGKPTHFTV YTKGAGKAPL NVQFNSPLPG DAVKDLDIID
NYDYSHTVKY TPTQQGNMQV LVTYGGDPIP KSPFTVGVAA PLDLSKIKLN GLENRVEVGK
DQEFTVDTRG AGGQGKLDVT ILSPSRKVVP CLVTPVTGRE NSTAKFIPRE EGLYAVDVTY
DGHPVPGSPY TVEASLPPDP SKVKAHGPGL EGGLVGKPAE FTIDTKGAGT GGLGLTVEGP
CEAKIECSDN GDGTCSVSYL PTKPGEYFVN ILFEEVHIPG SPFKADIEMP FDPSKVVASG
PGLEHGKVGE AGLLSVDCSE AGPGALGLEA VSDSGTKAEV SIQNNKDGTY AVTYVPLTAG
MYTLTMKYGG ELVPHFPARV KVEPAVDTSR IKVFGPGIEG KDVFREATTD FTVDSRPLTQ
VGGDHIKAHI ANPSGASTEC FVTDNADGTY QVEYTPFEKG LHVVEVTYDD VPIPNSPFKV
AVTEGCQPSR VQAQGPGLKE AFTNKPNVFT VVTRGAGIGG LGITVEGPSE SKINCRDNKD
GSCSAEYIPF APGDYDVNIT YGGAHIPGSP FRVPVKDVVD PSKVKIAGPG LGSGVRARVL
QSFTVDSSKA GLAPLEVRVL GPRGLVEPVN VVDNGDGTHT VTYTPSQEGP YMVSVKYADE
EIPRSPFKVK VLPTYDASKV TASGPGLSSY GVPASLPVDF AIDARDAGEG LLAVQITDQE
GKPKRAIVHD NKDGTYAVTY IPDKTGRYMI GVTYGGDDIP LSPYRIRATQ TGDASKCLAT
GPGIASTVKT GEEVGFVVDA KTAGKGKVTC TVLTPDGTEA EADVIENEDG TYDIFYTAAK
PGTYVIYVRF GGVDIPNSPF TVMATDGEVT AVEEAPVNAC PPGFRPWVTE EAYVPVSDMN
GLGFKPFDLV IPFAVRKGEI TGEVHMPSGK TATPEIVDNK DGTVTVRYAP TEVGLHEMHI
KYMGSHIPES PLQFYVNYPN SGSVSAYGPG LVYGVANKTA TFTIVTEDAG EGGLDLAIEG
PSKAEISCID NKDGTCTVTY LPTLPGDYSI LVKYNDKHIP GSPFTAKITD DSRRCSQVKL
GSAADFLLDI SETDLSSLTA SIKAPSGRDE PCLLKRLPNN HIGISFIPRE VGEHLVSIKK
NGNHVANSPV SIMVVQSEIG DARRAKVYGR GLSEGRTFEM SDFIVDTRDA GYGGISLAVE
GPSKVDIQTE DLEDGTCKVS YFPTVPGVYI VSTKFADEHV PGSPFTVKIS GEGRVKESIT
RTSRAPSVAT VGSICDLNLK IPEINSSDMS AHVTSPSGRV TEAEIVPMGK NSHCVRFVPQ
EMGVHTVSVK YRGQHVTGSP FQFTVGPLGE GGAHKVRAGG PGLERGEAGV PAEFSIWTRE
AGAGGLSIAV EGPSKAEITF DDHKNGSCGV SYIAQEPGNY EVSIKFNDEH IPESPYLVPV
IAPSDDARRL TVMSLQESGL KVNQPASFAI RLNGAKGKID AKVHSPSGAV EECHVSELEP
DKYAVRFIPH ENGVHTIDVK FNGSHVVGSP FKVRVGEPGQ AGNPALVSAY GTGLEGGTTG
IQSEFFINTT RAGPGTLSVT IEGPSKVKMD CQETPEGYKV MYTPMAPGNY LISVKYGGPN
HIVGSPFKAK VTGQRLVSPG SANETSSILV ESVTRSSTET CYSAIPKASS DASKVTSKGA
GLSKAFVGQK SSFLVDCSKA GSNMLLIGVH GPTTPCEEVS MKHVGNQQYN VTYVVKERGD
YVLAVKWGEE HIPGSPFHVT VP
//

MIM 108720
*RECORD*
*FIELD* NO
108720
*FIELD* TI
#108720 ATELOSTEOGENESIS, TYPE I; AOI
;;GIANT CELL CHONDRODYSPLASIA;;
SPONDYLOHUMEROFEMORAL HYPOPLASIA
read more*FIELD* TX
A number sign (#) is used with this entry because atelosteogenesis type
I is caused by mutations in the gene encoding filamin B (FLNB; 603381).

CLINICAL FEATURES

Atelosteogenesis is the name given by Maroteaux et al. (1982) to a
lethal chondrodysplasia characterized by distal hypoplasia of the humeri
and femurs, hypoplasia of the midthoracic spine, occasionally complete
lack of ossification of single hand bones, and the finding in cartilage
of multiple degenerated chondrocytes which are encapsulated in fibrous
tissue. Rimoin et al. (1980) termed it 'giant cell chondrodysplasia.'
Sillence et al. (1982) reported 2 sporadic cases. The fibulae were
absent. Only the distal phalanges of the hands were ossified. They
termed the disorder 'spondylohumerofemoral hypoplasia.' Hypocellular
areas of growth plate cartilage contained occasional multinuclear giant
cells. The genetics is unclear. Maroteaux et al. (1982) pointed to a
case reported by Kozlowski et al. (1981). Clubfoot and elbow or knee
subluxation may be present. Cleft palate has been observed. The patients
are stillborn or die very early of respiratory distress.

Yang et al. (1983) reported an infant in whom the findings were
consistent with atelosteogenesis. A second case also with giant
chondrocytes on histologic examination of bone, severe laryngeal
stenosis and lethal outcome appeared to have some other skeletal
dysplasia, an as yet unclassified form of spondyloepiphyseal dysplasia.
Yang et al. (1983) concluded, and Sillence and Kozlowski (1983) agreed
on the basis of further observations, that giant chondrocytes are not
specific to one lethal skeletal dysplasia.

According to Whitley et al. (1986), the possible case of de la Chapelle
dysplasia (256050) reported by Salonen (1982) has been reclassified as
atelosteogenesis type I.

Temple et al. (1990) reviewed 10 reported cases, all of which had been
sporadic, and reported an eleventh case, that in an infant with
first-cousin Bengali parents. Polyhydramnios had been a complication of
pregnancy. Multiple joint dislocations and radiological features, of
which the most characteristic were short, distally tapering humeri,
absent or hypoplastic fibulae, deficient vertebral ossification with
coronal clefting, and anarchic ossification of phalanges, were
described.

The disorder that has been called atelosteogenesis type II (Sillence et
al., 1987) may be the same as de la Chapelle dysplasia (256050). Stern
et al. (1990) recommended discarding the term atelosteogenesis type II,
but proposed the term atelosteogenesis III for a distinct condition
(AOIII; 108721).

Hunter and Carpenter (1991) reported a case of atelosteogenesis type I.
They concluded that boomerang dysplasia (112310) and AOI are 'part of a
spectrum, probably reflecting a common etiology.' In a male fetus with a
lethal chondrodysplasia, Greally et al. (1993) documented clinical and
radiologic overlap between AOI and boomerang dysplasia. From histologic
examination, they suggested a defect of cartilage and bone formation as
the basic abnormality.

MOLECULAR GENETICS

In 3 unrelated individuals with sporadically occurring AOI, Krakow et
al. (2004) found heterozygosity for point mutations in FLNB (603381)
that predicted single-residue substitutions in the N-terminal
actin-binding domain of filamin B. They also found 1 individual with
AOIII (108721) who was heterozygous for the same point mutation, 604A-G
(603381.0007), that had been identified in an individual with AOI.

*FIELD* SA
Maroteaux et al. (1982); Stevenson and Wilkes (1983)
*FIELD* RF
1. Greally, M. T.; Jewett, T.; Smith, W. L., Jr.; Penick, G. D.; Williamson,
R. A.: Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis
I and boomerang dysplasia. Am. J. Med. Genet. 47: 1086-1091, 1993.

2. Hunter, A. G. W.; Carpenter, B. F.: Atelosteogenesis I and boomerang
dysplasia: a question of nosology. Clin. Genet. 39: 471-480, 1991.

3. Kozlowski, K.; Tsuruta, T.; Kameda, Y.; Kan, A.; Leslie, G.: New
forms of neonatal death dwarfism: report of 3 cases. Pediat. Radiol. 10:
155-160, 1981.

4. Krakow, D.; Robertson, S. P.; King, L. M.; Morgan, T.; Sebald,
E. T.; Bertolotto, C.; Wachsmann-Hogiu, S.; Acuna, D.; Shapiro, S.
S.; Takafuta, T.; Aftimos, S.; Kim, C. A.; and 13 others: Mutations
in the gene encoding filamin B disrupt vertebral segmentation, joint
formation and skeletogenesis. Nature Genet. 36: 405-410, 2004.

5. Maroteaux, P.; Spranger, J.; Stanescu, V.; Le Marec, B.; Pfeiffer,
R. A.; Beighton, P.; Mattei, J. F.: Atelosteogenesis. Am. J. Med.
Genet. 13: 15-25, 1982.

6. Maroteaux, P.; Stanescu, V.; Stanescu, R.: Four recently described
osteochondrodysplasias.In: Papadatos, C. J.; Bartsocas, C. S.: Skeletal
Dysplasias. New York: Alan R. Liss (pub.) 1982. Pp. 345-350.

7. Rimoin, D. L.; Sillence, D. O.; Lachman, R. S.; Jenkins, T.; Riccardi,
V.: Giant cell chondrodysplasia: a second case of a rare lethal newborn
skeletal dysplasia. (Abstract) Am. J. Hum. Genet. 32: 125A only,
1980.

8. Salonen, R.: Neonatal osseous dysplasia I: second report. Prog.
Clin. Biol. Res. 104: 171-172, 1982.

9. Sillence, D.; Kozlowski, K.: 'Giant cell' chondrodysplasia. (Letter) Am.
J. Med. Genet. 15: 627 only, 1983.

10. Sillence, D.; Kozlowski, K.; Rogers, J.; Sprague, P.; Cullity,
G.; Osborn, R.: Atelosteogenesis: evidence for heterogeneity. Pediat.
Radiol. 17: 112-118, 1987.

11. Sillence, D. O.; Lachman, R. S.; Jenkins, T.; Riccardi, V. M.;
Rimoin, D. L.: Spondylohumerofemoral hypoplasia (giant cell chondrodysplasia):
a neonatally lethal short-limb skeletal dysplasia. Am. J. Med. Genet. 13:
7-14, 1982.

12. Stern, H. J.; Graham, J. M., Jr.; Lachman, R. S.; Horton, W.;
Bernini, P. M.; Spiegel, P. K.; Bodurtha, J.; Ives, E. J.; Bocian,
M.; Rimoin, D. L.: Atelosteogenesis type III: a distinct skeletal
dysplasia with features overlapping atelosteogenesis and oto-palato-digital
syndrome type II. Am. J. Med. Genet. 36: 183-195, 1990.

13. Stevenson, R. E.; Wilkes, G.: Atelosteogenesis with survival
beyond the neonatal period. Proc. Greenwood Genet. Center 2: 32-38,
1983.

14. Temple, K.; Hall, C. A.; Chitty, L.; Baraitser, M.: A case of
atelosteogenesis. J. Med. Genet. 27: 194-197, 1990.

15. Whitley, C. B.; Burke, B. A.; Granroth, G.; Gorlin, R. J.: De
la Chapelle dysplasia. Am. J. Med. Genet. 25: 29-39, 1986.

16. Yang, S. S.; Roskamp, J.; Liu, C. T.; Frates, R.; Singer, D. B.
: Two lethal chondrodysplasias with giant chondrocytes. Am. J. Med.
Genet. 15: 615-625, 1983.

*FIELD* CS
INHERITANCE:
Isolated cases

GROWTH:
[Height];
Short-limbed dwarfism

HEAD AND NECK:
[Face];
Frontal bossing;
Micrognathia;
Midface hypoplasia;
[Eyes];
Prominent globes;
Edematous eyelids;
[Nose];
Depressed nasal bridge;
Hypoplastic nose;
[Mouth];
Cleft palate;
[Neck];
Short neck

RESPIRATORY:
[Larynx];
Laryngeal stenosis

CHEST:
[External features];
Narrow thoracic cage;
[Ribs, sternum, clavicles, and scapulae];
11 pairs of ribs

GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
[Spine];
Fused cervical vertebrae;
Abnormal segmentation;
Thoracic platyspondyly;
Coronal clefts;
Sagittal clefts;
[Limbs];
Rhizomelic limb shortening;
Elbow dislocation;
Short humeri with proximal clubbing and distal tapering;
Short, bowed radius;
Absent-hypoplastic ulnae;
Short femora with proximal clubbing and distal tapering;
Short, bowed tibiae;
Absent-hypoplastic fibulae;
[Hands];
Brachydactyly;
Poor ossifications of metacarpal and proximal, middle phalanges;
Well-ossified distal phalanges;
Short metacarpals;
[Feet];
Talipes equinovarus;
Short metatarsals

NEUROLOGIC:
[Central nervous system];
Encephalocele

PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Polyhydramnios;
[Delivery];
Stillborn;
Premature delivery

LABORATORY ABNORMALITIES:
Giant cells (degenerating chondrocytes) in resting zone of epiphyseal
cartilage

MISCELLANEOUS:
All cases have been stillborn or immediate neonatal death

MOLECULAR BASIS:
Mutation in the filamin B gene (FLNB, 603381)

*FIELD* CN
Kelly A. Przylepa - revised: 8/20/2002

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

*FIELD* ED
joanna: 04/14/2010
joanna: 3/14/2005
alopez: 3/23/2004
joanna: 8/20/2002

*FIELD* CN
Marla J. F. O'Neill - updated: 3/16/2004

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

*FIELD* ED
wwang: 06/10/2011
carol: 10/25/2006
alopez: 4/2/2004
alopez: 3/23/2004
terry: 3/16/2004
carol: 11/24/1998
mimadm: 4/9/1994
carol: 11/22/1993
supermim: 3/16/1992
carol: 7/9/1991
carol: 2/21/1991
carol: 7/9/1990

MIM 108721
*RECORD*
*FIELD* NO
108721
*FIELD* TI
#108721 ATELOSTEOGENESIS, TYPE III; AOIII
;;AO3
*FIELD* TX
A number sign (#) is used with this entry because atelosteogenesis type
read moreIII is caused by mutations in the gene encoding filamin B (FLNB;
603381).

CLINICAL FEATURES

Stern et al. (1990) described 5 examples of a short-limb dwarfism
syndrome with manifestations overlapping those of atelosteogenesis
(108720) and otopalatodigital syndrome type II (304120). They presented
clinical, radiographic, genetic, and histologic data that demonstrated
differences between these patients and previously reported cases of the
other conditions. Like AOI, this new disorder, designated AOIII, has
been observed only in isolated cases, suggesting fresh dominant
mutation. In 1 of the 5 patients with AOIII, there was advanced paternal
age consistent with this possibility. On the other hand, Pyeritz (1993)
reported a case of affected sibs.

Schultz et al. (1999) reported a mother and son with atelosteogenesis
type III. They stated that this was the first report of survival to
adulthood, of prenatal diagnosis, and of dominant transmission. The
authors reviewed 9 previously published cases to describe the syndrome
more completely; they suggested that the physical and radiographic
findings of AOIII and Larsen syndrome (150250) are quite similar, and
that the disorders are probably allelic.

MOLECULAR GENETICS

In 2 unrelated individuals with sporadically occurring AOIII, Krakow et
al. (2004) found heterozygosity for point mutations in the FLNB gene
(603381) that predicted single-residue substitutions in the N-terminal
actin-binding domain of filamin B. One individual with AOIII was
heterozygous for the same point mutation, 604A-G, that had been
identified in an individual with AOI (see 603381.0007).

*FIELD* RF
1. Krakow, D.; Robertson, S. P.; King, L. M.; Morgan, T.; Sebald,
E. T.; Bertolotto, C.; Wachsmann-Hogiu, S.; Acuna, D.; Shapiro, S.
S.; Takafuta, T.; Aftimos, S.; Kim, C. A.; and 13 others: Mutations
in the gene encoding filamin B disrupt vertebral segmentation, joint
formation and skeletogenesis. Nature Genet. 36: 405-410, 2004.

2. Pyeritz, R. E.: Personal Communication. Baltimore, Md. 5/5/1993.

3. Schultz, C.; Langer, L. O.; Laxova, R.; Pauli, R. M.: Atelosteogenesis
type III: long term survival, prenatal diagnosis, and evidence for
dominant transmission. Am. J. Med. Genet. 83: 28-42, 1999.

4. Stern, H. J.; Graham, J. M., Jr.; Lachman, R. S.; Horton, W.; Bernini,
P. M.; Spiegel, P. K.; Bodurtha, J.; Ives, E. J.; Bocian, M.; Rimoin,
D. L.: Atelosteogenesis type III: a distinct skeletal dysplasia with
features overlapping atelosteogenesis and oto-palato-digital syndrome
type II. Am. J. Med. Genet. 36: 183-195, 1990.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Frontal bossing;
Midface hypoplasia;
Micrognathia;
[Nose];
Flat nasal bridge;
[Mouth];
Cleft palate;
[Neck];
Short neck

SKELETAL:
[Skull];
Hypoplastic maxilla;
Hypoplastic mandible;
Prominent occiput;
[Spine];
Scoliosis;
Cervical spine segmentation defects;
Cervical kyphosis;
[Pelvis];
Rounded iliac bones with shortened sacrosciatic notches;
Vertical, block-like ischia;
Flat acetabular roofs;
Horizontal sacrum;
[Limbs];
Rhizomelic shortening;
Elbow dislocations;
Club-shaped humeri with early proximal epiphyseal ossification;
Club-shaped femora;
Knee dislocations;
Radial bowing;
Tibial bowing;
[Hands];
Hitchhiker thumb;
Tombstone-shaped proximal phalanges;
Widened distal phalanges;
Bifid digits;
[Feet];
Hitchhiker halluces;
Talipes equinovarus;
Widened gap first and second toe

MOLECULAR BASIS:
Caused by mutation in the filamin B gene (FLNB, 603381.0006)

*FIELD* CN
Kelly A. Przylepa - revised: 8/14/2002

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

*FIELD* ED
joanna: 02/22/2011
alopez: 3/23/2004
joanna: 8/14/2002

*FIELD* CN
Marla J. F. O'Neill - updated: 3/16/2004
Ada Hamosh - updated: 4/20/1999

*FIELD* CD
Victor A. McKusick: 7/9/1990

*FIELD* ED
carol: 02/16/2011
alopez: 4/2/2004
alopez: 3/23/2004
terry: 3/16/2004
alopez: 4/20/1999
carol: 11/24/1998
mimadm: 4/9/1994
warfield: 4/7/1994
carol: 5/6/1993
supermim: 3/16/1992
carol: 7/9/1990

MIM 112310
*RECORD*
*FIELD* NO
112310
*FIELD* TI
#112310 BOOMERANG DYSPLASIA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreboomerang dysplasia can be caused by mutation in the FLNB gene (603381).

Kozlowski et al. (1981), Tenconi et al. (1983), and Kozlowski et al.
(1985) each described 1 case of a disorder termed boomerang dysplasia
because of the unusual shape of the long bones of the legs. All 3
subjects died in the neonatal period. They had dwarfism with short,
bowed, rigid limbs and characteristic facies. In particular, the nose
had a broad root and severe hypoplasia of the nares and septum.
Radiographically, the radii and fibulae were absent, while the remaining
long bones had the boomerang configuration. The iliac bodies were small
and ossification in the lower spine and digits was retarded. All 3
patients were sporadic males, derived from Japan, Italy, and Australia.
Winship et al. (1990) described a fourth case, again in a male infant.
Shortened boomerang-shaped radii, femora, and tibias were noted. The
vertebral borders showed coronal clefts. The genetic basis of the
syndrome is unknown. Hunter and Carpenter (1991) described a patient
with apparent manifestations of both type I atelosteogenesis (108720)
and boomerang dysplasia and concluded that these disorders are 'part of
a spectrum, probably reflecting a common etiology.' Greally et al.
(1993) presented a case that supported the hypothesis of Hunter and
Carpenter (1991).

Urioste et al. (1997) reported a possible case of boomerang dysplasia in
the offspring of healthy, nonconsanguineous parents. Delivery was
induced at 27 weeks of gestation. He was markedly disproportionate with
a large head, very short and flipper-like limbs, numerous malformations,
and generalized alopecia. Radiologic skeletal examination showed
generalized underossification. The pubic bones were absent. Only one
well-ossified and bowed bone was observed in the legs, which had the
appearance of a boomerang. Histologic studies showed multinucleated
giant chondrocytes in the cartilage. The karyotype was apparently
normal.

Odent et al. (1999) reported a female fetus of 24 weeks' gestation with
clinical and radiologic features compatible with boomerang dysplasia.
Histopathology, however, showed unusual lateral fan-shaped diaphyseal
ossification. Odent et al. (1999) concluded that these features
represented a variant of boomerang dysplasia with clinical
characteristics of both atelosteogenesis type I and boomerang dysplasia.

Wessels et al. (2003) reported a male fetus with boomerang dysplasia
that was diagnosed by ultrasound at 16 weeks of gestation. Delivery was
induced at 17 weeks of gestation; postdelivery examination revealed
dwarfism and micromelia of the 4 limbs. In each limb only 1 of the 3
long tubular bones was ossified; the presumed radius had a boomerang
shape and the presumed tibia had a segment shape. The hands and feet
were very short and broad with severe brachydactyly. The ossification
centers of all vertebrae except for T11-12 and L1-3 were absent. The
thorax was small and bell-shaped with short ribs. The skull showed
micrognathia.

MOLECULAR GENETICS

In a 22-week male fetus previously studied by Krakow et al. (2004) and a
17-week male fetus previously described by Wessels et al. (2003), both
diagnosed with boomerang dysplasia, Bicknell et al. (2005) identified
heterozygosity for mutations in the FLNB gene, leu171 to arg (L171R;
603381.0009) and ser235 to pro (S235P; 603381.0010), respectively.

*FIELD* SA
Beighton (1988)
*FIELD* RF
1. Beighton, P.: Inherited Disorders of the Skeleton. London: Churchill
Livingstone (pub.) (2nd ed.): 1988. Pp. 99-100.

2. Bicknell, L. S.; Morgan, T.; Bonafe, L.; Wessels, M. W.; Bialer,
M. G.; Willems, P. J.; Cohn, D. H.; Krakow, D.; Robertson, S. P.:
Mutations in FLNB cause boomerang dysplasia. J. Med. Genet. 42:
e43, 2005. Note: Electronic Article.

3. Greally, M. T.; Jewett, T.; Smith, W. L., Jr.; Penick, G. D.; Williamson,
R. A.: Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis
I and boomerang dysplasia. Am. J. Med. Genet. 47: 1086-1091, 1993.

4. Hunter, A. G. W.; Carpenter, B. F.: Atelosteogenesis I and boomerang
dysplasia: a question of nosology. Clin. Genet. 39: 471-480, 1991.

5. Kozlowski, K.; Sillence, D.; Cortis-Jones, R.; Osborn, R.: Boomerang
dysplasia. Brit. J. Radiol. 58: 369-371, 1985.

6. Kozlowski, K.; Tsuruta, T.; Kameda, Y.; Kan, A.; Leslie, G.: New
forms of neonatal death dwarfism: report of 3 cases. Pediat. Radiol. 10:
155-160, 1981.

7. Krakow, D.; Robertson, S. P.; King, L. M.; Morgan, T.; Sebald,
E. T.; Bertolotto, C.; Wachsmann-Hogiu, S.; Acuna, D.; Shapiro, S.
S.; Takafuta, T.; Aftimos, S.; Kim, C. A.; and 13 others: Mutations
in the gene encoding filamin B disrupt vertebral segmentation, joint
formation and skeletogenesis. Nature Genet. 36: 405-410, 2004.

8. Odent, S.; Loget, P.; Le Marec, B.; Delezoide, A.-L.; Maroteaux,
P.: Unusual fan shaped ossification in a female fetus with radiological
features of boomerang dysplasia. J. Med. Genet. 36: 330-332, 1999.

9. Tenconi, R.; Kozlowski, K.; Largaiolli, G.: Boomerang dysplasia:
a new form of neonatal death dwarfism. Fortschr. Geb. Roentgenstr. 138:
378-380, 1983.

10. Urioste, M.; Rodriguez, J. I.; Bofarull, J. M.; Toran, N.; Ferrer,
C.; Villa, A.: Giant-cell chondrodysplasia in a male infant with
clinical and radiological findings resembling the Piepkorn type of
lethal osteochondrodysplasia. Am. J. Med. Genet. 68: 342-346, 1997.

11. Wessels, M. W.; Den Hollander, N. S.; De Krijger, R. R.; Bonife,
L.; Superti-Furga, A.; Nikkels, P. G.; Willems, P. J.: Prenatal diagnosis
of boomerang dysplasia. Am. J. Med. Genet. 122A: 148-154, 2003.

12. Winship, I.; Cremin, B.; Beighton, P.: Boomerang dysplasia. Am.
J. Med. Genet. 36: 440-443, 1990.

*FIELD* CS

Growth:
Congential dwarfism

Limbs:
Short, bowed, rigid limbs

Nose:
Broad nasal root;
Hypoplastic nares and septum

Misc:
Neonatal death

Radiology:
Absent radii and fibulae with boomerang shaped remaining long bones;
Small iliac bodies;
Retarded ossification of lower spine and digits

Inheritance:
Autosomal dominant

*FIELD* CN
Marla J. F. O'Neill - updated: 9/19/2005
Marla J. F. O'Neill - updated: 8/24/2005
Wilson H. Y. Lo - updated: 4/27/2000
Michael J. Wright - updated: 7/9/1999

*FIELD* CD
Victor A. McKusick: 12/9/1989

*FIELD* ED
carol: 01/23/2007
wwang: 10/5/2005
terry: 9/19/2005
carol: 8/24/2005
carol: 5/3/2000
terry: 4/27/2000
jlewis: 7/26/1999
terry: 7/9/1999
davew: 7/28/1994
mimadm: 4/9/1994
carol: 11/22/1993
supermim: 3/16/1992
carol: 9/16/1991
carol: 8/20/1990

MIM 150250
*RECORD*
*FIELD* NO
150250
*FIELD* TI
#150250 LARSEN SYNDROME; LRS
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
read moreLarsen syndrome is caused by heterozygous mutation in the gene encoding
filamin B (FLNB; 603381) on chromosome 3p14.3..

An autosomal recessive syndrome with overlapping features (multiple
joint dislocations, short stature, craniofacial dysmorphism, and
congenital heart defects; 245600) has been found to be caused by
mutation in the B3GAT3 gene (606374) on chromosome 11q12.3.

DESCRIPTION

Larsen syndrome is an osteochondrodysplasia characterized by large-joint
dislocations and characteristic craniofacial abnormalities. The cardinal
features of the condition are dislocations of the hip, knee and elbow
joints, with equinovarus or equinovalgus foot deformities.
Spatula-shaped fingers, most marked in the thumb, are also present.
Craniofacial anomalies include hypertelorism, prominence of the
forehead, a depressed nasal bridge, and a flattened midface. Cleft
palate and short stature are often associated features. Spinal anomalies
include scoliosis and cervical kyphosis. Hearing loss is a
well-recognized complication (summary by Bicknell et al., 2007).

CLINICAL FEATURES

Larsen et al. (1950) called attention to a syndrome of multiple
congenital dislocations and characteristic facies (prominent forehead,
depressed nasal bridge, wide-spaced eyes). Clubfoot, bilateral
dislocation of elbows, hips and knees (most characteristically, anterior
dislocation of the tibia on the femur), and short metacarpals with
cylindrical fingers lacking the usual tapering were the skeletal
features of note. Cleft palate, hydrocephalus, and abnormalities of
spinal segmentation were found in some patients.

Harris and Cullen (1971) described affected mother and daughter.
Bilateral dislocation of the knees, pes cavus, cylindrically shaped
fingers, and characteristic facies (wide-spaced eyes, flattened nasal
bridge and prominent forehead) were present in both. The maternal
grandfather was said to have had similar facies. One of the original
cases of Larsen et al. (1950), 23 years of age in 1972, had an affected
child. Features in addition to knee dislocations included flat face,
accessory carpal bones, and short terminal phalanges creating
pseudoclubbing. Multiple congenital dislocations with osseous anomalies
and unusual facies are characteristic. Anterior dislocation of the tibia
on the femur is usual. A juxtacalcaneal accessory ossification center
and abnormality of vertebrae are observed.

Latta et al. (1971) made a point of a juxtacalcaneal accessory bone
which may be specific for this entity.

Tsang et al. (1986) reported 'new' oral and craniofacial findings in a
patient with Larsen syndrome.

Stanley et al. (1988) described mixed hearing loss in a child with
Larsen syndrome. On the basis of this and other cases, the authors
suggested that there may be involvement of the ossicular joints in this
disorder.

Le Marec et al. (1994) described a male infant who, in addition to the
typical manifestations of Larsen syndrome, had laryngomalacia with apnea
and multiple abnormalities of the cervical spine (segmentation defects,
kyphosis, atlantoaxial dislocation, and narrowing of subdural space at
the apex of the kyphosis).

Although abnormalities of the cervical spine were not emphasized in the
original description of the syndrome (Larsen et al., 1950), they may be
the most serious manifestation. Cervical kyphosis in particular may be
life-threatening because of the impingement on the spinal cord at the
apex of the kyphosis. Of the 9 affected infants followed by Johnston et
al. (1996), 5 were noted to have cervical kyphosis because of marked
hypoplasia of 1 or 2 vertebral bodies (usually the fourth or fifth
cervical vertebra, or both) at the apex of the kyphosis; the infants
were successfully managed by posterior cervical arthrodesis alone.
Johnston et al. (1996) suggested that the prevalence of cervical
kyphosis in Larsen syndrome has probably been underestimated but may
easily be documented because no dynamic studies or cooperation by the
patients are necessary. They concluded that early diagnosis followed by
operative stabilization should help such patients avoid neurologic
deficits.

Becker et al. (2000) reported the case of a mildly affected father and a
severe form of Larsen syndrome in a fetus detected by sonography. The
mother had requested prenatal diagnosis on the grounds of an unknown
congenital disorder in her husband. His height was 172 cm. He presented
with a flat palate and craniofacial dysmorphism (small teeth,
hypertelorism, and a prominent forehead). The fingers and toes had short
terminal phalanges creating pseudoclubbing. Congenital bilateral
clubfoot had required orthopedic correction. Sonographic examination in
the man's pregnant wife showed that both legs of the fetus were fixed in
an extended position at the knee joints with overstretching of the
joints, consistent with genua recurvata. Irregularities of the knee
joints and clubfeet were noted. The elbows were flexed and mobile. The
fingers seemed to be thickened and in a constantly flexed position. The
facial profile showed dysmorphism including a prominent forehead, flat
nose, and micrognathia. The parents opted to terminate the pregnancy.
Autopsy of the fetus confirmed the sonographic findings in the female
fetus with a normal 46,XX karyotype. The diagnosis of Larsen syndrome in
the father had been missed by highly skilled genetic counselors. A
similar experience of misdiagnosis was reported by Vujic et al. (1995),
who reported that none of 26 family members with Larsen syndrome who had
received medical treatment had been diagnosed correctly. Becker et al.
(2000) raised the possibility that the mild manifestation of Larsen
syndrome in the father was due to mosaicism.

INHERITANCE

Dominant inheritance of Larsen syndrome seemed certain from the reports
of Latta et al. (1971) and of McFarlane (1947). The mother of the
patient reported by Latta et al. (1971) had a saddle nose which
developed at age 18 after tennis-ball trauma. McFarlane (1947) reported
a woman with saddle nose, congenital dislocation of the knees, and
hyperextensibility of the elbows. By each of 3 different mates she
produced an affected child with bilateral knee dislocations.

Hall (1978) followed up on the 2-generation family reported by Latta et
al. (1971); she was convinced that the mother was affected and made the
further observation that in her 30s the mother had developed
polychondritis of her tracheobronchial cartilage with recurrent
pulmonary problems because of airway stenosis.

Sugarman (1975) described affected black mother and daughter. The
diagnosis in the cases of Henriksson et al. (1977) and of Marques (1980)
is doubtful (Gorlin, 1982). Gorlin (1982) observed affected mother and
son.

Petrella et al. (1993) provided follow-up on 2 sibs with Larsen syndrome
reported by Bloch and Peck (1965). This family had been cited as a
possible example of the recessive form of Larsen syndrome. Congenital
dislocation of the knees with unilateral cataract and unilateral
undescended testis was present in a newborn male; a sister was born with
bilateral dislocation of the knees and hips and cleft palate. The
parents were unaffected. However, reinterpretation as the autosomal
dominant form of Larsen syndrome with germline mosaicism was required
because the sister gave birth to an affected daughter (Petrella et al.,
1993).

Frints et al. (2000) and Debeer et al. (2003) described cases of
asymmetric Larsen syndrome which they interpreted as examples of
unilateral somatic mosaicism.

MAPPING

In a large Swedish kindred with autosomal dominant Larsen syndrome,
Vujic et al. (1995) found that the gene, which they symbolized LAR1, is
strongly linked to a region of 3p defined distally by D3S1581 and
proximally by D3S1600, which cytogenetically maps to 3p21.1-p14.1.
Linkage and recombination analysis using a COL7A1 (120120) PvuII
intragenic polymorphism versus Larsen syndrome and chromosome 3 markers
indicated that COL7A1 is located close to, but separate from, the LAR1
locus. The kindred contained a total of 49 individuals thought to be
carriers of the mutant gene. Altogether, 48 family members, of whom 26
were affected, were included in the DNA study.

MOLECULAR GENETICS

In 4 individuals with sporadically occurring Larsen syndrome and 1
family with a dominantly inherited form of the condition, Krakow et al.
(2004) found heterozygosity for de novo missense mutations in the FLNB
gene (603381.0004; 603381.0005).

Bicknell et al. (2007) identified several different heterozygous
mutations in the FLNB gene (see, e.g., 603381.0011; 603381.0012) in 20
unrelated patients with Larsen syndrome. One of the mutations was
detected in 6 unrelated probands.

HISTORY

One of the earliest reports of Larsen syndrome may have been that of
McFarland (1929).

*FIELD* SA
Houston et al. (1981); Oki et al. (1976); Robertson et al. (1975);
Trigueros et al. (1978)
*FIELD* RF
1. Becker, R.; Wegner, R.-D.; Kunze, J.; Runkel, S.; Vogel, M.; Entezami,
M.: Clinical variability of Larsen syndrome: diagnosis in a father
after sonographic detection of a severely affected fetus. Clin. Genet. 57:
148-150, 2000.

2. Bicknell, L. S.; Farrington-Rock, C.; Shafeghati, Y.; Rump, P.;
Alanay, Y.; Alembik, Y.; Al-Madani, N.; Firth, H.; Karimi-Nejad, M.
H.; Kim, C. A.; Leask, K.; Maisenbacher, M.; and 14 others: A molecular
and clinical study of Larsen syndrome caused by mutations in FLNB. J.
Med. Genet. 44: 89-98, 2007.

3. Bloch, C.; Peck, H. M.: Bilateral congenital dislocation of the
knees. J. Mt. Sinai Hosp. 32: 607-614, 1965.

4. Debeer, P. H.; De Borre, L.; De Smet, L.; Fryns, J. P.: Asymmetrical
Larsen syndrome in a young girl: a second example of somatic mosaicism
in this syndrome. Genet. Counsel. 14: 95-100, 2003.

5. Frints, S. G. M.; De Smet, L.; Fabry, G.; Fryns, J. P.: A young
female with asymmetric manifestations of Larsen syndrome: another
example of unilateral somatic cell-line mosaicism. Clin. Dysmorph. 9:
273-276, 2000.

6. Gorlin, R. J.: Personal Communication. Minneapolis, Minn. 1982.

7. Hall, J. G.: Personal Communication. Seattle, Wash. 1978.

8. Harris, R.; Cullen, C. H.: Autosomal dominant inheritance in Larsen's
syndrome. Clin. Genet. 2: 87-90, 1971.

9. Henriksson, P.; Ivarsson, S.; Theander, G.: The Larsen syndrome
and glial proliferation in the brain. Acta Paediat. Scand. 66: 653-658,
1977.

10. Houston, C. S.; Reed, M. H.; Desansch, J. E. L.: Separating Larsen's
syndrome from the 'arthrogryposis basket'. J. Canad. Assoc. Radiol. 32:
206-214, 1981.

11. Johnston, C. E., II; Birch, J. G.; Daniels, J. L.: Cervical kyphosis
in patients who have Larsen syndrome. J. Bone Joint Surg. Am. 78:
538-545, 1996.

12. Krakow, D.; Robertson, S. P.; King, L. M.; Morgan, T.; Sebald,
E. T.; Bertolotto, C.; Wachsmann-Hogiu, S.; Acuna, D.; Shapiro, S.
S.; Takafuta, T.; Aftimos, S.; Kim, C. A.; and 13 others: Mutations
in the gene encoding filamin B disrupt vertebral segmentation, joint
formation and skeletogenesis. Nature Genet. 36: 405-410, 2004.

13. Larsen, L. J.; Schottstaedt, E. R.; Bost, F. C.: Multiple congenital
dislocations associated with characteristic facial abnormality. J.
Pediat. 37: 574-581, 1950.

14. Latta, R. J.; Graham, C. B.; Aase, J. M.; Scham, S. M.; Smith,
D. W.: Larsen's syndrome: a skeletal dysplasia with multiple joint
dislocations and unusual facies. J. Pediat. 78: 291-298, 1971.

15. Le Marec, B.; Chapuis, M.; Treguier, C.; Odent, S.; Bracq, H.
: A case of Larsen syndrome with severe cervical malformations. Genet.
Counsel. 5: 179-181, 1994.

16. Marques, M. D. N. T.: Larsen's syndrome: clinical and genetic
aspects. J. Genet. Hum. 28: 83-88, 1980.

17. McFarland, B. L.: Congenital dislocation of the knee. J. Bone
Joint Surg. 11: 281-285, 1929.

18. McFarlane, A. L.: A report on four cases of congenital genu recurvatum
occurring in one family. Brit. J. Surg. 34: 388-391, 1947.

19. Oki, T.; Terashima, Y.; Murachi, S.; Nogami, H.: Clinical features
and treatment of joint dislocations in Larsen's syndrome: report of
three cases in one family. Clin. Orthop. 119: 206-210, 1976.

20. Petrella, R.; Rabinowitz, J. G.; Steinmann, B.; Hirschhorn, K.
: Long-term follow-up of two sibs with Larsen syndrome possibly due
to parental germ-line mosaicism. Am. J. Med. Genet. 47: 187-197,
1993.

21. Robertson, F. W.; Kozlowski, K.; Middleton, R. W.: Larsen's syndrome.
Three cases with multiple congenital joint dislocations and distinctive
facies. Clin. Pediat. 14: 53-60, 1975.

22. Stanley, C. S.; Thelin, J. W.; Miles, J. H.: Mixed hearing loss
in Larsen syndrome. Clin. Genet. 33: 395-398, 1988.

23. Sugarman, G. I.: The Larsen syndrome, autosomal dominant form.In:
Bergsma, D.: Malformation Syndromes. New York: National Foundation-March
of Dimes (pub.) 1975. Pp. 121-129.

24. Trigueros, A. P.; Vazquez, J. L. V.; De Miguel, G. F. D.: Larsen's
syndrome: report of three cases in one family, mother and two offspring. Acta
Orthop. Scand. 49: 582-588, 1978.

25. Tsang, M. C. K.; Ling, J. Y. K.; King, N. M.; Chow, S. K.: Oral
and craniofacial morphology of a patient with Larsen syndrome. J.
Craniofac. Genet. Dev. Biol. 6: 357-362, 1986.

26. Vujic, M.; Hallstensson, K.; Wahlstrom, J.; Lundberg, A.; Langmaack,
C.; Martinsson, T.: Localization of a gene for autosomal dominant
Larsen syndrome to chromosome region 3p21.1-14.1 in the proximity
of, but distinct from, the COL7A1 locus. Am. J. Hum. Genet. 57:
1104-1113, 1995.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Short stature (final adult height less than 152cm);
[Other];
Prenatal growth deficiency

HEAD AND NECK:
[Face];
Flat face;
Prominent forehead;
[Ears];
Hearing loss, conductive;
Malformations of the auditory ossicles;
[Eyes];
Hypertelorism;
Anterior corneal lens opacities;
[Nose];
Depressed nasal bridge;
[Mouth];
Cleft palate;
Cleft lip;
[Teeth];
Hypodontia

CARDIOVASCULAR:
[Heart];
Aortic dilatation;
Atrial septal defect;
Ventricular septal defect

RESPIRATORY:
[Airways];
Tracheal stenosis;
Tracheomalacia;
Bronchomalacia

CHEST:
[External features];
Pectus excavatum;
Pectus carinatum

GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism

SKELETAL:
[Skull];
Flattened frontal bone;
Small skull base;
Shallow orbits;
[Spine];
Cervical vertebrae hypoplasia;
Subluxation or fusion of the cervical vertebrae;
Cervical kyphosis;
Scoliosis;
Wedged vertebrae;
Spondylolysis;
Spina bifida occulta;
[Pelvis];
Dislocation of the hip;
[Limbs];
Joint laxity;
Dislocations of the elbows;
Dislocations of the wrists;
Dislocations of the knees;
Dysplastic epiphyseal centers;
[Hands];
Cylindric fingers;
Spatulate thumbs;
Short metacarpals;
Supernumerary carpal bones;
Multiple carpal ossification centers;
[Feet];
Talipes equinovalgus;
Talipes equinovarus;
Short metatarsals;
Supernumerary tarsal bones;
Delayed coalescence of calcaneal ossification centers

SKIN, NAILS, HAIR:
[Nails];
Short nails

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Spinal cord compression

MISCELLANEOUS:
Intrafamilial variation;
Autosomal recessive inheritance (245600) has also been suggested;
Joint dislocations become less frequent with age

MOLECULAR BASIS:
Caused by mutation in the filamin B gene (FLNB, 603381.0004)

*FIELD* CN
Cassandra L. Kniffin - updated: 2/26/2007
Kelly A. Przylepa - revised: 9/10/2001

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

*FIELD* ED
joanna: 06/05/2009
joanna: 12/5/2008
ckniffin: 2/26/2007
joanna: 12/12/2005
alopez: 3/23/2004
joanna: 9/12/2001
joanna: 9/10/2001

*FIELD* CN
Marla J. F. O'Neill - updated: 11/03/2011
Marla J. F. O'Neill - updated: 11/18/2010
Cassandra L. Kniffin - updated: 2/26/2007
Marla J. F. O'Neill - updated: 3/16/2004
Victor A. McKusick - updated: 7/15/2003
Victor A. McKusick - updated: 6/26/2003
Victor A. McKusick - updated: 4/21/2000
Beat Steinmann - updated: 5/16/1996

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

*FIELD* ED
carol: 11/03/2011
carol: 2/25/2011
terry: 1/13/2011
carol: 11/18/2010
carol: 9/7/2010
wwang: 3/2/2007
ckniffin: 2/26/2007
alopez: 4/2/2004
alopez: 3/23/2004
terry: 3/16/2004
carol: 7/15/2003
terry: 7/15/2003
carol: 7/15/2003
terry: 6/26/2003
mcapotos: 5/24/2000
mcapotos: 5/19/2000
mcapotos: 5/18/2000
terry: 4/21/2000
carol: 5/16/1996
terry: 5/16/1996
mark: 1/12/1996
terry: 11/6/1995
mimadm: 11/5/1994
davew: 8/15/1994
warfield: 4/12/1994
carol: 10/5/1993
supermim: 3/16/1992

MIM 272460
*RECORD*
*FIELD* NO
272460
*FIELD* TI
#272460 SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME; SCT
;;SPONDYLOCARPOTARSAL SYNDROME;;
read moreSYNSPONDYLISM, CONGENITAL;;
VERTEBRAL FUSION WITH CARPAL COALITION;;
SCOLIOSIS, CONGENITAL, WITH UNILATERAL UNSEGMENTED BAR
*FIELD* TX
A number sign (#) is used with this entry because spondylocarpotarsal
synostosis syndrome is caused by mutation in the gene encoding filamin B
(FLNB; 603381) on chromosome 3p14.3.

CLINICAL FEATURES

Wiles et al. (1992) used the designation congenital synspondylism for a
form of congenital familial extensive vertebral anomalies (CFEVA). They
suggested that this represents an entity separate from spondylocostal
dysplasia (SCD; 122600) and spondylothoracic dysplasia (STD; 277300).
They reported 2 brothers and an unrelated girl who had an unusual
constellation of vertebral fusions without rib anomalies as well as
carpal coalition. By analogy to symphalangism (185800), they chose the
designation synspondylism. The 2 brothers had Lebanese parents born in
the same district of Lebanon but not known to be consanguineous. Two
sibs with apparently the same disorder were reported by Langer and Moe
(1975) and by Akbarnia and Moe (1978). Scoliosis was a more impressive
feature than in the case of the Lebanese brothers reported by Wiles et
al. (1992). Akbarnia and Moe (1978) referred to the condition as
'familial congenital scoliosis with unilateral unsegmented bar.' Their
patients were an Iranian brother and sister whose parents were first
cousins. Both showed right thoracic lordoscoliosis with failure of
segmentation on the left from the third to the eleventh thoracic
vertebra. Both had clubfeet as well as partial coalition of the carpal
bones. Ventruto and Catani (1986) described 2 Italian brothers, aged 16
and 8 years, who had 8 normal sibs and whose gypsy parents were first
cousins. The unilateral unsegmented fusion bar was on the left in the
older brother and on the right in the younger brother. Ventruto and
Catani (1986) were impressed by the presence of joint laxity, congenital
inguinal hernias, clubfoot, and peculiar facies (hypertelorism, short
nasal septum, and broad bridge and tip of the nose).

Langer et al. (1994) reported 6 additional patients, 2 of them sibs.
They used the term spondylocarpotarsal synostosis syndrome, with or
without unilateral unsegmented bar, because carpal synostosis, usually
capitate-hamate and lunate-triquetrum, was a feature and tarsal
synostoses were present in all patients in whom the feet had been
radiographed. The patients were of short stature, with
disproportionately short trunk. The feet were flat. Cleft palate and
sensorineural or mixed hearing loss were variable manifestations. Wiles
et al. (1992) gave a useful review of several types of congenital
familial extensive vertebral anomalies, including the costovertebral
segmentation defect with mesomelia (COVESDEM syndrome; 268310).

Coelho et al. (1998) described 3 patients (2 of them sibs born to
first-cousin parents) with spondylocarpotarsal synostosis syndrome.
Sensorineural deafness was found in 2 of the 3 patients. Of 18 reported
patients, including these 3, 10 were sib pairs from 5 families, with
first-cousin consanguinity of parents in 3.

Seaver and Boyd (2000) reported a sporadic case, which they stated
brought the number of well-documented cases of spondylocarpotarsal
synostosis to 19 and was the first case documenting cervical spine
instability. The 5-year-old girl had hypoplasia of C1 and odontoid and
subluxation of C2 on C3.

Steiner et al. (2000) reported a Brazilian family with
spondylocarpotarsal synostosis. The parents were first cousins and had
10 children, 5 of whom were affected. The 3 described in the report had
short-trunk dwarfism of postnatal onset, scoliosis, unsegmented thoracic
vertebrae with unilateral bar, and carpal bone fusion. Lens opacities,
rarefaction of retinal pigmentation, and narrowing of retinal vessels
were seen in 2 patients. These ocular manifestations may be coincidental
or represent previously undescribed findings in this condition.

Mitter et al. (2008) described a 5-year-old German boy, born of
first-cousin parents, with spondylocarpotarsal synostosis and a mutation
in the FLNB gene (603381.0013). In addition to the typical findings of
this disorder, he demonstrated ossification delay of multiple epiphyses
(especially delayed carpal bone age) and bilateral proximal femoral
epiphyseal dysplasia. Similar radiographic findings were described in
another boy with spondylocarpotarsal synostosis reported by Honeywell et
al. (2002).

Brunetti-Pierri et al. (2008) reported an Italian girl, born of
consanguineous parents, with spondylocarpotarsal synostosis syndrome due
to a homozygous FLNB mutation (603381.0014). She had short stature,
scoliosis, short trunk, delayed bone age, vertebral fusions, and
capitate-hamate fusion. She did not have facial dysmorphic features.
Growth hormone (GH) deficiency was documented, but there was no response
to GH administration. MRI did not show any abnormality of the
hypothalamo-pituitary area, but there was platybasia and basilar
impression, stenosis of the foramen magnum, but no signs of medullary
compression at the cervicomedullary junction. A younger brother, who was
heterozygous for the mutation, had short stature and transient GH
deficiency.

INHERITANCE

Autosomal recessive inheritance of spondylocarpotarsal synostosis
syndrome was confirmed by the finding of homozygous or compound
heterozygous mutations in the FLNB gene (603381) in patients with the
disorder.

MAPPING

In a study of 4 families with spondylocarpotarsal synostosis syndrome, 3
of which were consanguineous, Steiner et al. (2004) used linkage
analysis to establish that the disease gene is located on chromosome
3p14. A common region of homozygosity was found between markers D3S3724
and D3S1300 on 3p, defining a physical interval of approximately 4
million bp.

MOLECULAR GENETICS

In 4 unrelated SCT families, Krakow et al. (2004) found that affected
individuals were either homozygous or compound heterozygous for nonsense
mutations in the FLNB gene (603381). In all 4 families, the segregation
of the mutations was compatible with autosomal recessive inheritance.
The premature stop codons all were located within the repeat domain of
filamin B, and Krakow et al. (2004) concluded that SCT results from the
absence or truncation of filamin B.

HETEROGENEITY

Isidor et al. (2008) described a mother and her son with clinical and
radiologic criteria for spondylocarpotarsal synostosis syndrome.
Molecular analysis failed to identify mutations in the FLNB or the NOG
gene (602991). Isidor et al. (2008) suggested that SCT is genetically
heterogeneous and that both dominant and autosomal recessive forms of
inheritance should be considered.

*FIELD* RF
1. Akbarnia, B. A.; Moe, J. H.: Familial congenital scoliosis with
unilateral unsegmented bar: case report of two siblings. J. Bone
Joint Surg. Am. 60: 259-261, 1978.

2. Brunetti-Pierri, N.; Esposito, B.; De Brasi, D.; Mattiacci, D.
M.; Krakow, D.; Lee, B.; Salerno, M.: Spondylocarpotarsal synostosis:
long-term follow-up of a case due to FLNB mutations. Am. J. Med.
Genet. 146A: 1230-1233, 2008.

3. Coelho, K.-E. F. A.; Ramos, E. S.; Felix, T. M.; Martelli, L.;
de Pina-Neto, J. M.; Niikawa, N.: Three new cases of spondylocarpotarsal
synostosis syndrome: clinical and radiographic studies. Am. J. Med.
Genet. 77: 12-15, 1998.

4. Honeywell, C.; Langer, L.; Allanson, J.: Spondylocarpotarsal synostosis
with epiphyseal dysplasia. Am. J. Med. Genet. 109: 318-322, 2002.

5. Isidor, B.; Cormier-Daire, V.; Le Merrer, M.; Lefrancois, T.; Hamel,
A.; Le Caignec, C.; David, A.; Jacquemont, S.: Autosomal dominant
spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and
genetic heterogeneity. Am. J. Med. Genet. 146A: 1593-1597, 2008.

6. Krakow, D.; Robertson, S. P.; King, L. M.; Morgan, T.; Sebald,
E. T.; Bertolotto, C.; Wachsmann-Hogiu, S.; Acuna, D.; Shapiro, S.
S.; Takafuta, T.; Aftimos, S.; Kim, C. A.; and 13 others: Mutations
in the gene encoding filamin B disrupt vertebral segmentation, joint
formation and skeletogenesis. Nature Genet. 36: 405-410, 2004.

7. Langer, L. O., Jr.; Gorlin, R. J.; Donnai, D.; Hamel, B. C. J.;
Clericuzio, C.: Spondylocarpotarsal synostosis syndrome (with or
without unilateral unsegmented bar). Am. J. Med. Genet. 51: 1-8,
1994.

8. Langer, L. O., Jr.; Moe, J. H.: A recessive form of congenital
scoliosis different from spondylothoracic dysplasia. Birth Defects
Orig. Art. Ser. XI(6): 83-86, 1975.

9. Mitter, D.; Krakow, D.; Farrington-Rock, C.; Meinecke, P.: Expanded
clinical spectrum of spondylocarpotarsal synostosis syndrome and possible
manifestation in a heterozygous father. Am. J. Med. Genet. 146A:
779-783, 2008.

10. Seaver, L. H.; Boyd, E.: Spondylocarpotarsal synostosis syndrome
and cervical instability. Am. J. Med. Genet. 91: 340-344, 2000.

11. Steiner, C.; Ehtesham, N.; Taylor, K. D.; Sebald, E.; Cantor,
R.; King, L. M.; Guo, X.; Hang, T.; Hu, M. S.; Cui, J.-R.; Friedman,
B.; Norato, D.; Allanson, J.; Honeywell, C.; Mettler, G.; Field, F.;
Lachman, R.; Cohn, D. H.; Krakow, D.: A locus for spondylocarpotarsal
synostosis syndrome at chromosome 3p14. J. Med. Genet. 41: 266-269,
2004.

12. Steiner, C. E.; Torriani, M.; Norato, D. Y. J.; Marques-de-Faria,
A. P.: Spondylocarpotarsal synostosis with ocular findings. Am.
J. Med. Genet. 91: 131-134, 2000.

13. Ventruto, V.; Catani, L.: Progressive scoliosis by unilateral
unsegmented fusion bar, foot deformity, joint laxity, congenital inguinal
herniae, peculiar face. Am. J. Med. Genet. 25: 429-432, 1986.

14. Wiles, C. R.; Taylor, T. F. K.; Sillence, D. O.: Congenital synspondylism. Am.
J. Med. Genet. 42: 288-295, 1992.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature, disproportionate (short trunk)

HEAD AND NECK:
[Face];
Round, broad face;
[Ears];
Sensorineural hearing loss;
Mixed hearing loss;
Preauricular skin tag;
[Eyes];
Hypertelorism;
Cataract;
Rarefaction of retinal pigmentation;
Narrowing of retinal vessels;
[Nose];
Short nose;
Anteverted nares;
Broad, square nasal tip;
[Mouth];
Cleft palate;
[Teeth];
Enamel hypoplasia;
[Neck];
Short neck

RESPIRATORY:
[Lung];
Restrictive lung disease

GENITOURINARY:
[Kidneys];
Renal cysts

SKELETAL:
Delayed bone age;
[Spine];
Abnormal spinal segmentation;
Block vertebrae;
Scoliosis;
Lordosis;
Odontoid hypoplasia;
C2-C3 subluxation;
Unilateral unsegmented bar;
Fusion of vertebral bodies;
[Pelvis];
Bilateral proximal femoral epiphyseal dysplasia;
[Limbs];
Decreased range of motion at elbows;
[Hands];
Carpal synostosis (especially capitate-hamate and lunate-triquetrum);
Fifth finger clinodactyly;
[Feet];
Tarsal synostosis;
Pes planus

MOLECULAR BASIS:
Caused by mutation in the beta filamin B gene (FLNB, 603381.0001)

*FIELD* CN
Kelly A. Przylepa - updated: 4/7/2008
Kelly A. Przylepa - revised: 12/31/2002

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

*FIELD* ED
ckniffin: 09/05/2008
joanna: 4/7/2008
joanna: 3/17/2008
alopez: 3/23/2004
joanna: 3/6/2003
joanna: 12/31/2002

*FIELD* CN
Nara Sobreira - updated: 11/20/2009
Cassandra L. Kniffin - updated: 8/21/2008
Kelly A. Przylepa - updated: 4/11/2008
Victor A. McKusick - updated: 4/29/2004
Marla J. F. O'Neill - updated: 3/16/2004
Sonja A. Rasmussen - updated: 4/24/2000
Victor A. McKusick - updated: 4/19/2000
Victor A. McKusick - updated: 4/21/1998

*FIELD* CD
Victor A. McKusick: 2/13/1992

*FIELD* ED
terry: 01/13/2011
carol: 11/24/2009
terry: 11/20/2009
wwang: 8/28/2008
ckniffin: 8/21/2008
carol: 4/11/2008
tkritzer: 5/3/2004
terry: 4/29/2004
alopez: 4/2/2004
alopez: 3/23/2004
terry: 3/16/2004
mcapotos: 5/3/2000
mcapotos: 5/1/2000
terry: 4/24/2000
carol: 4/19/2000
terry: 4/19/2000
carol: 5/9/1998
terry: 4/21/1998
jason: 6/28/1994
mimadm: 4/8/1994
carol: 11/20/1992
supermim: 3/17/1992
carol: 2/13/1992

MIM 603381
*RECORD*
*FIELD* NO
603381
*FIELD* TI
*603381 FILAMIN B; FLNB
;;FILAMIN, BETA;;
ACTIN-BINDING PROTEIN 276/278; ABP276/278
read moreTRUNCATED ACTIN-BINDING PROTEIN, INCLUDED; TABP, INCLUDED;;
ACTIN-BINDING PROTEIN, TRUNCATED, INCLUDED;;
FILAMIN HOMOLOG 1, INCLUDED; FH1, INCLUDED
*FIELD* TX

CLONING

The platelet GpIb complex (see 138720) mediates the adherence of
platelets at the site of vascular injury through the binding of
GpIb-alpha (231200) to subendothelial von Willebrand factor (VWF;
613160). In platelets, the GpIb complex is tightly bound to the actin
cytoskeleton via an interaction of GpIb-alpha with ABP280 (filamin A;
300017). Using a yeast 2-hybrid screen with the cytoplasmic tail of
GpIb-alpha as bait, Takafuta et al. (1998) isolated partial cDNAs
encoding a novel filamin homolog that they designated beta-filamin. They
used the partial cDNAs to screen a placenta library and recovered
additional cDNAs corresponding to the entire beta-filamin coding region.
Like ABP280, the predicted 2,602-amino acid protein contains an
N-terminal actin-binding domain, a backbone of 24 tandem repeats, and 2
hinge regions. Excluding the unique first hinge region of beta-filamin,
the sequences of beta-filamin and ABP280 are 70% identical. Antibodies
against beta-filamin detected a 280-kD protein on Western blots of human
umbilical vein endothelial cell (HUVEC) extracts and stained normal
human endothelial cells in culture and in situ. Takafuta et al. (1998)
determined that the GpIb-alpha-binding domain in beta-filamin is in
repeats 17-20, a region that corresponds to the GpIb-alpha-binding
domain in ABP280. Northern blot analysis revealed that beta-filamin is
expressed as 2 approximately 9.5-kb mRNAs in many adult tissues. The 2
different transcripts appear to result from use of alternative
polyadenylation signals. Takafuta et al. (1998) concluded that
beta-filamin is a new member of the filamin family that may have
significance for GpIb-alpha function in endothelial cells and platelets.

Independently, Xu et al. (1998) isolated cDNAs encoding beta-filamin,
which they referred to as ABP278. These authors also identified
alternatively spliced mRNAs encoding ABP276, a beta-filamin isoform
missing the first hinge region. RT-PCR analysis indicated that the 2
isoforms were expressed at different relative levels in various human
tissues.

The addition of thyroid-stimulating hormone (TSH; see 188540) to
cultured thyroid follicular cells induces rapid and profound disruption
of actin microfilaments. Using serum from a Graves disease (275000)
patient, Leedman et al. (1993) identified a thyroid cDNA encoding TABP
(truncated actin-binding protein), a predicted 195-amino acid protein
with homology to the C terminus of ABP280. Both Xu et al. (1998) and
Takafuta et al. (1998) considered TABP to be a truncated form of
beta-filamin.

MAPPING

By analysis of somatic cell hybrids, Zhang et al. (1998) mapped the FH1
gene to chromosome 3. Takafuta et al. (1998) refined the map position to
3p21.1-p14.3 based on inclusion of a previously mapped STS within the
beta-filamin sequence. By FISH, Brocker et al. (1999) assigned the FLNB
gene to 3p14.3. Chakarova et al. (2000) mapped FLNB to 3p14 by radiation
hybrid analysis.

GENE FUNCTION

Using antigen-capture ELISA, Takafuta et al. (1998) found that
beta-filamin associates with GpIb-alpha in both platelets and HUVEC
extracts.

Mutations in the presenilin genes PS1 (104311) and PS2 (600759) account
for approximately 50% of early-onset familial Alzheimer disease (AD;
104300). Zhang et al. (1998) identified beta-filamin as filamin homolog
1 (FH1), a filamin-related protein that interacts with the loop regions
of PS1 and PS2. A monoclonal antibody recognizing both ABP280 and FH1
bound to blood vessels and astrocytes in the normal brain. In the brains
of AD patients, Zhang et al. (1998) observed staining also in
neurofibrillary tangles, neuropil threads, and dystrophic neurites
within some senile plaques. The authors stated that detection of these
presenilin-interacting proteins in these brain structures suggests that
ABP280 and FH1 may be involved in the development of AD and that
interactions between presenilins and ABP280/FH1 may be functionally
significant. Takafuta et al. (1998) noted that the FH1 sequence is
identical to the C-terminal 291 amino acids of beta-filamin except for 2
residues, making it very likely that FH1 represents the C-terminal
region of beta-filamin.

Krakow et al. (2004) found that FLNB is expressed in human growth plate
chondrocytes and in developing vertebral bodies in the mouse. The
authors concluded that FLNB plays a role in vertebral segmentation,
joint formation, and endochondral ossification.

Mutation in the X-linked gene filamin A (FLNA) 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, 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.

MOLECULAR GENETICS

Krakow et al. (2004) identified mutations in the FLNB gene in 4 human
skeletal disorders: spondylocarpotarsal syndrome (SCT; 272460), Larsen
syndrome (150250), type I atelosteogenesis (AOI; 108720), and type III
atelosteogenesis (AOIII; 108721).

Biesecker (2004) commented that from the standpoint of the clinical
geneticist, 4 distinct disorders result from mutation in the FLNB gene.
In contrast, a basic scientist might view them as a single disorder with
inconsequential phenotypic differences. The information concerning the
multiple disorders caused by mutations in the FLNB gene followed closely
on the heels of reports of mutations in the FLNA gene (300017) as the
cause of 5 distinct disorders. This was of interest because there are
overlapping phenotypic features in the disorders associated with FLNA
and FLNB. Biesecker (2004) pointed out that the 'FLNB story' used
information from the International Skeletal Dysplasia Registry (ISDR),
which is maintained by a skilled group of clinical scientists and
includes information on more than 12,000 cases of individuals with
disorders that fall into 50 diagnostic groups. One reason for the
success of the registry is that it combines clinical service with
research archives. The motivation for a clinician to submit cases to the
registry is that he or she can receive an expert opinion on the
diagnosis (which is useful for medical care and estimating recurrence
risks) and, as in the FLNB story, contribute to research.

In a 22-week male fetus previously studied by Krakow et al. (2004) and a
17-week male fetus previously described by Wessels et al. (2003), both
diagnosed with boomerang dysplasia (112310), Bicknell et al. (2005)
identified heterozygosity for mutations in the FLNB gene, leu171 to arg
(L171R; 603381.0009) and ser235 to pro (S235P; 603381.0010),
respectively.

Farrington-Rock et al. (2006) found 14 novel missense mutations in FLNB
in 15 unrelated patients with atelosteogenesis I and/or atelosteogenesis
III. Most of the mutations resided in exons 2 and 3, which encode the
CH2 domain of the actin-binding region of filamin B. The remaining
mutations were found in exon 28 and exon 29, which encode repeats 14 and
15 of filamin B. Clinical and radiographic data were used to confirm the
diagnosis of atelosteogenesis in all the patients. The diagnosis of type
I was given to patients showing classic findings of absent, shortened,
or distally tapered humeri and femora; absent, shortened, or bowed
radii; shortened and bowed ulnae and tibiae; and absent fibulae. Other
findings included vertebral hypoplasia with coronal clefts, 11 ribs,
shortened wide distal phalanges, and unossified or partially ossified
metacarpals and middle and proximal phalanges. In addition, most type I
patients showed evidence of a hypoplastic pelvis, dislocations of the
hips, elbows, and knees, and clubbed feet. With the exception of 1
patient where the pregnancy was terminated after 24 weeks' gestation,
the patients given the diagnosis of type I either died in the neonatal
period or were stillborn. The diagnosis of type III was given to
patients when all bones were present in the extremities, when there was
distal tapering of the humeri or femora, and where the small tubular
bones of the hands and feet were shortened and broad. In 2 patients with
type III, the fibulae were absent. Dislocation of the elbows, hips, and
knees and clubbed feet were also present in the type III patients, as
was vertebral hypoplasia with coronal clefting. Cartilage of these
patients showed acellular areas within the growth plate and the presence
of large multinuclear cells ('giant cells') within the resting zone as
had been described previously.

Bicknell et al. (2007) identified heterozygous mutations in the FLNB
gene (see, e.g., 603381.0011; 603381.0012) in 20 unrelated patients with
Larsen syndrome. The distribution of mutations within the gene was
nonrandom, with clusters of mutations in the actin-binding domains and
filamin repeats 13 through 17 being the most common.

ANIMAL MODEL

Zhou et al. (2007) detected strong expression of the mouse Flnb gene in
vascular endothelial cells and chondrocytes. In Flnb -/- mice, the
authors observed a phenotype that resembled those of human skeletal
disorders with mutations in the FLNB gene. Less than than 3% of Flnb -/-
embryos reached term, indicating that the Flnb gene is important in
embryonic development, whereas Flnb +/- mice were indistinguishable from
their wildtype sibs. Flnb -/- embryos had impaired development of
microvasculature and skeletal systems. The few that were born were very
small and had scoliotic and kyphotic spines, lack of intervertebral
discs, fusion of vertebral bodies, and reduced hyaline matrix in bones
of the extremities, thorax, and vertebrae.

Farrington-Rock et al. (2008) generated Fnlb -/- mice and observed a
phenotype of short stature and skeletal abnormalities similar to those
of individuals with spondylocarpotarsal synostosis syndrome (SCT;
272460). Newborn Flnb -/- mice had fusions between the neural arches of
the vertebrae in the cervical and thoracic spine. At postnatal day 60,
the vertebral fusions were more widespread and involved the vertebral
bodies as well as the neural arches. In addition, fusions were seen in
sternum and carpal bones. Analysis of the Flnb -/- mice phenotype showed
that an absence of filamin B causes progressive vertebral fusions, in
contrast to the previous hypothesis that SCT results from failure of
normal spinal segmentation. Farrington-Rock et al. (2008) suggested that
spinal segmentation can occur normally in the absence of filamin B, but
that the protein is required for maintenance of intervertebral, carpal,
and sternal joints, and the joint fusion process commences antenatally.

*FIELD* AV
.0001
SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME
FLNB, SER2137TER

In a consanguineous family with spondylocarpotarsal syndrome (SCT;
272460), Krakow et al. (2004) found that affected individuals were
homozygous for a 6408delC mutation in exon 39 of the FLNB gene that
predicted a translational frameshift and a stop codon 4 codons
downstream.

.0002
SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME
FLNB, ARG818TER

In a nonconsanguineous family with spondylocarpotarsal syndrome (SCT;
272460), Krakow et al. (2004) found that the affected individual was a
compound heterozygote for 2 mutations in the FLNB gene that predicted
premature stop codons: arg818 to ter (R818X) and arg1607 to ter (R1607X;
603381.0003). The former mutation was a 2452C-T transition in exon 16;
the latter, a 4819C-T transition in exon 28.

.0003
SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME
FLNB, ARG1607TER

See 603381.0002 and Krakow et al. (2004).

.0004
LARSEN SYNDROME
FLNB, PHE161CYS

In a family with Larsen syndrome (150250), Krakow et al. (2004) found
heterozygosity for a de novo missense mutation in the FLNB gene, 482T-G
in exon 2, that predicted the substitution phe161-to-cys (F161C) in the
second calponin homology domain (CHD2) of filamin B.

.0005
LARSEN SYNDROME
FLNB, GLY1586ARG

In an individual with sporadically occurring Larsen syndrome (150250),
Krakow et al. (2004) found heterozygosity for a de novo mutation in the
FLNB gene, 4756G-A in exon 29, that predicted the substitution
gly1586-to-arg (G1586R) in repeat 14 of the protein.

.0006
ATELOSTEOGENESIS, TYPE I
FLNB, ALA173VAL

In an individual with atelosteogenesis type I (AOI; 108720), Krakow et
al. (2004) found heterozygosity for a point mutation, 518C-T, in exon 2
of the FNLB gene predicting an ala173-to-val (A173V) substitution in the
second calponin homology domain (CHD2) of filamin B.

.0007
ATELOSTEOGENESIS, TYPE I
ATELOSTEOGENESIS, TYPE III, INCLUDED
FLNB, MET202VAL

In 1 individual with AOI (108720) and in 1 with AOIII (108721), Krakow
et al. (2004) found heterozygosity for the same point mutation in exon 3
of the FLNB gene, 604A-G, predicting a met202-to-val (M202V)
substitution in the second calponin homology domain (CHD2) of filamin B.

.0008
ATELOSTEOGENESIS, TYPE III
FLNB, GLY751ARG

In an individual with AOIII (108721), Krakow et al. (2004) found
heterozygosity for a point mutation in exon 15 of the FLNB gene,
2251G-C, predicting a gly751-to-arg (G751R) substitution in repeat 6 of
filamin B.

.0009
BOOMERANG DYSPLASIA
FLNBA, LEU171ARG

In a 22-week male fetus with boomerang dysplasia (112310), previously
studied by Krakow et al. (2004), Bicknell et al. (2005) identified
heterozygosity for a 512T-G transversion in the FLNB gene, predicted to
cause a leu171-to-arg (L171R) substitution in the second calponin
homology domain of filamin B. The authors noted that this residue is
highly evolutionarily conserved among vertebrate filamins. The mutation
was not found in the unaffected parents.

.0010
BOOMERANG DYSPLASIA
FLNB, SER235PRO

In a 17-week male fetus with boomerang dysplasia (112310), previously
described by Wessels et al. (2003), Bicknell et al. (2005) identified
heterozygosity for a 703T-C transition in exon 4 of the FLNB gene,
predicted to cause a ser235-to-pro (S235P) substitution in the second
calponin homology domain of filamin B. The authors noted that this
residue is highly evolutionarily conserved among vertebrate filamins.
The mutation was not found in 100 control chromosomes.

.0011
LARSEN SYNDROME
FLNB, GLU227LYS

In 13 affected individuals from a large family with Larsen syndrome
(150250), Bicknell et al. (2007) identified a heterozygous 679G-A
transition in the FLNB gene, resulting in a glu227-to-lys (E227K)
substitution. Clinical signs and symptoms of the disorder were variable
in this family, although all had the characteristic facies and most had
spatulate fingers and supernumerary carpal bones.

.0012
LARSEN SYNDROME
FLNB, GLY1691SER

In 6 of 20 unrelated patients with Larsen syndrome (150250), Bicknell et
al. (2007) identified a heterozygous 5071G-A transition in the FLNB
gene, resulting in a gly1691-to-ser (G1691S) substitution.

.0013
SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME
FLNB, ARG2004TER

In a 5-year-old boy with spondylocarpotarsal synostosis syndrome (SCT;
272460), Mitter et al. (2008) detected a homozygous 6010C-T transition
in exon 36 of the FLNB gene, resulting in an arg2004-to-ter (R2004X)
substitution. In addition to the typical findings of SCT, the boy
demonstrated ossification delay of multiple epiphyses and bilateral
proximal femoral epiphyseal dysplasia.

.0014
SPONDYLOCARPOTARSAL SYNOSTOSIS SYNDROME
FLNB, GLY1850TER

In an Italian girl with spondylocarpotarsal synostosis syndrome
(272460), born of consanguineous parents, Brunetti-Pierri et al. (2008)
identified a homozygous 5548G-T transversion in the FLNB gene, resulting
in a gly1850-to-ter (G1850X) substitution. She had short stature,
scoliosis, short trunk, delayed bone age, vertebral fusions, and
capitate-hamate fusion. She did not have facial dysmorphic features.
Growth hormone (GH) deficiency was documented, but there was no response
to GH administration. MRI scan did not show any abnormality of the
hypothalamo-pituitary area, but there was platybasia and basilar
impression, stenosis of the foramen magnum, but no signs of medullary
compression at the cervicomedullary junction. A younger brother, who was
heterozygous for the mutation, had short stature and transient GH
deficiency.

*FIELD* RF
1. Bicknell, L. S.; Farrington-Rock, C.; Shafeghati, Y.; Rump, P.;
Alanay, Y.; Alembik, Y.; Al-Madani, N.; Firth, H.; Karimi-Nejad, M.
H.; Kim, C. A.; Leask, K.; Maisenbacher, M.; and 14 others: A molecular
and clinical study of Larsen syndrome caused by mutations in FLNB. J.
Med. Genet. 44: 89-98, 2007.

2. Bicknell, L. S.; Morgan, T.; Bonafe, L.; Wessels, M. W.; Bialer,
M. G.; Willems, P. J.; Cohn, D. H.; Krakow, D.; Robertson, S. P.:
Mutations in FLNB cause boomerang dysplasia. J. Med. Genet. 42:
e43, 2005. Note: Electronic Article.

3. Biesecker, L. G.: Phenotype matters. Nature Genet. 36: 323-324,
2004.

4. Brocker, F.; Bardenheuer, W.; Vieten, L.; Julicher, K.; Werner,
N.; Marquitan, G.; Michael, D.; Opalka, B.; Schutte, J.: Assignment
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5. Brunetti-Pierri, N.; Esposito, B.; De Brasi, D.; Mattiacci, D.
M.; Krakow, D.; Lee, B.; Salerno, M.: Spondylocarpotarsal synostosis:
long-term follow-up of a case due to FLNB mutations. Am. J. Med.
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*FIELD* CN
Marla J. F. O'Neill - updated: 08/22/2011
Marla J. F. O'Neill - updated: 5/24/2010
Cassandra L. Kniffin - updated: 8/21/2008
Kelly A. Przylepa - updated: 4/11/2008
Cassandra L. Kniffin - updated: 3/23/2007
Cassandra L. Kniffin - updated: 2/26/2007
Victor A. McKusick - updated: 9/29/2006
Marla J. F. O'Neill - updated: 9/19/2005
Victor A. McKusick - updated: 4/5/2004
George E. Tiller - updated: 3/30/2004
Marla J. F. O'Neill - updated: 3/16/2004
Victor A. McKusick - updated: 12/18/2000
Carol A. Bocchini - updated: 10/1/1999

*FIELD* CD
Rebekah S. Rasooly: 12/23/1998

*FIELD* ED
carol: 08/22/2011
terry: 12/8/2010
carol: 10/4/2010
alopez: 5/24/2010
wwang: 10/16/2009
terry: 10/15/2009
wwang: 8/28/2008
ckniffin: 8/21/2008
carol: 4/11/2008
wwang: 4/11/2007
ckniffin: 3/23/2007
wwang: 3/2/2007
ckniffin: 2/26/2007
alopez: 10/13/2006
terry: 9/29/2006
wwang: 10/5/2005
terry: 9/19/2005
carol: 1/26/2005
alopez: 4/7/2004
terry: 4/5/2004
alopez: 4/2/2004
tkritzer: 3/31/2004
tkritzer: 3/30/2004
alopez: 3/23/2004
alopez: 3/22/2004
terry: 3/16/2004
mcapotos: 1/18/2001
terry: 12/18/2000
alopez: 9/5/2000
carol: 10/1/1999
alopez: 12/23/1998