RBCC Red Blood Cell Collection

TGFBR1 (ALK5, SKR4) [Confidence: low (only semi-automatic identification from reviews)]
TGF-beta receptor type-1; TGFR-1; 2.7.11.30 (Activin A receptor type II-like protein kinase of 53kD; Activin receptor-like kinase 5; ALK-5; ALK5; Serine/threonine-protein kinase receptor R4; SKR4; TGF-beta type I receptor; Transforming growth factor-beta receptor type I; TGF-beta receptor type I; TbetaR-I; Flags: Precursor)

UniProt P36897
ID TGFR1_HUMAN Reviewed; 503 AA.
AC P36897; Q6IR47; Q706C0; Q706C1;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-1994, sequence version 1.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=TGF-beta receptor type-1;
DE Short=TGFR-1;
DE EC=2.7.11.30;
DE AltName: Full=Activin A receptor type II-like protein kinase of 53kD;
DE AltName: Full=Activin receptor-like kinase 5;
DE Short=ALK-5;
DE Short=ALK5;
DE AltName: Full=Serine/threonine-protein kinase receptor R4;
DE Short=SKR4;
DE AltName: Full=TGF-beta type I receptor;
DE AltName: Full=Transforming growth factor-beta receptor type I;
DE Short=TGF-beta receptor type I;
DE Short=TbetaR-I;
DE Flags: Precursor;
GN Name=TGFBR1; Synonyms=ALK5, SKR4;
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).
RX PubMed=8242743; DOI=10.1016/0092-8674(93)90489-D;
RA Franzen P., ten Dijke P., Ichijo H., Yamashita H., Schulz P.,
RA Heldin C.-H., Miyazono K.;
RT "Cloning of a TGF beta type I receptor that forms a heteromeric
RT complex with the TGF beta type II receptor.";
RL Cell 75:681-692(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9417915; DOI=10.1006/geno.1997.5023;
RA Vellucci V.F., Reiss M.;
RT "Cloning and genomic organization of the human transforming growth
RT factor-beta type I receptor gene.";
RL Genomics 46:278-283(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Lynch M.A., Song H., DeGroff V.L., Alam K.Y., Adams E.M.,
RA Weghorst C.M.;
RT "The genomic structure of the gene encoding the human transforming
RT growth factor beta type I receptor.";
RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 34-40, SIGNAL SEQUENCE CLEAVAGE SITE,
RP GLYCOSYLATION, CHARACTERIZATION OF VARIANT TGFBR1*6A ALA-24--26-ALA
RP DEL, AND VARIANT TGFBR1*10A ALA-26 INS.
RX PubMed=9661882;
RA Pasche B., Luo Y., Rao P.H., Nimer S.D., Dmitrovsky E., Caron P.,
RA Luzzatto L., Offit K., Cordon-Cardo C., Renault B., Satagopan J.M.,
RA Murty V.V., Massague J.;
RT "Type I transforming growth factor beta receptor maps to 9q22 and
RT exhibits a polymorphism and a rare variant within a polyalanine
RT tract.";
RL Cancer Res. 58:2727-2732(1998).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [MRNA] OF
RP 61-155 (ISOFORM 1), AND ALTERNATIVE SPLICING.
RC TISSUE=Prostate;
RX PubMed=17845732; DOI=10.1186/1471-2164-8-318;
RA Konrad L., Scheiber J.A., Volck-Badouin E., Keilani M.M., Laible L.,
RA Brandt H., Schmidt A., Aumuller G., Hofmann R.;
RT "Alternative splicing of TGF-betas and their high-affinity receptors T
RT beta RI, T beta RII and T beta RIII (betaglycan) reveal new variants
RT in human prostatic cells.";
RL BMC Genomics 8:318-318(2007).
RN [9]
RP SEQUENCE REVISION (ISOFORM 1).
RA Konrad L.;
RL Submitted (MAR-2011) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP FUNCTION, PHOSPHORYLATION AT THR-185; THR-186; SER-187; SER-189 AND
RP SER-191 BY TGFBR2, SUBCELLULAR LOCATION, SUBUNIT, AND MUTAGENESIS OF
RP 185-THR-THR-186; SER-187; SER-189; SER-191; THR-200 AND THR-204.
RX PubMed=7774578;
RA Wieser R., Wrana J.L., Massague J.;
RT "GS domain mutations that constitutively activate T beta R-I, the
RT downstream signaling component in the TGF-beta receptor complex.";
RL EMBO J. 14:2199-2208(1995).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF SMAD2.
RX PubMed=8752209; DOI=10.1016/S0092-8674(00)80128-2;
RA Eppert K., Scherer S.W., Ozcelik H., Pirone R., Hoodless P., Kim H.,
RA Tsui L.-C., Bapat B., Gallinger S., Andrulis I.L., Thomsen G.H.,
RA Wrana J.L., Attisano L.;
RT "MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related
RT protein that is functionally mutated in colorectal carcinoma.";
RL Cell 86:543-552(1996).
RN [12]
RP INTERACTION WITH SMAD2, FUNCTION IN PHOSPHORYLATION OF SMAD2, AND
RP FUNCTION IN TRANSCRIPTION REGULATION.
RX PubMed=8980228; DOI=10.1016/S0092-8674(00)81817-6;
RA Macias-Silva M., Abdollah S., Hoodless P.A., Pirone R., Attisano L.,
RA Wrana J.L.;
RT "MADR2 is a substrate of the TGFbeta receptor and its phosphorylation
RT is required for nuclear accumulation and signaling.";
RL Cell 87:1215-1224(1996).
RN [13]
RP INTERACTION WITH FKBP1A, ENZYME REGULATION, AND MUTAGENESIS OF LEU-193
RP AND PRO-194.
RX PubMed=9233797; DOI=10.1093/emboj/16.13.3866;
RA Chen Y.G., Liu F., Massague J.;
RT "Mechanism of TGFbeta receptor inhibition by FKBP12.";
RL EMBO J. 16:3866-3876(1997).
RN [14]
RP INTERACTION WITH SMAD3.
RX PubMed=9311995; DOI=10.1093/emboj/16.17.5353;
RA Nakao A., Imamura T., Souchelnytskyi S., Kawabata M., Ishisaki A.,
RA Oeda E., Tamaki K., Hanai J., Heldin C.H., Miyazono K., ten Dijke P.;
RT "TGF-beta receptor-mediated signalling through Smad2, Smad3 and
RT Smad4.";
RL EMBO J. 16:5353-5362(1997).
RN [15]
RP INTERACTION WITH SMAD2, FUNCTION IN PHOSPHORYLATION OF SMAD2, AND
RP FUNCTION IN TRANSCRIPTION REGULATION.
RX PubMed=9346908; DOI=10.1074/jbc.272.44.27678;
RA Abdollah S., Macias-Silva M., Tsukazaki T., Hayashi H., Attisano L.,
RA Wrana J.L.;
RT "TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for
RT Smad2-Smad4 complex formation and signaling.";
RL J. Biol. Chem. 272:27678-27685(1997).
RN [16]
RP INTERACTION WITH ZFYVE9.
RX PubMed=9865696; DOI=10.1016/S0092-8674(00)81701-8;
RA Tsukazaki T., Chiang T.A., Davison A.F., Attisano L., Wrana J.L.;
RT "SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta
RT receptor.";
RL Cell 95:779-791(1998).
RN [17]
RP HOMODIMERIZATION, AND SUBCELLULAR LOCATION.
RX PubMed=9472030; DOI=10.1083/jcb.140.4.767;
RA Gilboa L., Wells R.G., Lodish H.F., Henis Y.I.;
RT "Oligomeric structure of type I and type II transforming growth factor
RT beta receptors: homodimers form in the ER and persist at the plasma
RT membrane.";
RL J. Cell Biol. 140:767-777(1998).
RN [18]
RP INTERACTION WITH SMAD7 AND SMURF2, AND PROTEASOMAL AND LYSOSOMAL
RP DEGRADATION.
RX PubMed=11163210; DOI=10.1016/S1097-2765(00)00134-9;
RA Kavsak P., Rasmussen R.K., Causing C.G., Bonni S., Zhu H.,
RA Thomsen G.H., Wrana J.L.;
RT "Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the
RT TGF-beta receptor for degradation.";
RL Mol. Cell 6:1365-1375(2000).
RN [19]
RP INTERACTION WITH SMAD7 AND SMURF1, AND PROTEASOMAL DEGRADATION.
RX PubMed=11278251; DOI=10.1074/jbc.C100008200;
RA Ebisawa T., Fukuchi M., Murakami G., Chiba T., Tanaka K., Imamura T.,
RA Miyazono K.;
RT "Smurf1 interacts with transforming growth factor-beta type I receptor
RT through Smad7 and induces receptor degradation.";
RL J. Biol. Chem. 276:12477-12480(2001).
RN [20]
RP INTERACTION WITH VPS39.
RX PubMed=12941698; DOI=10.1093/emboj/cdg428;
RA Felici A., Wurthner J.U., Parks W.T., Giam L.R., Reiss M.,
RA Karpova T.S., McNally J.G., Roberts A.B.;
RT "TLP, a novel modulator of TGF-beta signaling, has opposite effects on
RT Smad2- and Smad3-dependent signaling.";
RL EMBO J. 22:4465-4477(2003).
RN [21]
RP INTERACTION WITH NEDD4L, AND UBIQUITINATION.
RX PubMed=15496141; DOI=10.1042/BJ20040738;
RA Kuratomi G., Komuro A., Goto K., Shinozaki M., Miyazawa K.,
RA Miyazono K., Imamura T.;
RT "NEDD4-2 (neural precursor cell expressed, developmentally down-
RT regulated 4-2) negatively regulates TGF-beta (transforming growth
RT factor-beta) signalling by inducing ubiquitin-mediated degradation of
RT Smad2 and TGF-beta type I receptor.";
RL Biochem. J. 386:461-470(2005).
RN [22]
RP FUNCTION IN EPITHELIAL TO MESENCHYMAL TRANSITION, SUBCELLULAR
RP LOCATION, INTERACTION WITH PARD6A, AND FUNCTION IN PHOSPHORYLATION OF
RP PARD6A.
RX PubMed=15761148; DOI=10.1126/science.1105718;
RA Ozdamar B., Bose R., Barrios-Rodiles M., Wang H.R., Zhang Y.,
RA Wrana J.L.;
RT "Regulation of the polarity protein Par6 by TGFbeta receptors controls
RT epithelial cell plasticity.";
RL Science 307:1603-1609(2005).
RN [23]
RP FUNCTION IN CELLULAR GROWTH INHIBITION, AND INTERACTION WITH CD109.
RX PubMed=16754747; DOI=10.1096/fj.05-5229fje;
RA Finnson K.W., Tam B.Y.Y., Liu K., Marcoux A., Lepage P., Roy S.,
RA Bizet A.A., Philip A.;
RT "Identification of CD109 as part of the TGF-beta receptor system in
RT human keratinocytes.";
RL FASEB J. 20:1525-1527(2006).
RN [24]
RP INTERACTION WITH RBPMS.
RX PubMed=17099224; DOI=10.1093/nar/gkl914;
RA Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J.,
RA Song H., Ye Q.;
RT "Potentiation of Smad-mediated transcriptional activation by the RNA-
RT binding protein RBPMS.";
RL Nucleic Acids Res. 34:6314-6326(2006).
RN [25]
RP FUNCTION IN APOPTOSIS, AND INTERACTION WITH TRAF6 AND MAP3K7.
RX PubMed=18758450; DOI=10.1038/ncb1780;
RA Sorrentino A., Thakur N., Grimsby S., Marcusson A., von Bulow V.,
RA Schuster N., Zhang S., Heldin C.H., Landstrom M.;
RT "The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a
RT receptor kinase-independent manner.";
RL Nat. Cell Biol. 10:1199-1207(2008).
RN [26]
RP REVIEW ON PROCESSES REGULATED BY THE TGF-BETA CYTOKINES.
RX PubMed=9759503; DOI=10.1146/annurev.biochem.67.1.753;
RA Massague J.;
RT "TGF-beta signal transduction.";
RL Annu. Rev. Biochem. 67:753-791(1998).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-165, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [28]
RP UBIQUITINATION, AND DEUBIQUITINATION BY USP15.
RX PubMed=22344298; DOI=10.1038/nm.2619;
RA Eichhorn P.J., Rodon L., Gonzalez-Junca A., Dirac A., Gili M.,
RA Martinez-Saez E., Aura C., Barba I., Peg V., Prat A., Cuartas I.,
RA Jimenez J., Garcia-Dorado D., Sahuquillo J., Bernards R., Baselga J.,
RA Seoane J.;
RT "USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through
RT the activation of TGF-beta signaling in glioblastoma.";
RL Nat. Med. 18:429-435(2012).
RN [29]
RP 3D-STRUCTURE MODELING OF 34-114.
RX PubMed=8521960; DOI=10.1016/0014-5793(95)01239-7;
RA Jokiranta T.S., Tissari J., Teleman O., Meri S.;
RT "Extracellular domain of type I receptor for transforming growth
RT factor-beta: molecular modelling using protectin (CD59) as a
RT template.";
RL FEBS Lett. 376:31-36(1995).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 162-503 IN COMPLEX WITH
RP FKBP1A.
RX PubMed=10025408; DOI=10.1016/S0092-8674(00)80555-3;
RA Huse M., Chen Y.-G., Massague J., Kuriyan J.;
RT "Crystal structure of the cytoplasmic domain of the type I TGF beta
RT receptor in complex with FKBP12.";
RL Cell 96:425-436(1999).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 162-503, PHOSPHORYLATION, AND
RP INTERACTION WITH SMAD2 AND FKBP1A.
RX PubMed=11583628; DOI=10.1016/S1097-2765(01)00332-X;
RA Huse M., Muir T.W., Xu L., Chen Y.-G., Kuriyan J., Massague J.;
RT "The TGF beta receptor activation process: an inhibitor- to substrate-
RT binding switch.";
RL Mol. Cell 8:671-682(2001).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 175-500 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR.
RX PubMed=15177479; DOI=10.1016/j.bmcl.2004.04.007;
RA Sawyer J.S., Beight D.W., Britt K.S., Anderson B.D., Campbell R.M.,
RA Goodson T. Jr., Herron D.K., Li H.-Y., McMillen W.T., Mort N.,
RA Parsons S., Smith E.C.R., Wagner J.R., Yan L., Zhang F.,
RA Yingling J.M.;
RT "Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-
RT dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming
RT growth factor-beta type I receptor kinase domain.";
RL Bioorg. Med. Chem. Lett. 14:3581-3584(2004).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 201-503 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR.
RX PubMed=15317461; DOI=10.1021/jm0400247;
RA Gellibert F., Woolven J., Fouchet M.-H., Mathews N., Goodland H.,
RA Lovegrove V., Laroze A., Nguyen V.-L., Sautet S., Wang R., Janson C.,
RA Smith W., Krysa G., Boullay V., De Gouville A.-C., Huet S.,
RA Hartley D.;
RT "Identification of 1,5-naphthyridine derivatives as a novel series of
RT potent and selective TGF-beta type I receptor inhibitors.";
RL J. Med. Chem. 47:4494-4506(2004).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 33-111 IN COMPLEX WITH
RP TGFBR2 AND TGFB3, AND DISULFIDE BONDS.
RX PubMed=18243111; DOI=10.1016/j.molcel.2007.11.039;
RA Groppe J., Hinck C.S., Samavarchi-Tehrani P., Zubieta C.,
RA Schuermann J.P., Taylor A.B., Schwarz P.M., Wrana J.L., Hinck A.P.;
RT "Cooperative assembly of TGF-beta superfamily signaling complexes is
RT mediated by two disparate mechanisms and distinct modes of receptor
RT binding.";
RL Mol. Cell 29:157-168(2008).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 31-115 IN COMPLEX WITH
RP TGFBR2 AND TGFB1, RECEPTOR AFFINITY FOR LIGANDS, AND DISULFIDE BONDS.
RX PubMed=20207738; DOI=10.1074/jbc.M109.079921;
RA Radaev S., Zou Z., Huang T., Lafer E.M., Hinck A.P., Sun P.D.;
RT "Ternary complex of transforming growth factor-beta1 reveals isoform-
RT specific ligand recognition and receptor recruitment in the
RT superfamily.";
RL J. Biol. Chem. 285:14806-14814(2010).
RN [36]
RP ANALYSIS OF VARIANT TGFBR1*6A ALA-24--26-ALA DEL IN CANCER RISK.
RX PubMed=12947057; DOI=10.1200/JCO.2003.11.524;
RA Kaklamani V.G., Hou N., Bian Y., Reich J., Offit K., Michel L.S.,
RA Rubinstein W.S., Rademaker A., Pasche B.;
RT "TGFBR1*6A and cancer risk: a meta-analysis of seven case-control
RT studies.";
RL J. Clin. Oncol. 21:3236-3243(2003).
RN [37]
RP ANALYSIS OF VARIANT TGFBR1*6A ALA-24--26-ALA DEL IN PROSTATE CANCER.
RX PubMed=15385056; DOI=10.1186/1471-2156-5-28;
RA Kaklamani V.G., Baddi L., Rosman D., Liu J., Ellis N., Oddoux C.,
RA Ostrer H., Chen Y., Ahsan H., Offit K., Pasche B.;
RT "No major association between TGFBR1*6A and prostate cancer.";
RL BMC Genet. 5:28-28(2004).
RN [38]
RP VARIANTS LDS1A ILE-200; ARG-318; GLY-400 AND PRO-487.
RX PubMed=15731757; DOI=10.1038/ng1511;
RA Loeys B.L., Chen J., Neptune E.R., Judge D.P., Podowski M., Holm T.,
RA Meyers J., Leitch C.C., Katsanis N., Sharifi N., Xu F.L., Myers L.A.,
RA Spevak P.J., Cameron D.E., De Backer J.F., Hellemans J., Chen Y.,
RA Davis E.C., Webb C.L., Kress W., Coucke P.J., Rifkin D.B.,
RA De Paepe A.M., Dietz H.C.;
RT "A syndrome of altered cardiovascular, craniofacial, neurocognitive
RT and skeletal development caused by mutations in TGFBR1 or TGFBR2.";
RL Nat. Genet. 37:275-281(2005).
RN [39]
RP ANALYSIS OF VARIANT TGFBR1*6A ALA-24--26-ALA DEL IN PROSTATE CANCER.
RX PubMed=15505640; DOI=10.1038/sj.pcan.4500765;
RA Suarez B.K., Pal P., Jin C.H., Kaushal R., Sun G., Jin L., Pasche B.,
RA Deka R., Catalona W.J.;
RT "TGFBR1(*)6A is not associated with prostate cancer in men of European
RT ancestry.";
RL Prostate Cancer Prostatic Dis. 8:50-53(2005).
RN [40]
RP VARIANT LDS1A LEU-241.
RX PubMed=16596670; DOI=10.1002/ajmg.a.31202;
RA Ades L.C., Sullivan K., Biggin A., Haan E.A., Brett M., Holman K.J.,
RA Dixon J., Robertson S., Holmes A.D., Rogers J., Bennetts B.;
RT "FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation
RT disorders revisited.";
RL Am. J. Med. Genet. A 140:1047-1058(2006).
RN [41]
RP VARIANT LDS1A LEU-241, VARIANT LDS2A GLN-487, AND VARIANT HIS-267.
RX PubMed=16791849; DOI=10.1002/humu.20353;
RA Matyas G., Arnold E., Carrel T., Baumgartner D., Boileau C.,
RA Berger W., Steinmann B.;
RT "Identification and in silico analyses of novel TGFBR1 and TGFBR2
RT mutations in Marfan syndrome-related disorders.";
RL Hum. Mutat. 27:760-769(2006).
RN [42]
RP VARIANTS LDS2A GLU-232; TRP-487; PRO-487 AND GLN-487.
RX PubMed=16928994; DOI=10.1056/NEJMoa055695;
RA Loeys B.L., Schwarze U., Holm T., Callewaert B.L., Thomas G.H.,
RA Pannu H., De Backer J.F., Oswald G.L., Symoens S., Manouvrier S.,
RA Roberts A.E., Faravelli F., Greco M.A., Pyeritz R.E., Milewicz D.M.,
RA Coucke P.J., Cameron D.E., Braverman A.C., Byers P.H., De Paepe A.M.,
RA Dietz H.C.;
RT "Aneurysm syndromes caused by mutations in the TGF-beta receptor.";
RL N. Engl. J. Med. 355:788-798(2006).
RN [43]
RP VARIANTS [LARGE SCALE ANALYSIS] ILE-153 AND CYS-291.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [44]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-139.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J.,
RA Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C.,
RA Graubert T.A., DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
RN [45]
RP VARIANT LDS1A GLY-351.
RX PubMed=19883511; DOI=10.1186/1750-1172-4-24;
RA Drera B., Ritelli M., Zoppi N., Wischmeijer A., Gnoli M., Fattori R.,
RA Calzavara-Pinton P.G., Barlati S., Colombi M.;
RT "Loeys-Dietz syndrome type I and type II: clinical findings and novel
RT mutations in two Italian patients.";
RL Orphanet J. Rare Dis. 4:24-24(2009).
RN [46]
RP VARIANTS LDS1A TYR-266; ILE-375 AND GLN-487.
RX PubMed=22113417; DOI=10.1038/jhg.2011.130;
RA Yang J.H., Ki C.S., Han H., Song B.G., Jang S.Y., Chung T.Y., Sung K.,
RA Lee H.J., Kim D.K.;
RT "Clinical features and genetic analysis of Korean patients with Loeys-
RT Dietz syndrome.";
RL J. Hum. Genet. 57:52-56(2012).
RN [47]
RP VARIANTS MSSE TYR-41; SER-45; ARG-52 AND LEU-83.
RX PubMed=21358634; DOI=10.1038/ng.780;
RA Goudie D.R., D'Alessandro M., Merriman B., Lee H., Szeverenyi I.,
RA Avery S., O'Connor B.D., Nelson S.F., Coats S.E., Stewart A.,
RA Christie L., Pichert G., Friedel J., Hayes I., Burrows N.,
RA Whittaker S., Gerdes A.M., Broesby-Olsen S., Ferguson-Smith M.A.,
RA Verma C., Lunny D.P., Reversade B., Lane E.B.;
RT "Multiple self-healing squamous epithelioma is caused by a disease-
RT specific spectrum of mutations in TGFBR1.";
RL Nat. Genet. 43:365-369(2011).
CC -!- FUNCTION: Transmembrane serine/threonine kinase forming with the
CC TGF-beta type II serine/threonine kinase receptor, TGFBR2, the
CC non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2
CC and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the
CC cell surface to the cytoplasm and is thus regulating a plethora of
CC physiological and pathological processes including cell cycle
CC arrest in epithelial and hematopoietic cells, control of
CC mesenchymal cell proliferation and differentiation, wound healing,
CC extracellular matrix production, immunosuppression and
CC carcinogenesis. The formation of the receptor complex composed of
CC 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the
CC cytokine dimer results in the phosphorylation and the activation
CC of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1
CC phosphorylates SMAD2 which dissociates from the receptor and
CC interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently
CC translocated to the nucleus where it modulates the transcription
CC of the TGF-beta-regulated genes. This constitutes the canonical
CC SMAD-dependent TGF-beta signaling cascade. Also involved in non-
CC canonical, SMAD-independent TGF-beta signaling pathways. For
CC instance, TGFBR1 induces TRAF6 autoubiquitination which in turn
CC results in MAP3K7 ubiquitination and activation to trigger
CC apoptosis. Also regulates epithelial to mesenchymal transition
CC through a SMAD-independent signaling pathway through PARD6A
CC phosphorylation and activation.
CC -!- CATALYTIC ACTIVITY: ATP + [receptor-protein] = ADP + [receptor-
CC protein] phosphate.
CC -!- COFACTOR: Magnesium or manganese (By similarity).
CC -!- ENZYME REGULATION: Kept in an inactive conformation by FKBP1A
CC preventing receptor activation in absence of ligand. CD109 is
CC another inhibitor of the receptor.
CC -!- SUBUNIT: Homodimer; in the endoplasmic reticulum but also at the
CC cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric
CC ligands assemble a functional receptor composed of two TGFBR1 and
CC TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The
CC respective affinity of TGBRB1 and TGFBR2 for the ligands may
CC modulate the kinetics of assembly of the receptor and may explain
CC the different biological activities of TGFB1, TGFB2 and TGFB3.
CC Interacts with CD109; inhibits TGF-beta receptor activation in
CC keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated)
CC with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and
CC stabilizes it in the inactive conformation. Interacts with SMAD2,
CC SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta
CC receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7
CC activation by TRAF6. Interacts with PARD6A; involved in TGF-beta
CC induced epithelial to mesenchymal transition. Interacts with
CC SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1
CC and SMURF2 to the TGF-beta receptor. Interacts with USP15 and
CC VPS39.
CC -!- INTERACTION:
CC P01137:TGFB1; NbExp=2; IntAct=EBI-1027557, EBI-779636;
CC P63104:YWHAZ; NbExp=4; IntAct=EBI-1027557, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Cell junction, tight junction.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P36897-1; Sequence=Displayed;
CC Name=2; Synonyms=B;
CC IsoId=P36897-2; Sequence=VSP_041326;
CC Name=3;
CC IsoId=P36897-3; Sequence=VSP_041327;
CC -!- TISSUE SPECIFICITY: Found in all tissues examined, most abundant
CC in placenta and least abundant in brain and heart.
CC -!- PTM: Phosphorylated at basal levels in the absence of ligand.
CC Activated upon phosphorylation by TGFBR2, mainly in the GS domain.
CC Phosphorylation in the GS domain abrogates FKBP1A-binding.
CC -!- PTM: N-Glycosylated.
CC -!- PTM: Ubiquitinated; undergoes ubiquitination catalyzed by several
CC E3 ubiquitin ligases including SMURF1, SMURF2 and NEDD4L2. Results
CC in the proteasomal and/or lysosomal degradation of the receptor
CC thereby negatively regulating its activity. Deubiquitinated by
CC USP15, leading to stabilization of the protein and enhanced TGF-
CC beta signal.
CC -!- DISEASE: Loeys-Dietz syndrome 1A (LDS1A) [MIM:609192]: An aortic
CC aneurysm syndrome with widespread systemic involvement. The
CC disorder is characterized by arterial tortuosity and aneurysms,
CC craniosynostosis, hypertelorism, and bifid uvula or cleft palate.
CC Other findings include exotropy, micrognathia and retrognathia,
CC structural brain abnormalities, intellectual deficit, congenital
CC heart disease, translucent skin, joint hyperlaxity and aneurysm
CC with dissection throughout the arterial tree. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Loeys-Dietz syndrome 2A (LDS2A) [MIM:608967]: An aortic
CC aneurysm syndrome with widespread systemic involvement. Physical
CC findings include diffuse arterial aneurysms and dissections,
CC prominent joint laxity, easy bruising, wide and atrophic scars,
CC velvety and translucent skin with easily visible veins,
CC spontaneous rupture of the spleen or bowel, and catastrophic
CC complications of pregnancy, including rupture of the gravid uterus
CC and the arteries, either during pregnancy or in the immediate
CC postpartum period. Loeys-Dietz syndrome type 2 is characterized by
CC the absence of craniofacial abnormalities with the exception of
CC bifid uvula that can be present in some patients. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry. TGFBR1 mutation Gln-487 has been reported to be associated
CC with thoracic aortic aneurysms and dissection (TAAD)
CC (PubMed:16791849). This phenotype, also known as thoracic aortic
CC aneurysms type 5 (AAT5), is distinguised from LDS2A by having
CC aneurysms restricted to thoracic aorta. It is unclear, however, if
CC this condition is fulfilled in individuals bearing Gln-487
CC mutation, that is why they are considered as LDS2A by the OMIM
CC resource.
CC -!- DISEASE: Multiple self-healing squamous epithelioma (MSSE)
CC [MIM:132800]: A disorder characterized by multiple skin tumors
CC that undergo spontaneous regression. Tumors appear most often on
CC sun-exposed regions, are locally invasive, and undergo spontaneous
CC resolution over a period of months leaving pitted scars. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. TGFB receptor subfamily.
CC -!- SIMILARITY: Contains 1 GS domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TGFBR1";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/tgfbr1/";
CC -----------------------------------------------------------------------
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DR EMBL; L11695; AAA16073.1; -; mRNA.
DR EMBL; AF054598; AAC08998.1; -; Genomic_DNA.
DR EMBL; AF054590; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF054591; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF054592; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF054593; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF054594; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF054595; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF054596; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF054597; AAC08998.1; JOINED; Genomic_DNA.
DR EMBL; AF035670; AAD02042.1; -; Genomic_DNA.
DR EMBL; AF035662; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AF035663; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AF035664; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AF035665; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AF035666; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AF035667; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AF035668; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AF035669; AAD02042.1; JOINED; Genomic_DNA.
DR EMBL; AY497473; AAR32097.1; -; Genomic_DNA.
DR EMBL; AL162427; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC071181; AAH71181.1; -; mRNA.
DR EMBL; AJ619019; CAF02096.2; -; mRNA.
DR EMBL; AJ619020; CAF02097.1; -; mRNA.
DR PIR; A49432; A49432.
DR RefSeq; NP_001124388.1; NM_001130916.1.
DR RefSeq; NP_004603.1; NM_004612.2.
DR RefSeq; XP_005252207.1; XM_005252150.1.
DR UniGene; Hs.494622; -.
DR PDB; 1B6C; X-ray; 2.60 A; B/D/F/H=162-503.
DR PDB; 1IAS; X-ray; 2.90 A; A/B/C/D/E=162-503.
DR PDB; 1PY5; X-ray; 2.30 A; A=175-500.
DR PDB; 1RW8; X-ray; 2.40 A; A=200-500.
DR PDB; 1TBI; Model; -; A=34-114.
DR PDB; 1VJY; X-ray; 2.00 A; A=201-503.
DR PDB; 2L5S; NMR; -; A=31-115.
DR PDB; 2PJY; X-ray; 3.00 A; C=33-111.
DR PDB; 2WOT; X-ray; 1.85 A; A=200-503.
DR PDB; 2WOU; X-ray; 2.30 A; A=200-503.
DR PDB; 2X7O; X-ray; 3.70 A; A/B/C/D/E=162-503.
DR PDB; 3FAA; X-ray; 3.35 A; A/B/C/D/E=162-503.
DR PDB; 3GXL; X-ray; 1.80 A; A=201-503.
DR PDB; 3HMM; X-ray; 1.70 A; A=201-503.
DR PDB; 3KCF; X-ray; 2.80 A; A/B/C/D/E=162-503.
DR PDB; 3KFD; X-ray; 3.00 A; I/J/K/L=31-115.
DR PDB; 3TZM; X-ray; 1.70 A; A=200-503.
DR PDBsum; 1B6C; -.
DR PDBsum; 1IAS; -.
DR PDBsum; 1PY5; -.
DR PDBsum; 1RW8; -.
DR PDBsum; 1TBI; -.
DR PDBsum; 1VJY; -.
DR PDBsum; 2L5S; -.
DR PDBsum; 2PJY; -.
DR PDBsum; 2WOT; -.
DR PDBsum; 2WOU; -.
DR PDBsum; 2X7O; -.
DR PDBsum; 3FAA; -.
DR PDBsum; 3GXL; -.
DR PDBsum; 3HMM; -.
DR PDBsum; 3KCF; -.
DR PDBsum; 3KFD; -.
DR PDBsum; 3TZM; -.
DR ProteinModelPortal; P36897; -.
DR SMR; P36897; 31-115, 175-500.
DR DIP; DIP-5935N; -.
DR IntAct; P36897; 9.
DR MINT; MINT-152959; -.
DR STRING; 9606.ENSP00000364133; -.
DR BindingDB; P36897; -.
DR ChEMBL; CHEMBL4439; -.
DR GuidetoPHARMACOLOGY; 1788; -.
DR PhosphoSite; P36897; -.
DR DMDM; 547777; -.
DR PaxDb; P36897; -.
DR PRIDE; P36897; -.
DR DNASU; 7046; -.
DR Ensembl; ENST00000374990; ENSP00000364129; ENSG00000106799.
DR Ensembl; ENST00000374994; ENSP00000364133; ENSG00000106799.
DR Ensembl; ENST00000552516; ENSP00000447297; ENSG00000106799.
DR GeneID; 7046; -.
DR KEGG; hsa:7046; -.
DR UCSC; uc004azc.3; human.
DR CTD; 7046; -.
DR GeneCards; GC09P101867; -.
DR HGNC; HGNC:11772; TGFBR1.
DR HPA; CAB002441; -.
DR HPA; CAB031481; -.
DR MIM; 132800; phenotype.
DR MIM; 190181; gene.
DR MIM; 608967; phenotype.
DR MIM; 609192; phenotype.
DR neXtProt; NX_P36897; -.
DR Orphanet; 91387; Familial thoracic aortic aneurysm and aortic dissection.
DR Orphanet; 60030; Loeys-Dietz syndrome type 1.
DR Orphanet; 65748; Multiple keratoacanthoma, Ferguson-Smith type.
DR PharmGKB; PA36485; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000230587; -.
DR HOVERGEN; HBG054502; -.
DR InParanoid; P36897; -.
DR KO; K04674; -.
DR OMA; LYICHNR; -.
DR PhylomeDB; P36897; -.
DR BRENDA; 2.7.10.2; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR SignaLink; P36897; -.
DR ChiTaRS; TGFBR1; human.
DR EvolutionaryTrace; P36897; -.
DR GeneWiki; TGF_beta_receptor_1; -.
DR GenomeRNAi; 7046; -.
DR NextBio; 27533; -.
DR PRO; PR:P36897; -.
DR ArrayExpress; P36897; -.
DR Bgee; P36897; -.
DR CleanEx; HS_TGFBR1; -.
DR Genevestigator; P36897; -.
DR GO; GO:0005923; C:tight junction; IDA:UniProtKB.
DR GO; GO:0070022; C:transforming growth factor beta receptor homodimeric complex; IC:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IDA:HGNC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046332; F:SMAD binding; IDA:BHF-UCL.
DR GO; GO:0050431; F:transforming growth factor beta binding; IDA:BHF-UCL.
DR GO; GO:0005025; F:transforming growth factor beta receptor activity, type I; IDA:BHF-UCL.
DR GO; GO:0005114; F:type II transforming growth factor beta receptor binding; IDA:BHF-UCL.
DR GO; GO:0000186; P:activation of MAPKK activity; IDA:BHF-UCL.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0009952; P:anterior/posterior pattern specification; ISS:BHF-UCL.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0048844; P:artery morphogenesis; ISS:BHF-UCL.
DR GO; GO:0001824; P:blastocyst development; IEA:Ensembl.
DR GO; GO:0007050; P:cell cycle arrest; TAS:UniProtKB.
DR GO; GO:0030199; P:collagen fibril organization; ISS:BHF-UCL.
DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; ISS:BHF-UCL.
DR GO; GO:0043542; P:endothelial cell migration; IEA:Ensembl.
DR GO; GO:0001837; P:epithelial to mesenchymal transition; IDA:UniProtKB.
DR GO; GO:0008354; P:germ cell migration; ISS:BHF-UCL.
DR GO; GO:0007507; P:heart development; ISS:BHF-UCL.
DR GO; GO:0001701; P:in utero embryonic development; ISS:BHF-UCL.
DR GO; GO:0001822; P:kidney development; ISS:BHF-UCL.
DR GO; GO:0002088; P:lens development in camera-type eye; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0032331; P:negative regulation of chondrocyte differentiation; ISS:BHF-UCL.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IMP:BHF-UCL.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048663; P:neuron fate commitment; ISS:BHF-UCL.
DR GO; GO:0060021; P:palate development; ISS:BHF-UCL.
DR GO; GO:0060017; P:parathyroid gland development; ISS:BHF-UCL.
DR GO; GO:0060389; P:pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0060037; P:pharyngeal system development; ISS:BHF-UCL.
DR GO; GO:2001235; P:positive regulation of apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; IDA:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IMP:HGNC.
DR GO; GO:0051272; P:positive regulation of cellular component movement; IMP:BHF-UCL.
DR GO; GO:0051491; P:positive regulation of filopodium assembly; IEA:Ensembl.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IDA:BHF-UCL.
DR GO; GO:0060391; P:positive regulation of SMAD protein import into nucleus; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:BHF-UCL.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0043393; P:regulation of protein binding; IEA:Ensembl.
DR GO; GO:0031396; P:regulation of protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0070723; P:response to cholesterol; IDA:BHF-UCL.
DR GO; GO:0048538; P:thymus development; ISS:BHF-UCL.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0042060; P:wound healing; TAS:UniProtKB.
DR InterPro; IPR000472; Activin_rcpt.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR003605; TGF_beta_rcpt_GS.
DR Pfam; PF01064; Activin_recp; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF08515; TGF_beta_GS; 1.
DR SMART; SM00467; GS; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51256; GS; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Aortic aneurysm; Apoptosis;
KW ATP-binding; Cell junction; Cell membrane; Complete proteome;
KW Craniosynostosis; Differentiation; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Growth regulation;
KW Isopeptide bond; Kinase; Magnesium; Manganese; Membrane;
KW Metal-binding; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Receptor; Reference proteome; Serine/threonine-protein kinase; Signal;
KW Tight junction; Transferase; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT SIGNAL 1 33
FT CHAIN 34 503 TGF-beta receptor type-1.
FT /FTId=PRO_0000024423.
FT TOPO_DOM 34 126 Extracellular (Potential).
FT TRANSMEM 127 147 Helical; (Potential).
FT TOPO_DOM 148 503 Cytoplasmic (Potential).
FT DOMAIN 175 204 GS.
FT DOMAIN 205 495 Protein kinase.
FT NP_BIND 211 219 ATP (By similarity).
FT MOTIF 193 194 FKBP1A-binding.
FT ACT_SITE 333 333 Proton acceptor (By similarity).
FT BINDING 232 232 ATP (By similarity).
FT MOD_RES 165 165 Phosphoserine.
FT MOD_RES 185 185 Phosphothreonine; by TGFBR2.
FT MOD_RES 186 186 Phosphothreonine; by TGFBR2.
FT MOD_RES 187 187 Phosphoserine; by TGFBR2.
FT MOD_RES 189 189 Phosphoserine; by TGFBR2.
FT MOD_RES 191 191 Phosphoserine; by TGFBR2.
FT CARBOHYD 45 45 N-linked (GlcNAc...) (Potential).
FT DISULFID 36 54
FT DISULFID 38 41
FT DISULFID 48 71
FT DISULFID 86 100
FT DISULFID 101 106
FT CROSSLNK 391 391 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in SUMO) (By
FT similarity).
FT VAR_SEQ 114 114 T -> TGPFS (in isoform 2).
FT /FTId=VSP_041326.
FT VAR_SEQ 115 191 Missing (in isoform 3).
FT /FTId=VSP_041327.
FT VARIANT 24 26 Missing (in allele TGFBR1*6A; could be a
FT tumor susceptibility allele).
FT /FTId=VAR_022342.
FT VARIANT 26 26 A -> AA (in allele TGFBR1*10A; rare
FT polymorphism).
FT /FTId=VAR_022343.
FT VARIANT 41 41 C -> Y (in MSSE; hypomorphic mutation).
FT /FTId=VAR_065826.
FT VARIANT 45 45 N -> S (in MSSE; hypomorphic mutation).
FT /FTId=VAR_065827.
FT VARIANT 52 52 G -> R (in MSSE; hypomorphic mutation).
FT /FTId=VAR_065828.
FT VARIANT 83 83 P -> L (in MSSE; hypomorphic mutation).
FT /FTId=VAR_065829.
FT VARIANT 139 139 I -> V.
FT /FTId=VAR_054160.
FT VARIANT 153 153 V -> I (in dbSNP:rs56014374).
FT /FTId=VAR_041412.
FT VARIANT 200 200 T -> I (in LDS1A).
FT /FTId=VAR_022344.
FT VARIANT 232 232 K -> E (in LDS2A).
FT /FTId=VAR_029481.
FT VARIANT 241 241 S -> L (in LDS1A).
FT /FTId=VAR_029482.
FT VARIANT 266 266 D -> Y (in LDS1A).
FT /FTId=VAR_066720.
FT VARIANT 267 267 N -> H (in a patient with Marfan
FT syndrome).
FT /FTId=VAR_029483.
FT VARIANT 291 291 Y -> C (in dbSNP:rs35974499).
FT /FTId=VAR_041413.
FT VARIANT 318 318 M -> R (in LDS1A).
FT /FTId=VAR_022345.
FT VARIANT 351 351 D -> G (in LDS1A).
FT /FTId=VAR_066721.
FT VARIANT 375 375 T -> I (in LDS1A).
FT /FTId=VAR_066722.
FT VARIANT 400 400 D -> G (in LDS1A).
FT /FTId=VAR_022346.
FT VARIANT 487 487 R -> P (in LDS1A and LDS2A).
FT /FTId=VAR_022347.
FT VARIANT 487 487 R -> Q (in LDS1A and LDS2A).
FT /FTId=VAR_029484.
FT VARIANT 487 487 R -> W (in LDS2A).
FT /FTId=VAR_029485.
FT MUTAGEN 185 186 TT->VV: Loss of phosphorylation on
FT threonine residues. Loss of threonine
FT phosphorylation, reduced phosphorylation
FT on serine residues and loss of response
FT to TGF-beta; when associated with A-187;
FT A-189 and A-191.
FT MUTAGEN 187 187 S->A: Loss of threonine phosphorylation,
FT reduced phosphorylation on serine
FT residues and loss of response to TGF-
FT beta; when associated with 185-VV-186; A-
FT 189 and A-191.
FT MUTAGEN 189 189 S->A: Loss of threonine phosphorylation,
FT reduced phosphorylation on serine
FT residues and loss of response to TGF-
FT beta; when associated with 185-VV-186; A-
FT 187 and A-191.
FT MUTAGEN 191 191 S->A: Loss of threonine phosphorylation,
FT reduced phosphorylation on serine
FT residues and loss of response to TGF-
FT beta; when associated with 185-VV-186; A-
FT 187 and A-189.
FT MUTAGEN 193 193 L->G: Loss of interaction with FKBP1A.
FT MUTAGEN 194 194 P->K: Loss of interaction with FKBP1A.
FT MUTAGEN 200 200 T->D: Loss of response to TGF-beta.
FT MUTAGEN 200 200 T->V: Loss of phosphorylation. Loss of
FT response to TGF-beta.
FT MUTAGEN 204 204 T->D: Constitutive activation.
FT MUTAGEN 204 204 T->V: Reduced phosphorylation. Reduced
FT response to TGF-beta.
FT STRAND 35 37
FT TURN 42 46
FT STRAND 51 57
FT STRAND 61 63
FT STRAND 69 72
FT TURN 74 76
FT STRAND 77 82
FT TURN 84 86
FT HELIX 89 92
FT STRAND 94 101
FT STRAND 102 105
FT HELIX 107 109
FT HELIX 177 183
FT STRAND 187 190
FT STRAND 191 193
FT HELIX 202 204
FT STRAND 205 213
FT STRAND 215 224
FT STRAND 227 234
FT HELIX 236 238
FT HELIX 239 249
FT STRAND 251 253
FT STRAND 262 269
FT STRAND 271 281
FT HELIX 288 294
FT HELIX 299 317
FT STRAND 322 324
FT STRAND 328 330
FT STRAND 338 341
FT STRAND 347 349
FT HELIX 352 354
FT STRAND 356 359
FT TURN 360 363
FT STRAND 364 366
FT HELIX 376 378
FT HELIX 381 384
FT HELIX 393 413
FT STRAND 417 419
FT TURN 427 431
FT HELIX 438 445
FT HELIX 456 459
FT HELIX 462 472
FT HELIX 479 481
FT HELIX 485 497
SQ SEQUENCE 503 AA; 55960 MW; 179F11404725DDCB CRC64;
MEAAVAAPRP RLLLLVLAAA AAAAAALLPG ATALQCFCHL CTKDNFTCVT DGLCFVSVTE
TTDKVIHNSM CIAEIDLIPR DRPFVCAPSS KTGSVTTTYC CNQDHCNKIE LPTTVKSSPG
LGPVELAAVI AGPVCFVCIS LMLMVYICHN RTVIHHRVPN EEDPSLDRPF ISEGTTLKDL
IYDMTTSGSG SGLPLLVQRT IARTIVLQES IGKGRFGEVW RGKWRGEEVA VKIFSSREER
SWFREAEIYQ TVMLRHENIL GFIAADNKDN GTWTQLWLVS DYHEHGSLFD YLNRYTVTVE
GMIKLALSTA SGLAHLHMEI VGTQGKPAIA HRDLKSKNIL VKKNGTCCIA DLGLAVRHDS
ATDTIDIAPN HRVGTKRYMA PEVLDDSINM KHFESFKRAD IYAMGLVFWE IARRCSIGGI
HEDYQLPYYD LVPSDPSVEE MRKVVCEQKL RPNIPNRWQS CEALRVMAKI MRECWYANGA
ARLTALRIKK TLSQLSQQEG IKM
//

MIM 132800
*RECORD*
*FIELD* NO
132800
*FIELD* TI
#132800 MULTIPLE SELF-HEALING SQUAMOUS EPITHELIOMA, SUSCEPTIBILITY TO; MSSE
;;FERGUSON-SMITH TYPE EPITHELIOMA;;
read moreESS1, FORMERLY
*FIELD* TX
A number sign (#) is used with this entry because susceptibility to
multiple self-healing squamous epithelioma (MSSE) is conferred by
heterozygous loss-of-function mutation in the TGFBR1 gene (190181).

DESCRIPTION

Individuals with multiple self-healing squamous epithelioma (MSSE)
develop multiple invasive skin tumors that undergo spontaneous
regression leaving pitted scars. Age at onset is highly variable,
ranging from 8 to 62 years. The disorder shows autosomal dominant
inheritance, and most affected families have originated from western
Scotland (Bose et al., 2006). MSSE has been considered to be a variety
of multiple keratoacanthoma (Epstein et al., 1957; Haydey et al., 1980).

CLINICAL FEATURES

Ferguson Smith (1934) first described this disorder in a single case,
that of a 23-year-old miner, who first developed spots on the legs at
age 16 years. The lesions healed spontaneously, but were replaced by
others at neighboring sites and later on the face and ears. A depressed
scar remained after healing. The lesions resembled squamous carcinoma
clinically and histologically. He continued to work except for a few
months when lesions on the knees prevented him from kneeling. Ferguson
Smith (1948) provided a follow-up of this patient. Treatment of large
lesions on his right leg with radium was 'followed by necrosis of the
tibia, and ultimately, at the patient's own request...amputation below
the knee.' He was wearing a prosthesis to cover an extensive destruction
of the nose. Ferguson-Smith (1974) reported that the patient died of
'suppurative meningitis' in December 1948. Autopsy findings were
reported by Currie and Ferguson Smith (1952). In addition to the face,
ears, arms and legs, the skin of the anus, scrotum and anterior
abdominal wall were affected. All tumors were well-differentiated
squamous epitheliomata with lymphatic infiltration of the anal and aural
lesions. The anal tumor infiltrated the sphincter and muscle coats of
the anal canal.

Sommerville and Milne (1950) reported 2 cases in each of 2 successive
generations. Affected father and son were referred to by Epstein et al.
(1957). Degos et al. (1964) described the condition in a woman and 2
daughters. Ereaux and Schopflocher (1965) observed affected brother and
sister.

Ferguson-Smith et al. (1971), the geneticist son of the dermatologist
who first described this condition, reviewed 62 cases in western
Scotland. The lesions were found more frequently on exposed areas of the
skin. Two girls had their first lesion during their thirteenth year; the
oldest onset in a male was at age 56 and in a female at age 55. The mean
age of onset in women was 25.5 and in men 26.9. Many examples of
male-to-male transmission, equal involvement of the sexes, and precise
agreement with the 50:50 segregation ratio proved autosomal dominant
inheritance. A single instance of 'skipped generation' was found: the
daughter of an affected male and mother of 2 affected daughters had
unblemished skin when fully examined at age 57.

MAPPING

In studies of 13 affected families, Goudie et al. (1991) demonstrated
linkage between the MSSE locus and several markers on chromosome 9q31
(maximum lod score of 8.05 at marker D9S29). Goudie et al. (1993) found
tight linkage of the locus, which they designated ESS1, to 9q31 (maximum
lod score of 9.02 at D9S53). Multipoint linkage analysis demonstrated
that the disease locus probably lies between D9S58 (9q22.3-q31) and
ASSP3, a pseudogene of argininosuccinate synthetase (ASS; 603470),
located at 9q11-q22. Comparison of markers associated with MESS in
independently ascertained families suggested a common origin of the
disease.

By direct sequencing and polymorphism analysis of affected individuals,
Richards et al. (1997) excluded the XPA (611153) gene as the site of the
mutation in MSSE. The Patched (PTCH; 601309) gene is mutated in Gorlin
syndrome (109400); MSSE families were shown to share a common haplotype
at 3 novel intragenic PTCH polymorphisms. Although no mutations were
detected in MSSE families, PTCH was not excluded as the MSSE gene.
Richards et al. (1997) concluded that the MSSE gene is on chromosome
9q22.3 between D9S197 and D9S287/D9S1809.

Blair et al. (1998) generated an integrated physical and genetic map of
9q22.1-q22.3. This region encompasses the MSSE critical interval, which
the authors estimated at 2 Mb.

Bose et al. (2006) refined the MSSE critical region to a less than 1-cM
interval between the ZNF169 (603404) and FANCC (227645) genes. The
authors noted that there were some discrepancies between the physical
assembly of the genome and the genetic map of this region. They found
the order of markers to be D9S196-ZNF169-D9S280-FANCC-D9S1816-D9S287.
Genetic mapping excluded the ZNF169, FANCC, PTCH, and TGFBR1 (190181)
genes as involved in MSSE; further molecular analysis excluded the
CDC14B (603505) gene. Molecular analysis of tissue from 5 of 12 tumors
showed loss of heterozygosity of the MSSE region, with loss of the
normal allele. The findings indicated that the MSSE gene is likely a
tumor suppressor gene.

MOLECULAR GENETICS

In affected members of 18 different families with MSSE, Goudie et al.
(2011) identified 11 different heterozygous mutations in the TGFBR1 gene
(see, e.g., 190181.0009-190181.0012). The first mutations were found
using high-throughput genomic sequencing and exon array capture of a
24.2-Mb region containing the MSSE locus; additional families were
studied by sequencing. One mutation, G52R (190181.0010), was found in 6
Scottish families, including those reported by Ferguson-Smith et al.
(1971). The mutations identified by Goudie et al. (2011) occurred in
either the extracellular ligand-binding domain or in the
serine/threonine kinase domain of the protein, and all were predicted or
demonstrated to result in loss of receptor function. Several mutation
carriers were unaffected, and tumor tissue from some patients showed
loss of heterozygosity for the wildtype allele. Overall, the findings
were consistent with wildtype TGFBR1 acting as a tumor suppressor, until
somatic deletion by a classic second hit results in carcinogenesis.

POPULATION GENETICS

Ferguson-Smith et al. (1971) assembled reliable information on 62 cases
in western Scotland, and suggested that all the Scottish cases derived
from a single mutation which occurred before 1790. The Scottish cases
were in 11 independently ascertained families but the genealogic
connections of some could be demonstrated.

NOMENCLATURE

The symbol for the self-healing squamous epithelioma locus on chromosome
9 was changed from ESS1 to MSSE when it was discovered that the symbol
ESS1 was already used for a cell division gene in Saccharomyces
cerevisiae (Richards et al., 1997).

*FIELD* RF
1. Blair, I. P.; Hulme, D.; Dawkins, J. L.; Nicholson, G. A.: A YAC-based
transcript map of human chromosome 9q22.1-q22.3 encompassing the loci
for hereditary sensory neuropathy type I and multiple self-healing
squamous epithelioma. Genomics 51: 277-281, 1998.

2. Bose, S.; Morgan, L. J.; Booth, D. R.; Goudie, D. R.; Ferguson-Smith,
M. A.; Richards, F. M.: The elusive multiple self-healing squamous
epithelioma (MSSE) gene: further mapping, analysis of candidates,
and loss of heterozygosity. Oncogene 25: 806-812, 2006.

3. Currie, A. R.; Ferguson Smith, J.: Multiple primary spontaneous-healing
squamous-cell carcinomata of the skin. J. Path. Bact. 64: 827-839,
1952.

4. Degos, R.; Civatte, J.; Touraine, B.; Guilaine, J.: Spontan-heilende
Epitheliome Ferguson-Smith und multiple familiaere Keratoacanthome. Hautarzt 15:
7-11, 1964.

5. Epstein, N. N.; Biskind, G. R.; Pollack, R. S.: Multiple primary
self-healing squamous-cell 'epitheliomas' of the skin: generalized
keratoacanthoma. Arch. Derm. 75: 210-223, 1957.

6. Ereaux, L. P.; Schopflocher, P.: Familial primary self-healing
squamous epithelioma of skin. Arch. Derm. 91: 589-594, 1965.

7. Ferguson-Smith, M. A.: Personal Communication. Glasgow, Scotland
1974.

8. Ferguson-Smith, M. A.; Wallace, D. C.; James, Z. H.; Renwick, J.
H.: Multiple self-healing squamous epithelioma. Birth Defects Orig.
Art. Ser. VII(8): 157-163, 1971.

9. Ferguson Smith, J.: Multiple primary, self-healing squamous epithelioma
of the skin. Brit. J. Derm. 60: 315-319, 1948.

10. Ferguson Smith, J.: A case of multiple primary squamous-celled
carcinomata of the skin in a young man, with spontaneous healing. Brit.
J. Derm. 46: 267-272, 1934.

11. Goudie, D. R.; D'Alessandro, M.; Merriman, B.; Lee, H.; Szeverenyi,
I.; Avery, S.; O'Connor, B. D.; Nelson, S. F.; Coats, S. E.; Stewart,
A.; Christie, L.; Pichert, G.; and 11 others: Multiple self-healing
squamous epithelioma is caused by a disease-specific spectrum of mutations
in TGFBR1. Nature Genet. 43: 365-369, 2011.

12. Goudie, D. R.; Yuille, M. A. R.; Affara, N. A.; Ferguson-Smith,
M. A.: Localisation of the gene for multiple self-healing squamous
epithelioma (Ferguson-Smith type) to the long arm of chromosome 9.
(Abstract) Cytogenet. Cell Genet. 58: 1939 only, 1991.

13. Goudie, D. R.; Yuille, M. A. R.; Leversha, M. A.; Furlong, R.
A.; Carter, N. P.; Lush, M. J.; Affara, N. A.; Ferguson-Smith, M.
A.: Multiple self-healing squamous epitheliomata (ESS1) mapped to
chromosome 9q22-q31 in families with common ancestry. Nature Genet. 3:
165-169, 1993.

14. Haydey, R. P.; Reed, M. L.; Dzubow, L. M.; Shupack, J. L.: Treatment
of keratoacanthomas with oral 13-cis-retinoic acid. New Eng. J. Med. 303:
560-562, 1980.

15. Richards, F. M.; Goudie, D. R.; Cooper, W. N.; Jene, Q.; Barroso,
I.; Wicking, C.; Wainwright, B. J.; Ferguson-Smith, M. A.: Mapping
the multiple self-healing squamous epithelioma (MSSE) gene and investigation
of xeroderma pigmentosum group A (XPA) and patched (PTCH) as candidate
genes. Hum. Genet. 101: 317-322, 1997.

16. Sommerville, J.; Milne, J. A.: Familial primary self-healing
squamous epithelioma of the skin. Brit. J. Derm. 62: 485-490, 1950.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKIN, NAILS, HAIR:
[Skin];
Squamous epitheliomas, multiple;
Tumors appear most often on sun-exposed regions;
Tumors are locally invasive;
Tumors undergo spontaneous resolution over a period of months;
Tumors leave pitting scars;
HISTOLOGY:;
Tumors are morphologically similar to well-differentiated squamous
cell carcinoma

NEOPLASIA:
Squamous epitheliomas, multiple

MISCELLANEOUS:
Variable age at onset (8 to 62 years);
Increased frequency in individuals originating from Western Scotland

MOLECULAR BASIS:
Susceptibility conferred by mutation in the transforming growth factor-beta
receptor, type I gene (TGFBR1, 190181.0009).

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

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

*FIELD* ED
ckniffin: 05/05/2011
ckniffin: 5/2/2006

*FIELD* CN
Cassandra L. Kniffin - updated: 4/22/2011
Cassandra L. Kniffin - updated: 5/2/2006
Sheryl A. Jankowski - updated: 12/22/1998
Victor A. McKusick - updated: 2/11/1998

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

*FIELD* ED
wwang: 04/25/2011
ckniffin: 4/22/2011
wwang: 7/29/2009
carol: 7/12/2007
carol: 5/4/2006
ckniffin: 5/2/2006
carol: 3/18/2004
psherman: 12/22/1998
carol: 7/8/1998
alopez: 2/11/1998
dholmes: 2/4/1998
mimadm: 9/24/1994
davew: 6/27/1994
warfield: 4/20/1994
carol: 2/21/1994
carol: 3/30/1993
supermim: 3/16/1992

MIM 190181
*RECORD*
*FIELD* NO
190181
*FIELD* TI
*190181 TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE I; TGFBR1
;;ACTIVIN RECEPTOR-LIKE KINASE 5; ALK5
read more*FIELD* TX

DESCRIPTION

The TGFBR1 gene encodes a serine/threonine kinase receptor for
transforming growth factor-beta (TGFB1; 190180). Most growth factor
receptors are transmembrane tyrosine kinases or are associated with
cytoplasmic tyrosine kinases. Another class of transmembrane receptors,
however, is predicted to function as serine/threonine kinases. On the
basis of their various biologic activities, different species of
TGF-beta are probably potent developmental regulators of cell
proliferation and differentiation. Several types of TGF-beta-binding
proteins have been detected at the cell surface. Type I and type II
receptors are defined on the basis of the mobility of their
(125)I-TGF-beta cross-linked products in denaturing gels. These
receptors probably mediate most activities of TGF-beta. The type II
receptor (TGFBR2; 190182) functions as a transmembrane serine/threonine
kinase and is required for the antiproliferative activity of TGF-beta,
whereas the type I receptor mediates the induction of several genes
involved in cell-matrix interactions (summary by Ebner et al., 1993).

CLONING

Ebner et al. (1993) cloned a murine serine/threonine kinase receptor
that shares a conserved extracellular domain with the type II TGF-beta
receptor. Overexpression of this receptor alone did not increase cell
surface binding of TGF-beta, but coexpression with the type II TGF-beta
receptor caused TGF-beta to bind to this receptor, which had the size of
the type I TGF-beta receptor. Overexpression of this newly cloned
receptor inhibited binding of TGF-beta to the type II receptor in a
dominant-negative fashion. Combinatorial interactions and stoichiometric
ratios between the type I and II receptors may therefore determine the
extent of TGF-beta binding and the resulting biologic activities.

By PCR analysis on human erythroleukemia cell cDNA using degenerate
primers based on conserved regions of ser/thr kinase receptors, Franzen
et al. (1993) isolated a cDNA encoding TGFBR1, which they called ALK5
(activin receptor-like kinase-5). The deduced 503-amino acid, 53-kD
TGFBR1 ser/thr kinase contains a signal peptide; an extracellular
cysteine-rich region with a single N-glycosylation site; a transmembrane
region; and a putative cytoplasmic protein kinase domain. SDS-PAGE
analysis showed that immunoprecipitation of TGFBR1 incubated with
labeled TGFB1 produced a 70-kD complex as well as a heteromeric 94-kD
TGFBR2 complex. Northern blot analysis detected a 5.5-kb TGFBR1
transcript in all tissues tested, with highest expression in placenta
and lowest expression in brain and heart. Transient expression of TGFBR1
in a receptor-negative cell line led to the production of plasminogen
activator inhibitor-1 (PAI1; 173360) in response to stimulation with
TGFB1.

GENE STRUCTURE

TGFB1 regulates cell cycle progression by a unique signaling mechanism
that involves its binding to TGFBR2 and activation of TGFBR1. Both are
transmembrane serine/threonine receptor kinases. The TGFBR1 receptor may
be inactivated in many of the cases of human tumor cells refractory to
TGFB-mediated cell cycle arrest. Vellucci and Reiss (1997) reported that
the TGFBR1 gene is approximately 31 kb long and contains 9 exons. The
organization of the segment of the gene that encodes the C-terminal
portion of the serine/threonine kinase domain appears to be highly
conserved among members of the gene family.

MAPPING

Johnson et al. (1995) used PCR with a hybrid cell DNA panel and FISH to
localize the TGFBR1 gene to chromosome 9q33-q34. By FISH, Pasche et al.
(1998) localized the gene to chromosome 9q22. Kuan and Kono (1998)
mapped the Tgfbr1 gene to mouse chromosome 4.

GENE FUNCTION

Wang et al. (1994) reported that the type I receptor may be a natural
ligand for immunophilin FKBP12 (186945).

The membrane-bound protein encoded by TGFBR1 binds TGF-beta and forms a
heterodimeric complex with the TGF-beta II receptor (Franzen et al.,
1993; Johnson et al., 1995). Ligand binding by TGF-beta I receptors is
dependent on coexpression with type II receptors. Type II receptors
alone can bind ligand, but require association with type I receptors for
activation of their kinase (signaling) function.

TGFB stimulation leads to phosphorylation and activation of SMAD2
(601366) and SMAD3 (603109), which form complexes with SMAD4 (600993)
that accumulate in the nucleus and regulate transcription of target
genes. Inman et al. (2002) demonstrated that following TGFB stimulation
of epithelial cells, receptors remain active for at least 3 to 4 hours,
and continuous receptor activity is required to maintain active SMADs in
the nucleus and for TGFB-induced transcription. Continuous
nucleocytoplasmic shuttling of the SMADs during active TGFB signaling
provides the mechanism whereby the intracellular transducers of the
signal continuously monitor receptor activity. These data explain how,
at all times, the concentration of active SMADs in the nucleus is
directly dictated by the levels of activated receptors in the cytoplasm.

Barrios-Rodiles et al. (2005) developed LUMIER (luminescence-based
mammalian interactome mapping), an automated high-throughput technology,
to map protein-protein interaction networks systematically in mammalian
cells and applied it to the TGFB pathway. Analysis using self-organizing
maps and k-means clustering identified links of the TGF-beta pathway to
the p21-activated kinase (PAK; see 602590) network, to the polarity
complex, and to occludin (602876), a structural component of tight
junctions. Barrios-Rodiles et al. (2005) showed the occludin regulates
TGFBR1 localization for efficient TGF-beta-dependent dissolution of
tight junctions during epithelial-mesenchymal transitions.

Studying a Caucasian-dominated population in the U.S., Valle et al.
(2008) showed that germline allele-specific expression (ASE) of the
TGFBR1 gene is a quantitative trait that occurs in 10 to 20% of CRC
patients and 1 to 3% of controls. ASE results in a reduced expression of
the gene, is dominantly inherited, segregates in families, and occurs in
sporadic CRC cases. Although subtle, the reduction in constitutive
TGFBR1 expression alters SMAD-mediated TGF-beta signaling. Two major
TGFBR1 haplotypes are predominant among ASE cases, which suggested
ancestral mutations, but causative germline changes were not identified.
Conservative estimates suggested that ASE confers a substantially
increased risk of CRC (odds ratio, 8.7; 95% confidence interval, 2.6 to
29.1), but these estimates required confirmation and were predicted to
show ethnic differences.

MOLECULAR GENETICS

- Loeys-Dietz Syndrome

Loeys et al. (2005) described 10 families with an aortic aneurysm
syndrome characterized by hypertelorism, bifid uvula and/or cleft
palate, and generalized arterial tortuosity with ascending aortic
aneurysm and dissection (see LDS1A, 609192). This syndrome showed
autosomal dominant inheritance and variable clinical expression. Other
findings in multiple systems included craniosynostosis, structural brain
abnormalities such as type I Chiari malformation (118420), mental
retardation, congenital heart disease (patent ductus arteriosus, atrial
septal defect), and aneurysms with dissection throughout the arterial
tree. Heterozygous mutations were found in the TGFBR1 gene in 4 of the
10 families and in the TGFBR2 gene (190182) in 6. Tissues derived from
affected individuals showed increased expression of both collagen (see
120150) and connective tissue growth factor (121009), as well as nuclear
enrichment of phosphorylated SMAD2, indicative of increased TGF-beta
signaling.

Loeys et al. (2006) undertook the clinical and molecular
characterization of the families of 40 probands presenting with typical
manifestations of the Loeys-Dietz syndrome (LDS1A). In view of the
phenotypic overlap between this syndrome and vascular Ehlers-Danlos
syndrome (EDS; 130050), they screened an additional cohort of 40
patients who had been diagnosed provisionally with vascular EDS but
lacked the characteristic abnormalities of type III collagen (120180).
Of these 40 probands, 4 carried a heterozygous mutation in TGFBR1 (3 of
which involved codon 487; see, e.g., 190181.0004 and 190181.0007) and
were classified as Loeys-Dietz syndrome type 2 (see LDS2A, 608967).
Overall, 13 mutations were found in TGFBR1.

Ades et al. (2006) discussed the phenotypes and genotypes of 5
individuals with conditions within the Marfan
syndrome/marfanoid-craniosynostosis/marfanoid-metal retardation spectrum
in light of evidence of abnormal TGF-beta signaling in the pathogenesis
of Marfan-like phenotypes. In 2 unrelated patients with Furlong syndrome
(LDS1A; 609192) they described the same missense mutation in TGFBR1
(190181.0005). The other 3 patients had alterations of the FBN1 gene
(134797). Ades et al. (2006) concluded that their findings supported the
notion that perturbation of extracellular matrix homeostasis and/or
remodeling caused by abnormal TGF-beta signaling is the core
pathogenetic mechanism in Marfan syndrome and related entities.

In patients with phenotypes classified as type 2 Marfan syndrome,
Loeys-Dietz syndrome, or thoracic aortic aneurysm with dissection (TAAD)
(see LDS2A), Matyas et al. (2006) detected 3 novel mutations in the
TGFBR1 gene. A heterozygous arg487-to-gln (R487Q) mutation (190181.0006)
was present in a patient with TAAD; mutation of the same residue to pro
(R487P; 190181.0004) had been previously reported in a family whose
phenotype was identified as Loeys-Dietz syndrome.

Singh et al. (2006) searched for TGFBR1 and TGFBR2 mutations in 41
unrelated patients fulfilling the diagnostic criteria of the Ghent
nosology (De Paepe et al., 1996) or with a tentative diagnosis of Marfan
syndrome, in whom mutations in the FBN1 coding region were not
identified. In TGFBR1, 2 mutations and 2 polymorphisms were detected. In
TGFBR2, 5 mutations and 6 polymorphisms were identified. Reexamination
of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical
overlap between these patients.

- Susceptibility To Multiple Self-Healing Squamous Epithelioma

In affected members of 18 different families with autosomal dominant
multiple self-healing squamous epithelioma (MSSE; 132800), Goudie et al.
(2011) identified 11 different heterozygous mutations in the TGFBR1 gene
(see, e.g., 190181.0009-190181.0012). The phenotype is characterized by
the development of multiple squamous carcinoma-like locally invasive
skin tumors that grow rapidly for a few weeks before showing spontaneous
regression, leaving scars. The mutations identified by Goudie et al.
(2011) occurred in either the extracellular ligand-binding domain (exon
2) or in the serine/threonine kinase domain (exons 4, 6, and 7), and all
were predicted or demonstrated to result in loss of receptor function.
Several mutation carriers were unaffected, and tumor tissue from some
patients showed loss of heterozygosity for the wildtype allele. Overall,
the findings were consistent with wildtype TGFBR1 acting as a tumor
suppressor, until somatic deletion by a classic second hit results in
carcinogenesis. Goudie et al. (2011) noted that TGFBR1 mutations causing
Loeys-Dietz syndrome result in activation of the TGFB1 signaling
pathway, whereas TGFBR1 mutations causing MSSE result in loss of the
TGFB1 signaling pathway.

- Susceptibility To Abdominal Aortic Aneurysm

For a discussion of a possible association between variation in the
TGFBR1 gene and susceptibility to abdominal aortic aneurysm, see AAA
(100070).

ANIMAL MODEL

To better define the function of TGF-beta in hematopoiesis and
angiogenesis, Larsson et al. (2001) used gene targeting to inactivate
the Tgfbr1 gene in mice. Mice lacking Tgfbr1 died at midgestation,
exhibited severe defects in the vascular development of the yolk sac and
placenta, and lacked circulating red blood cells. Analysis of yolk
sac-derived hematopoietic precursors of Tgfbr1 null mice revealed normal
hematopoietic potential. However, endothelial cells from these embryos
showed enhanced cell proliferation, improper migratory behavior, and
impaired fibronectin (135600) production in vitro. Larsson et al. (2001)
noted that these endothelial defects are associated with the vascular
defects seen in vivo. They concluded that Tgfbr1-dependent signaling is
required for angiogenesis, but not for the development of hematopoietic
progenitor cells and functional hematopoiesis.

*FIELD* AV
.0001
LOEYS-DIETZ SYNDROME, TYPE 1A
TGFBR1, MET318ARG

In a family with Loeys-Dietz syndrome (609192), Loeys et al. (2005)
found a 953T-G transversion on exon 5 of the TGFBR1 gene that resulted
in a met318-to-arg (M318R) substitution in the kinase domain of the
protein. The mutation occurred de novo.

.0002
LOEYS-DIETZ SYNDROME, TYPE 1A
TGFBR1, ASP400GLY

In a family with Loeys-Dietz syndrome (609192), Loeys et al. (2005)
identified an 1199A-G transition in exon 7 of the TGFBR1 gene, resulting
in an asp400-to-gly (D400G) substitution in the kinase domain of the
protein. The mutation occurred de novo.

.0003
LOEYS-DIETZ SYNDROME, TYPE 1A
TGFBR1, THR200ILE

In a family with Loeys-Dietz syndrome (609192), Loeys et al. (2005)
identified a 599C-T transition in exon 4 of the TGFBR1 gene that
resulted in a thr200-to-ile (T200I) substitution at the junction of the
glycine-serine-rich domain and the kinase domain of the TGFBR1 protein.
The mutation occurred de novo.

.0004
LOEYS-DIETZ SYNDROME, TYPE 1A
LOEYS-DIETZ SYNDROME, TYPE 2A, INCLUDED
TGFBR1, ARG487PRO

In a family with Loeys-Dietz syndrome (609192), Loeys et al. (2005)
found a 1460G-C transversion in exon 9 of the TGFBR1 gene that resulted
in an arg487-to-pro (R487P) amino acid substitution. The R487P mutation
segregated with the disorder in a father and 2 sons.

Loeys et al. (2006) classified the family with LDS identified by Loeys
et al. (2005) as LDS type 1, but apparently found the same mutation in
another patient classified as LDS type 2 (LDS2A; 608967). It is
noteworthy that another missense mutation involving the same codon,
R487W (190181.0007), was observed.

.0005
LOEYS-DIETZ SYNDROME, TYPE 1A
TGFBR1, SER241LEU

In 2 patients judged to have Furlong syndrome (LDS1A; 609192), Ades et
al. (2006) found an identical heterozygous missense mutation, ser241 to
leu (S241L), in the TGFBR1 gene. The mutation, which arose from a C-to-T
transition at nucleotide position 722, alters a highly conserved
nonpolar serine in the serine-threonine kinase domain to a polar leucine
residue.

.0006
LOEYS-DIETZ SYNDROME, TYPE 2A
TGFBR1, ARG487GLN

In a 43-year-old patient with thoracic aortic aneurysm and dissection
(LDS2A; 608967), Matyas et al. (2006) found a de novo heterozygous
1460G-A transition in exon 9 of the TGFBR1 gene that caused an
arg487-to-gln substitution in the protein (R487Q). Mutation at this
codon had been found previously (190181.0004). The mutation occurred in
the kinase domain of the protein and was predicted to affect protein
function.

.0007
LOEYS-DIETZ SYNDROME, TYPE 2A
TGFBR1, ARG487TRP

In a woman with Loeys-Dietz syndrome classified as type 2 (LDS2A;
608967), Loeys et al. (2006) found an arg487-to-trp (R487W) missense
mutation in the TGFBR1 gene. The patient had aortic root aneurysm with
dissection, other arterial aneurysm, arterial tortuosity, vascular
rupture during pregnancy, uterine hemorrhage, bowel rupture, inguinal
hernia, velvety skin, skin hyperextensibility, atrophic scars, and joint
laxity. Another missense mutation in the same codon had been described
(R487P; 190181.0004).

In 11 affected members of a 4-generation family with thoracic aortic
aneurysm as well as aneurysms and dissections of other arteries,
originally reported by Nicod et al. (1989), Tran-Fadulu et al. (2009)
identified heterozygosity for the R487W mutation in the TGFBR1 gene.
Imaging of the cerebrovascular circulation in 2 affected family members
showed tortuous vessels and fusiform dilation of the basilar artery.
Tran-Fadulu et al. (2009) stated that examination of 6 family members
revealed no features of Loeys-Dietz syndrome type 1; specifically, none
had bifid uvula, craniosynostosis, hypertelorism, or translucent skin.

.0008
LOEYS-DIETZ SYNDROME, TYPE 2A
TGFBR1, GLY174VAL

In a 45-year-old Italian man with LDS2A (608967), Drera et al. (2008)
identified a heterozygous 521G-T transversion in exon 3 of the TGFBR1
gene, resulting in a gly174-to-val (G174V) substitution in the
intracellular region of the receptor. The mutation was not identified in
200 chromosomes from Italian controls nor in the patient's unaffected
daughter. The patient had a prominent and narrow nose, thin lips, bifid
uvula and cleft palate, hypermobility of small joints, and soft skin. He
also had a history of dissection of both internal iliac arteries and the
right femoral artery. There was no aortic root dilatation or tortuosity
of the great vessels.

.0009
MULTIPLE SELF-HEALING SQUAMOUS EPITHELIOMA, SUSCEPTIBILITY TO
TGFBR1, ASN45SER

In 2 symptomatic members of a Scottish family with autosomal dominant
multiple self-healing squamous epithelioma (132800), Goudie et al.
(2011) identified a heterozygous 134A-G transition in exon 2 of the
TGFBR1 gene, resulting in an asn45-to-ser (N45S) substitution in the
extracellular ligand-binding domain. One additional asymptomatic family
member also carried the mutation, which was not found in 80 Scottish
controls.

.0010
MULTIPLE SELF-HEALING SQUAMOUS EPITHELIOMA, SUSCEPTIBILITY TO
TGFBR1, GLY52ARG

In affected individuals from 7 Scottish families with autosomal dominant
multiple self-healing squamous epithelioma (132800), previously reported
by Ferguson-Smith et al., 1971 and Goudie et al., 1993, Goudie et al.
(2011) identified a heterozygous 154G-C transversion in exon 2 of the
TGFBR1 gene, resulting in a gly52-to-arg (G52R) substitution in the
extracellular ligand-binding domain. Asymptomatic family members in
several families also carried the mutation, which was not found in 80
Scottish controls. Studies of tumor tissue from an affected individual
showed that the mutant protein was expressed and localized to the plasma
membrane, but there was some loss of heterozygosity for the wildtype
allele. SMAD reporter assay showed that the mutant G52R receptor protein
gave lower activation than the wildtype protein in response to TGFB1
stimulation, consistent with a loss of function. Overall, the findings
were consistent with wildtype TGFBR1 acting as a tumor suppressor, until
somatic deletion by a classic second hit results in carcinogenesis.

.0011
MULTIPLE SELF-HEALING SQUAMOUS EPITHELIOMA, SUSCEPTIBILITY TO
TGFBR1, IVS4AS, A-C, -2

In 2 affected individuals from an English family with autosomal dominant
multiple self-healing squamous epithelioma (132800), Goudie et al.
(2011) identified a heterozygous A-to-C transversion (806-2A-C) in
intron 4 of the TGFBR1 gene, resulting in a splice site mutation in a
region containing the serine/threonine kinase domain. The mutation was
predicted to result in loss of receptor signaling. The mutation was not
found in 80 Scottish controls. Tumor tissue from an affected individual
showed loss of heterozygosity for the wildtype allele.

.0012
MULTIPLE SELF-HEALING SQUAMOUS EPITHELIOMA, SUSCEPTIBILITY TO
TGFBR1, ARG414TER

In 2 affected individuals from an English family with autosomal dominant
multiple self-healing squamous epithelioma (132800), Goudie et al.
(2011) identified a heterozygous 1240C-T transition in exon 7 of the
TGFBR1 gene, resulting in an arg414-to-ter (R414X) substitution in the
serine/threonine kinase domain. The mutation resulted in
nonsense-mediated mRNA decay, causing a loss of receptor signaling. The
mutation was not found in 80 Scottish controls.

*FIELD* RF
1. Ades, L. C.; Sullivan, K.; Biggin, A.; Haan, E. A.; Brett, M.;
Holman, K. J.; Dixon, J.; Robertson, S.; Holmes, A. D.; Rogers, J.;
Bennetts, B.: FBN1, TGFBR1, and the Marfan-craniosynostosis/mental
retardation disorders revisited. Am. J. Med. Genet. 140A: 1047-1058,
2006.

2. Barrios-Rodiles, M.; Brown, K. R.; Ozdamar, B.; Bose, R.; Liu,
Z.; Donovan, R. S.; Shinjo, F.; Liu, Y.; Dembowy, J.; Taylor, I. W.;
Luga, V.; Przulj, N.; Robinson, M.; Suzuki, H.; Hayashizaki, Y.; Jurisica,
I.; Wrana, J. L.: High-throughput mapping of a dynamic signaling
network in mammalian cells. Science 307: 1621-1625, 2005.

3. De Paepe, A.; Devereux, R. B.; Dietz, H. C.; Hennekam, R. C. M.;
Pyeritz, R. E.: Revised diagnostic criteria for the Marfan syndrome. Am.
J. Med. Genet. 62: 417-426, 1996.

4. Drera, B.; Tadini, G.; Barlati, S.; Colombi, M.: Identification
of a novel TGFBR1 mutation in a Loeys-Dietz syndrome type II patient
with vascular Ehlers-Danlos syndrome phenotype. (Letter) Clin. Genet. 73:
290-293, 2008.

5. Ebner, R.; Chen, R.-H.; Shum, L.; Lawler, S.; Zioncheck, T. F.;
Lee, A.; Lopez, A. R.; Derynck, R.: Cloning of a type I TGF-beta
receptor and its effect on TGF-beta binding to the type II receptor. Science 260:
1344-1348, 1993.

6. Ferguson-Smith, M. A.; Wallace, D. C.; James, Z. H.; Renwick, J.
H.: Multiple self-healing squamous epithelioma. Birth Defects Orig.
Art. Ser. VII(8): 157-163, 1971.

7. Franzen, P.; ten Dijke, P.; Ichijo, H.; Yamashita, H.; Schulz,
P.; Heldin, C.-H.; Miyazono, K.: Cloning of a TGF-beta type I receptor
that forms a heteromeric complex with the TGF-beta type II receptor. Cell 75:
681-692, 1993.

8. Goudie, D. R.; D'Alessandro, M.; Merriman, B.; Lee, H.; Szeverenyi,
I.; Avery, S.; O'Connor, B. D.; Nelson, S. F.; Coats, S. E.; Stewart,
A.; Christie, L.; Pichert, G.; and 11 others: Multiple self-healing
squamous epithelioma is caused by a disease-specific spectrum of mutations
in TGFBR1. Nature Genet. 43: 365-369, 2011.

9. Goudie, D. R.; Yuille, M. A. R.; Leversha, M. A.; Furlong, R. A.;
Carter, N. P.; Lush, M. J.; Affara, N. A.; Ferguson-Smith, M. A.:
Multiple self-healing squamous epitheliomata (ESS1) mapped to chromosome
9q22-q31 in families with common ancestry. Nature Genet. 3: 165-169,
1993.

10. Inman, G. J.; Nicolas, F. J.; Hill, C. S.: Nucleocytoplasmic
shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor
activity. Molec. Cell 10: 283-294, 2002.

11. Johnson, D. W.; Qumsiyeh, M.; Benkhalifa, M.; Marchuk, D. A.:
Assignment of human transforming growth factor-beta type I and type
III receptor genes (TGFBR1 and TGFBR3) to 9q33-q34 and 1p32-p33, respectively. Genomics 28:
356-357, 1995.

12. Kuan, J.; Kono, D. H.: Tgfbr1 maps to chromosome 4. Mammalian
Genome 9: 95-96, 1998.

13. Larsson, J.; Goumans, M.-J.; Sjostrand, L. J.; van Rooijen, M.
A.; Ward, D.; Leveen, P.; Xu, X.; Dijke, P.; Mummery, C. L.; Karlsson,
S.: Abnormal angiogenesis but intact hematopoietic potential in TGF-beta
type I receptor-deficient mice. EMBO J. 20: 1663-1673, 2001.

14. Loeys, B. L.; Chen, J.; Neptune, E. R.; Judge, D. P.; Podowski,
M.; Holm, T.; Meyers, J.; Leitch, C. C.; Katsanis, N.; Sharifi, N.;
Xu, F. L.; Myers, L. A.; and 12 others: A syndrome of altered cardiovascular,
craniofacial, neurocognitive and skeletal development caused by mutations
in TGFBR1 or TGFBR2. Nature Genet. 37: 275-281, 2005.

15. Loeys, B. L.; Schwarze, U.; Holm, T.; Callewaert, B. L.; Thomas,
G. H.; Pannu, H.; De Backer, J. F.; Oswald, G. L.; Symoens, S.; Manouvrier,
S.; Roberts, A. E.; Faravelli, F.; and 9 others: Aneurysm syndromes
caused by mutations in the TGF-beta receptor. New Eng. J. Med. 355:
788-798, 2006.

16. Matyas, G.; Arnold, E.; Carrel, T.; Baumgartner, D.; Boileau,
C.; Berger, W.; Steinmann, B.: Identification and in silico analyses
of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum.
Mutat. 27: 760-769, 2006.

17. Nicod, P.; Bloor, C.; Godfrey, M.; Hollister, D.; Pyeritz, R.
E.; Dittrich, H.; Polikar, R.; Peterson, K. L.: Familial aortic dissecting
aneurysm. J. Am. Coll. Cardiol. 13: 811-819, 1989.

18. Pasche, B.; Luo, Y.; Rao, P. H.; Nimer, S. D.; Dmitrovsky, E.;
Caron, P.; Luzzatto, L.; Offit, K.; Cordon-Cardo, C.; Renault, B.;
Satagopan, J. M.; Murty, V. V.; Massague, J.: Type I transforming
growth factor beta receptor maps to 9q22 and exhibits a polymorphism
and a rare variant within a polyalanine tract. Cancer Res. 58: 2727-2732,
1998.

19. Singh, K. K.; Rommel, K.; Mishra, A.; Karck, M.; Haverich, A.;
Schmidtke, J.; Arslan-Kirchner, M.: TGFBR1 and TGFBR2 mutations in
patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum.
Mutat. 27: 770-777, 2006.

20. Tran-Fadulu, V.; Pannu, H.; Kim, D. H.; Vick, G. W., III; Lonsford,
C. M.; Lafont, A. L.; Boccalandro, C.; Smart, S.; Peterson, K. L.;
Hain, J. Z.; Willing, M. C.; Coselli, J. S.; LeMaire, S. A.; Ahn,
C.; Byers, P. H.; Milewicz, D. M.: Analysis of multigenerational
families with thoracic aortic aneurysms and dissections due to TGFBR1
or TGFBR2 mutations. J. Med. Genet. 46: 607-613, 2009.

21. Valle, L.; Serena-Acedo, T.; Liyanarachchi, S.; Hampel, H.; Comeras,
I.; Li, Z.; Zeng, Q.; Zhang, H.-T.; Pennison, M. J.; Sadim, M.; Pasche,
B.; Tanner, S. M.; de la Chapelle, A.: Germline allele-specific expression
of TGFBR1 confers an increased risk of colorectal cancer. Science 321:
1361-1365, 2008.

22. Vellucci, V. F.; Reiss, M.: Cloning and genomic organization
of the human transforming growth factor-beta type I receptor gene. Genomics 46:
278-283, 1997.

23. Wang, T.; Donahoe, P. K.; Zervos, A. S.: Specific interaction
of type I receptors of the TGF-beta family with the immunophilin FKBP-12. Science 265:
674-676, 1994.

*FIELD* CN
Cassandra L. Kniffin - updated: 4/22/2011
Marla J. F. O'Neill - updated: 1/28/2010
Ada Hamosh - updated: 10/1/2008
Cassandra L. Kniffin - updated: 5/6/2008
Victor A. McKusick - updated: 9/20/2006
Victor A. McKusick - updated: 8/24/2006
Victor A. McKusick - updated: 6/5/2006
Ada Hamosh - updated: 6/1/2005
Victor A. McKusick - updated: 2/4/2005
Patricia A. Hartz - updated: 12/16/2002
Stylianos E. Antonarakis - updated: 9/11/2002
Paul J. Converse - updated: 7/17/2000
Carol A. Bocchini - updated: 11/30/1999
Victor A. McKusick - updated: 2/19/1998
Victor A. McKusick - updated: 2/4/1998

*FIELD* CD
Victor A. McKusick: 6/10/1993

*FIELD* ED
alopez: 01/11/2012
wwang: 4/25/2011
ckniffin: 4/22/2011
wwang: 2/2/2010
terry: 1/28/2010
alopez: 10/3/2008
terry: 10/1/2008
wwang: 5/13/2008
ckniffin: 5/6/2008
alopez: 3/31/2008
alopez: 3/7/2008
alopez: 10/11/2006
terry: 9/20/2006
alopez: 9/7/2006
alopez: 9/5/2006
terry: 8/24/2006
alopez: 6/8/2006
terry: 6/5/2006
carol: 1/18/2006
wwang: 6/2/2005
wwang: 6/1/2005
terry: 6/1/2005
alopez: 3/2/2005
alopez: 2/7/2005
terry: 2/4/2005
mgross: 12/18/2002
terry: 12/16/2002
mgross: 9/11/2002
mgross: 7/17/2000
carol: 12/1/1999
carol: 11/30/1999
alopez: 11/3/1998
dkim: 9/11/1998
terry: 2/19/1998
mark: 2/5/1998
terry: 2/4/1998
mark: 8/25/1995
carol: 9/30/1994
carol: 6/10/1993

MIM 608967
*RECORD*
*FIELD* NO
608967
*FIELD* TI
#608967 LOEYS-DIETZ SYNDROME, TYPE 2A; LDS2A
;;AORTIC ANEURYSM, FAMILIAL THORACIC 5; AAT5
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
Loeys-Dietz syndrome type 2, designated LDS2A, is caused by heterozygous
mutation in the TGFBR1 gene (190181) on chromosome 9q22.

For a general phenotypic description and a discussion of genetic
heterogeneity of Loeys-Dietz syndrome, see LDS1A (609192).

CLINICAL FEATURES

Nicod et al. (1989) described a family in which 9 members over 2
generations had aortic dissecting aneurysm or aortic or arterial
dilatation at a young age. Three died of ruptured aortic dissecting
aneurysms at ages 14, 18, and 24 years, respectively. A fourth member of
the family died suddenly at age 48 years, a few years after aortic
repair for aneurysmal dilatation. One member underwent surgical repair
of an ascending aortic dissecting aneurysm at age 18 years and was still
living at the time of report. Histologic examination of the aortic wall
in 3 patients showed a loss of elastic fibers, deposition of
mucopolysaccharide-like material in the media, and cystic medial
changes--the typical findings of Erdheim cystic medial necrosis.
Collagen of types I (see 120150) and III (see 120180) from cultured
fibroblasts appeared to be normal on gel electrophoresis.

In view of the phenotypic overlap between the Loeys-Dietz syndrome (LDS)
and vascular Ehlers-Danlos syndrome (EDS; 130050), Loeys et al. (2006)
screened the TGFBR1 and TGFBR2 genes in 40 probands who had previously
received a provisional diagnosis of vascular EDS by a medical
geneticist, but in whom the diagnosis had been ruled out by studies of
type III collagen (see 120180) biosynthesis. Twelve of these patients
carried a heterozygous mutation in one of these genes and were assigned
to the LDS type 2 category. Physical findings in these patients included
prominent joint laxity, easy bruising, wide and atrophic scars, velvety
and translucent skin with easily visible veins, spontaneous rupture of
the spleen or bowel, diffuse arterial aneurysms and dissections, and
catastrophic complications of pregnancy, including rupture of the gravid
uterus and the arteries, either during pregnancy or in the immediate
postpartum period. None of these patients had cleft palate,
hypertelorism, or craniosynostosis. Three patients had bifid uvula, and
one had a family history of cleft palate. Mean age at the first major
vascular event was 29.8 years, versus 24.5 years for LDS type 1
patients. The extent of vascular and skin involvement was similar in the
patients with true vascular EDS and in those with LDS2; only joint
laxity was significantly more prevalent in those with LDS2 (12 of 12 vs
18 of 28, P = 0.03).

Loeys et al. (2006) pointed out that in both LDS and vascular EDS,
dissection can occur without marked arterial dilatation. However,
incidence of fatal complications during or immediately after vascular
surgery is about 45% in vascular EDS but only 4.8% in LDS2, and only
1.7% in LDS overall. Thus, genotyping is beneficial in patients who
present with features of vascular EDS.

Matyas et al. (2006) screened a cohort of 70 individuals with phenotypes
related to Marfan syndrome (154700) without mutations in the FBN1 gene
(134797) for mutations in TGFBR1. In a 43-year-old patient with thoracic
aortic aneurysm and dissection they found a heterozygous missense
mutation (190181.0006). No abnormality of the skeletal system or eyes
was described, and family history was negative.

Drera et al. (2008) reported a 45-year-old Italian man with LDS2A
confirmed by genetic analysis (190181.0008). He had a prominent and
narrow nose, thin lips, bifid uvula and cleft palate, hypermobility of
small joints, and soft skin. He also had a history of dissection of both
internal iliac arteries and the right femoral artery. There was no
aortic root dilatation or tortuosity of the great vessels. The phenotype
was reminiscent of vascular EDS.

Ades (2008) described the evolution of craniofacial features in 7
patients with LDS type 2 and proven mutations in the TGFBR1 or TGFBR2
genes. Most patients had dolichocephaly, a tall broad forehead, frontal
bossing, high anterior hairline, hypoplastic supraorbital margins, a
'jowly' appearance in the first 3 years of life, translucent and
redundant facial skin that was most pronounced in the periorbital area,
prominent upper central incisors in late childhood/adulthood, and an
open-mouthed myopathic face. The adult faces appeared prematurely aged.
Although not exclusive to the LDS type 2 phenotype, Ades (2008)
suggested that recognition of these facial features and their evolution
might assist in the differentiation of some cases of LDS type 2 from
related clinical entities.

MOLECULAR GENETICS

In 4 patients with LDS2, Loeys et al. (2006) detected heterozygosity for
4 different missense mutations in the TGFBR1 gene. Three of these
involved the same codon and occurred at the same codon, arg487 at the
C-terminal end of the kinase domain (see 190181.0004). The fourth
mutation occurred in exon 4 of the TGFBR1 gene at codon lys232 at the
N-terminal end of the kinase domain.

GENOTYPE/PHENOTYPE CORRELATIONS

Tran-Fadulu et al. (2009) analyzed the TGFBR1 gene in 150 unrelated
families with thoracic aortic aneurysm (AAT) and identified heterozygous
missense mutations in 4 families, including a 4-generation family
originally described by Nicod et al. (1989) (190181.0007). Tran-Fadulu
et al. (2009) compared the clinical features of 30 affected individuals
from these 4 families with TGFBR1 mutations to those of 77 patients from
4 families previously reported with mutations in the TGFBR2 gene (Pannu
et al., 2005) and found that the average age of onset of vascular
disease was significantly younger in the TGFBR1 cohort compared to the
TGFBR2 cohort (31.4 vs 45.6 years; p = 0.002). In addition, men in
TGFBR1 families presented with vascular disease at a statistically
significant younger age compared with affected women (23 vs 39 years; p
= 0.019). Thoracic aortic aneurysm was the predominant vascular
presentation in both cohorts of patients, but the TGFBR1 patients were
twice as likely to present with vascular disease elsewhere (23% vs 8%,
respectively; p = 0.039), and vascular disease presentation differed
based on gender in the TGFBR1 families: all men but 1 presented with
AAT, whereas half of the affected women presented with disease in other
vascular beds, including abdominal aortic aneurysms and carotid and
coronary artery dissections (p = 0.038). In a combined analysis of the
families, there was no difference in overall survival; however, survival
was significantly worse in men than in women in TGFBR1 families (p =
0.017) but not in TGFBR2 families. The data also suggested that
individuals with TGFBR2 mutations were more likely to dissect at aortic
diameters less than 5.0 cm than individuals with TGFBR1 mutations: 3
TGFBR2 patients had dissections with aortic diameters under 5.0 cm,
whereas there were no dissections under 5.0 cm in TGFBR1 patients, who
often had dramatically enlarged aortic diameters at dissection (6.5 cm
to 14.0 cm) or repair (8.5 cm). One TGFBR1 patient who refused repair
had been stable for 3 years with an aortic diameter of 5.6 cm.

*FIELD* RF
1. Ades, L. C.: Evolution of the face in Loeys-Dietz syndrome type
II: longitudinal observations from infancy in seven cases. Clin.
Dysmorph. 17: 243-248, 2008.

2. Drera, B.; Tadini, G.; Barlati, S.; Colombi, M.: Identification
of a novel TGFBR1 mutation in a Loeys-Dietz syndrome type II patient
with vascular Ehlers-Danlos syndrome phenotype. (Letter) Clin. Genet. 73:
290-293, 2008.

3. Loeys, B. L.; Schwarze, U.; Holm, T.; Callewaert, B. L.; Thomas,
G. H.; Pannu, H.; De Backer, J. F.; Oswald, G. L.; Symoens, S.; Manouvrier,
S.; Roberts, A. E.; Faravelli, F.; and 9 others: Aneurysm syndromes
caused by mutations in the TGF-beta receptor. New Eng. J. Med. 355:
788-798, 2006.

4. Matyas, G.; Arnold, E.; Carrel, T.; Baumgartner, D.; Boileau, C.;
Berger, W.; Steinmann, B.: Identification and in silico analyses
of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum.
Mutat. 27: 760-769, 2006.

5. Nicod, P.; Bloor, C.; Godfrey, M.; Hollister, D.; Pyeritz, R. E.;
Dittrich, H.; Polikar, R.; Peterson, K. L.: Familial aortic dissecting
aneurysm. J. Am. Coll. Cardiol. 13: 811-819, 1989.

6. Pannu, H.; Fadulu, V. T.; Chang, J.; Lafont, A.; Hasham, S. N.;
Sparks, E.; Giampietro, P. F.; Zaleski, C.; Estrera, A. L.; Safi,
H. J.; Shete, S.; Willing, M. C.; Raman, C. S.; Milewicz, D. M.:
Mutations in transforming growth factor-beta receptor type II cause
familial thoracic aortic aneurysms and dissections. Circulation 112:
513-520, 2005.

7. Tran-Fadulu, V.; Pannu, H.; Kim, D. H.; Vick, G. W., III; Lonsford,
C. M.; Lafont, A. L.; Boccalandro, C.; Smart, S.; Peterson, K. L.;
Hain, J. Z.; Willing, M. C.; Coselli, J. S.; LeMaire, S. A.; Ahn,
C.; Byers, P. H.; Milewicz, D. M.: Analysis of multigenerational
families with thoracic aortic aneurysms and dissections due to TGFBR1
or TGFBR2 mutations. J. Med. Genet. 46: 607-613, 2009.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Mouth];
Bifid uvula (in some patients)

CARDIOVASCULAR:
[Vascular];
Ascending aortic aneurysm;
Ascending aortic dissection;
Arterial aneurysm and/or dissection (abdominal aorta, carotid, and
coronary arteries);
Arterial tortuosity, generalized;
Vascular rupture during pregnancy;
Loss of elastic fibers of aortic wall;
Deposition of mucopolysaccharide-like material in the media;
Erdheim cystic medial necrosis

ABDOMEN:
[Gastrointestinal];
Bowel rupture (some)

GENITOURINARY:
[External genitalia, female];
Inguinal hernia (some);
[Internal genitalia, female];
Uterine hemorrhage (some)

SKELETAL:
Joint laxity

SKIN, NAILS, HAIR:
[Skin];
Velvety skin;
Translucent skin;
Atrophic scars (rare);
Skin hyperextensibility (rare);
Easy bruisability

MISCELLANEOUS:
Average age of onset earlier with TGFBR1 mutations;
Men present with vascular disease earlier than women (23 vs 39 years);
Survival worse in men than women

MOLECULAR BASIS:
Caused by mutation in the transforming growth factor, beta receptor
I gene (TGFBR1, 190181.0004)

*FIELD* CN
Marla J. F. O'Neill - updated: 10/25/2011

*FIELD* CD
Marla J. F. O'Neill: 3/17/2008

*FIELD* ED
joanna: 10/25/2011
alopez: 3/17/2008

*FIELD* CN
Marla J. F. O'Neill - updated: 7/6/2010
Marla J. F. O'Neill - updated: 1/28/2010
Cassandra L. Kniffin - updated: 5/6/2008
Victor A. McKusick - updated: 12/13/2005

*FIELD* CD
Marla J. F. O'Neill: 10/13/2004

*FIELD* ED
alopez: 03/09/2011
wwang: 7/13/2010
wwang: 7/12/2010
terry: 7/6/2010
wwang: 2/2/2010
terry: 1/28/2010
alopez: 6/24/2008
wwang: 5/13/2008
ckniffin: 5/6/2008
alopez: 3/7/2008
alopez: 3/6/2008
wwang: 3/14/2006
alopez: 2/24/2006
terry: 12/13/2005
carol: 10/13/2004

MIM 609192
*RECORD*
*FIELD* NO
609192
*FIELD* TI
#609192 LOEYS-DIETZ SYNDROME, TYPE 1A; LDS1A
;;FURLONG SYNDROME;;
LOEYS-DIETZ AORTIC ANEURYSM SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
Loeys-Dietz syndrome type 1, designated LDS1A, is caused by heterozygous
mutation in the TGFBR1 gene (190181) on chromosome 9q22.

DESCRIPTION

The Loeys-Dietz syndrome (LDS) is an autosomal dominant aortic aneurysm
syndrome with widespread systemic involvement. As defined by Loeys et
al. (2006), the disorder is characterized by the triad of arterial
tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft
palate. Patients with LDS type 1 have craniofacial involvement
consisting of cleft palate, craniosynostosis, or hypertelorism. Patients
with LDS type 2 do not have these findings, but some have a bifid uvula.
The natural history of both types is characterized by aggressive
arterial aneurysms and a high rate of pregnancy-related complications.

- Genetic Heterogeneity of Loeys-Dietz Syndrome

LDS1A and LDS2A (608967) are both caused by mutation in the TGFBR1 gene;
LDS1B (610168) and LDS2B (610380) are both caused by mutation in the
TGFBR2 gene (190182). LDS1A and LDS1B are clinically indistinguishable,
as are LDS2A and LDS2B.

Another form of Loeys-Dietz syndrome (LDS3; 613795), which is associated
with early-onset osteoarthritis, is caused by mutation in the SMAD3 gene
(603109).

LDS4 is caused by mutation in the TGFB2 gene (190220).

CLINICAL FEATURES

Furlong et al. (1987) described a male of normal height and intelligence
with dolichocephaly, a high palate, dolichostenomelia, a mild scoliosis,
L4-5 spondylolisthesis, long thorax, prominent pectus carinatum,
camptodactyly, pes planus, mitral valve insufficiency, bilateral
recurrent inguinal herniae, myopia with normal lenses, mitral valve
prolapse, and a dilated aortic root which subsequently dissected at age
18 years. Features atypical for Marfan syndrome (154700) included
multisutural craniosynostosis, ptosis, hypertelorism, and hypospadias.

The patient of Lacombe and Battin (1993) had sagittal craniosynostosis,
marfanoid habitus, cleft palate and micrognathia, and aortic root
dilatation but normal height and intelligence. Pronounced craniofacial
dysmorphism (scaphocephaly, facial asymmetry, unilateral ptosis, orbital
dystopia, downslanting palpebral fissures) was reminiscent of that seen
in Shprintzen-Goldberg syndrome (SGS; 182212). Other features included
arachnodactyly, camptodactyly, kyphoscoliosis, and normal lenses.

Megarbane and Hokayem (1998) described the osseous findings in a
16-year-old male with marfanoid habitus and craniosynostosis.
Observations included dolichocephaly, malar hypoplasia, low set,
posteriorly rotated ears, ptosis, downslanting palpebral fissures, and
microretrognathia. Prominent pectus carinatum, kyphoscoliosis, and
limited mobility at the elbows were present, as well as camptodactyly of
the fourth and fifth fingers and fifth finger clinodactyly. Flat feet,
long toes, and hallux valgus were observed. Echocardiography documented
aortic root dilatation. Although early psychomotor development was
delayed, intelligence was normal. The authors described radiologic
abnormalities that included atlantooccipital joint dislocation, biconvex
vertebral bodies, a fusion defect of the dorsal arches of L4 and L5,
hypoplasia of the posterior arches of L5 and S1, and elongated
diaphyses. Megarbane and Hokayem (1998) considered the clinical findings
of their propositus to be similar to those reported by Furlong et al.
(1987).

Lacombe and Battin (1993) compared their case with that of Furlong et
al. (1987) and 3 other cases. They suggested that the 5 patients might
represent variable expressivity of the same syndrome with mental
retardation as an inconstant feature, or that there may be 2 distinct
syndromes, one with mental retardation (Shprintzen-Goldberg syndrome;
182212) and one without (Furlong syndrome). Megarbane and Hokayem (1998)
noted similarities between Shprintzen-Goldberg syndrome and Furlong
syndrome and proposed dividing craniosynostosis with marfanoid habitus
into 2 types, nominating type 1 as Shprintzen-Goldberg syndrome and type
2 as those with normal intelligence, aortic root abnormalities, and mild
skeletal dysplasia.

Loeys et al. (2005) described 10 families with a previously undescribed
aortic aneurysm syndrome characterized by hypertelorism, bifid uvula
and/or cleft palate, and generalized arterial tortuosity with ascending
aortic aneurysm and dissection. The syndrome showed autosomal dominant
inheritance and variable clinical expression. Other findings in multiple
systems included craniosynostosis, structural brain abnormalities,
mental retardation, congenital heart disease, and aneurysms with
dissection throughout the arterial tree.

Loeys et al. (2005) noted that some individuals with LDS had phenotypes
that overlapped to some extent with that of Marfan syndrome (MFS;
154700), but none met the diagnostic criteria for MFS (De Paepe et al.,
1996). All individuals with LDS had manifestations in multiple organ
systems that are not associated with MFS. In these individuals,
aneurysms tended to be particularly aggressive and to rupture at an
early age or to be of a size not associated with high risk in MFS. From
a management prospective, the distinction from MFS is neither ambiguous
nor unimportant.

Loeys et al. (2006) presented the clinical characteristics of the series
of 40 probands, including the 10 previously described patients (Loeys et
al., 2005). Besides the triad of hypertelorism, cleft palate or bifid
uvula, and arterial tortuosity with aneurysms, patients in this group
had additional cardiovascular, skeletal, and cutaneous findings.
Neurocognitive signs included delayed development in 6 patients,
hydrocephalus in 6 patients, and Arnold-Chiari malformation in 4
patients. When present, delayed development was not always associated
with craniosynostosis or hydrocephalus, suggesting that learning
disability is a rare primary manifestation. No patient had ectopia
lentis, and few patients (18%) had dolichostenomelia.

Loeys et al. (2006) stated that using 3-dimensional reconstruction of
images from the head to the pelvis obtained by computed tomography with
intravenous contrast material or magnetic resonance angiography, they
identified aneurysms distant from the aortic root in 53% of their
patients with LDS type 1; these aneurysms were not detected with the use
of echocardiography. Most of these lesions were amenable to surgical
repair. This imaging technique also detected arterial tortuosity, a
finding of diagnostic importance.

Loeys et al. (2006) noted that the natural history of both types of LDS
among 52 probands was characterized by aggressive arterial aneurysms
(mean age at death, 26.0 years) and a high incidence of
pregnancy-related complications (in 6 of 12 women). Patients with
Loeys-Dietz syndrome type 1, as compared with those with type 2,
underwent cardiovascular surgery earlier (mean age, 16.9 years vs 26.9
years) and died earlier (22.6 years vs 31.8 years). There were 59
vascular surgeries in the cohort, with one death during the procedure.
This low rate of intraoperative mortality distinguishes the Loeys-Dietz
syndrome from vascular EDS.

MOLECULAR GENETICS

In 4 families with Loeys-Dietz syndrome who did not carry a mutation in
TGFBR2 (190182), Loeys et al. (2005) identified a unique missense
mutation in TGFBR1 (190181). Two mutations occurred in the kinase
domain, one occurred at the junction of the glycine-serine-rich domain
and kinase domain, and one occurred just past the kinase domain at the C
terminus. Loeys et al. (2006) added observations on 30 new probands with
a phenotype consistent with LDS type 1. Of the 30 newly identified
probands, 9 had mutations in TGFBR1 and 21 had mutations in TGFBR2.

Ades et al. (2006) found that 2 patients with a phenotype resembling
Furlong syndrome were heterozygous for the same de novo missense
mutation in the TGFBR1 gene (190181.0005).

In 7 individuals referred with classic MFS in whom no mutation in
fibrillin-1 (FBN1; 134797) was found, Loeys et al. (2005) sequenced the
TGFBR1 and TGFBR2 genes and found no mutations.

At the extreme of clinical severity some individuals with LDS had
phenotypes that overlapped considerably with the Shprintzen-Goldberg
craniosynostosis syndrome (SGS; 182212), also known as the marfanoid
craniosynostosis syndrome. However, SGS is not associated with cleft
palate, arterial tortuosity, or risk of aneurysm or dissection other
than at the aortic root, and most affected individuals demonstrate no
vascular pathology. Loeys et al. (2005) found no mutations in the TGFBR1
and TGFBR2 genes in 5 individuals with classic SGS. Nevertheless, given
the extent of phenotypic overlap between SGS, MFS, and selected
individuals with mutations in either TGFBR1 or TGFBR2, Loeys et al.
(2005) concluded that the pathogenesis of SGS probably relates to
alteration in TGF-beta (190180) signaling.

*FIELD* RF
1. Ades, L. C.; Sullivan, K.; Biggin, A.; Haan, E. A.; Brett, M.;
Holman, K. J.; Dixon, J.; Robertson, S.; Holmes, A. D.; Rogers, J.;
Bennetts, B.: FBN1, TGFBR1, and the Marfan-craniosynostosis/mental
retardation disorders revisited. Am. J. Med. Genet. 140A: 1047-1058,
2006.

2. De Paepe, A.; Devereux, R. B.; Dietz, H. C.; Hennekam, R. C. M.;
Pyeritz, R. E.: Revised diagnostic criteria for the Marfan syndrome. Am.
J. Med. Genet. 62: 417-426, 1996.

3. Furlong, J.; Kurczynski, T. W.; Hennessy, J. R.: New marfanoid
syndrome with craniosynostosis. Am. J. Med. Genet. 26: 599-604,
1987.

4. Lacombe, D.; Battin, J.: Marfanoid features and craniosynostosis:
report of one case and review. Clin. Dysmorph. 2: 220-224, 1993.

5. Loeys, B. L.; Chen, J.; Neptune, E. R.; Judge, D. P.; Podowski,
M.; Holm, T.; Meyers, J.; Leitch, C. C.; Katsanis, N.; Sharifi, N.;
Xu, F. L.; Myers, L. A.; and 12 others: A syndrome of altered cardiovascular,
craniofacial, neurocognitive and skeletal development caused by mutations
in TGFBR1 or TGFBR2. Nature Genet. 37: 275-281, 2005.

6. Loeys, B. L.; Schwarze, U.; Holm, T.; Callewaert, B. L.; Thomas,
G. H.; Pannu, H.; De Backer, J. F.; Oswald, G. L.; Symoens, S.; Manouvrier,
S.; Roberts, A. E.; Faravelli, F.; and 9 others: Aneurysm syndromes
caused by mutations in the TGF-beta receptor. New Eng. J. Med. 355:
788-798, 2006.

7. Megarbane, A.; Hokayem, N.: Craniosynostosis and marfanoid habitus
without mental retardation: report of a third case. (Letter) Am.
J. Med. Genet. 77: 170-171, 1998.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Dolichostenomelia (uncommon)

HEAD AND NECK:
[Face];
Micrognathia;
Retrognathia;
[Eyes];
Hypertelorism;
Exotropia;
Blue sclerae;
Proptosis;
[Mouth];
Bifid uvula;
Cleft palate (uncommon)

CARDIOVASCULAR:
[Heart];
Atrial septal defect (uncommon);
Bicuspid aortic valve (uncommon);
Bicuspid pulmonary valve (rare);
Mitral valve prolapse (uncommon);
[Vascular];
Arterial tortuosity, generalized;
Patent ductus arteriosus;
Ascending aortic aneurysm;
Ascending aortic dissection;
Pulmonary artery aneurysm;
Descending aortic aneurysm (uncommon);
Cerebral aneurysm (uncommon)

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

SKELETAL:
Joint laxity;
[Skull];
Craniosynostosis (uncommon);
Malar hypoplasia;
[Spine];
Scoliosis;
[Hands];
Arachnodactyly;
Camptodactyly;
Postaxial polydactyly (rare);
[Feet];
Talipes equinovarus

SKIN, NAILS, HAIR:
[Skin];
Velvety texture;
Translucent skin

NEUROLOGIC:
[Central nervous system];
Mental retardation (uncommon);
Developmental delay (uncommon);
Chiari malformation (uncommon);
Hydrocephalus (uncommon)

MISCELLANEOUS:
Genetic heterogeneity (see 610168);
Uncommon and rare features seen in the most severely affected patients

MOLECULAR BASIS:
Caused by mutation in the transforming growth factor, beta receptor
I, 53kD gene (TGFBR1, 190181.0001)

*FIELD* CN
Ada Hamosh - reviewed: 4/5/2005

*FIELD* CD
Joanna S. Amberger: 4/5/2005

*FIELD* ED
joanna: 12/01/2008
alopez: 3/17/2008
ckniffin: 5/22/2007
joanna: 4/5/2005

*FIELD* CN
Marla J. F. O'Neill - updated: 9/11/2012
Marla J. F. O'Neill - updated: 3/7/2011
Marla J. F. O'Neill - updated: 7/6/2010
Anne M. Stumpf - reorganized: 3/6/2008
Victor A. McKusick - updated: 9/20/2006
Marla J. F. O'Neill - updated: 3/7/2006
Victor A. McKusick - updated: 8/19/2005

*FIELD* CD
Victor A. McKusick: 2/4/2005

*FIELD* ED
alopez: 09/12/2012
terry: 9/11/2012
carol: 9/6/2012
alopez: 3/9/2011
carol: 3/7/2011
wwang: 7/13/2010
terry: 7/6/2010
alopez: 3/10/2008
alopez: 3/7/2008
alopez: 3/6/2008
alopez: 10/11/2006
terry: 9/20/2006
wwang: 3/7/2006
terry: 1/25/2006
terry: 8/19/2005
carol: 5/10/2005
alopez: 4/27/2005
alopez: 3/2/2005
alopez: 2/9/2005
alopez: 2/7/2005