1ktz

Structural highlights

Disease

[TGFB3_HUMAN] Defects in TGFB3 are a cause of familial arrhythmogenic right ventricular dysplasia type 1 (ARVD1) [MIM:107970]; also known as arrhythmogenic right ventricular cardiomyopathy 1 (ARVC1). ARVD is an autosomal dominant disease characterized by partial degeneration of the myocardium of the right ventricle, electrical instability, and sudden death. It is clinically defined by electrocardiographic and angiographic criteria; pathologic findings, replacement of ventricular myocardium with fatty and fibrous elements, preferentially involve the right ventricular free wall.^[1] [TGFR2_HUMAN] Defects in TGFBR2 are the cause of hereditary non-polyposis colorectal cancer type 6 (HNPCC6) [MIM:614331]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term "suspected HNPCC" or "incomplete HNPCC" can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. HNPCC6 is a type of colorectal cancer complying with the clinical criteria of HNPCC, except that the onset of cancer was beyond 50 years of age in all cases.^[2] Defects in TGFBR2 are a cause of esophageal cancer (ESCR) [MIM:133239]. Defects in TGFBR2 are the cause of Loeys-Dietz syndrome type 1B (LDS1B) [MIM:610168]. LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.^{[3] [4] [5] [6] [7] [8]} Defects in TGFBR2 are the cause of Loeys-Dietz syndrome type 2B (LDS2B) [MIM:610380]. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include 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. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR2 mutations Cys-460 and His-460 have been reported to be associated with thoracic aortic aneurysms and dissection (TAAD). This phenotype, also known as thoracic aortic aneurysms type 3 (AAT3), is distinguised from LDS2B by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit descending aortic disease and aneurysms of other arteries (PubMed:16027248), they have been considered as LDS2B by the OMIM resource.

Function

[TGFB3_HUMAN] Involved in embryogenesis and cell differentiation. [TGFR2_HUMAN] Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFRB1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways.^[9]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, Bauce B, Carraro G, Thiene G, Towbin JA, Danieli GA, Rampazzo A. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res. 2005 Feb 1;65(2):366-73. PMID:15639475 doi:S0008-6363(04)00440-7
2. ↑ Lu SL, Kawabata M, Imamura T, Akiyama Y, Nomizu T, Miyazono K, Yuasa Y. HNPCC associated with germline mutation in the TGF-beta type II receptor gene. Nat Genet. 1998 May;19(1):17-8. PMID:9590282 doi:10.1038/ng0598-17
3. ↑ Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, De Paepe AM, Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar;37(3):275-81. Epub 2005 Jan 30. PMID:15731757 doi:ng1511
4. ↑ Disabella E, Grasso M, Marziliano N, Ansaldi S, Lucchelli C, Porcu E, Tagliani M, Pilotto A, Diegoli M, Lanzarini L, Malattia C, Pelliccia A, Ficcadenti A, Gabrielli O, Arbustini E. Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects. Eur J Hum Genet. 2006 Jan;14(1):34-8. PMID:16251899 doi:10.1038/sj.ejhg.5201502
5. ↑ Muramatsu Y, Kosho T, Magota M, Yokotsuka T, Ito M, Yasuda A, Kito O, Suzuki C, Nagata Y, Kawai S, Ikoma M, Hatano T, Nakayama M, Kawamura R, Wakui K, Morisaki H, Morisaki T, Fukushima Y. Progressive aortic root and pulmonary artery aneurysms in a neonate with Loeys-Dietz syndrome type 1B. Am J Med Genet A. 2010 Feb;152A(2):417-21. doi: 10.1002/ajmg.a.33263. PMID:20101701 doi:10.1002/ajmg.a.33263
6. ↑ Kirmani S, Tebben PJ, Lteif AN, Gordon D, Clarke BL, Hefferan TE, Yaszemski MJ, McGrann PS, Lindor NM, Ellison JW. Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome. Am J Med Genet A. 2010 Apr;152A(4):1016-9. doi: 10.1002/ajmg.a.33356. PMID:20358619 doi:10.1002/ajmg.a.33356
7. ↑ Yang JH, Ki CS, Han H, Song BG, Jang SY, Chung TY, Sung K, Lee HJ, Kim DK. Clinical features and genetic analysis of Korean patients with Loeys-Dietz syndrome. J Hum Genet. 2012 Jan;57(1):52-6. doi: 10.1038/jhg.2011.130. Epub 2011 Nov 24. PMID:22113417 doi:10.1038/jhg.2011.130
8. ↑ Ha JS, Kim YH. A sporadic case of Loeys-Dietz syndrome type I with two novel mutations of the TGFBR2 gene. Korean J Pediatr. 2011 Jun;54(6):272-5. doi: 10.3345/kjp.2011.54.6.272. Epub 2011, Jun 30. PMID:21949523 doi:10.3345/kjp.2011.54.6.272
9. ↑ Wieser R, Wrana JL, Massague J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J. 1995 May 15;14(10):2199-208. PMID:7774578
10. ↑ Hart PJ, Deep S, Taylor AB, Shu Z, Hinck CS, Hinck AP. Crystal structure of the human TbetaR2 ectodomain--TGF-beta3 complex. Nat Struct Biol. 2002 Mar;9(3):203-8. PMID:11850637 doi:http://dx.doi.org/10.1038/nsb766