TABLE 1.
Monogenic diseases associated with TGFβ pathway components.
| Gene and Ensemble ID | Protein | Monogenic Disease/OMIM reference | Examples of pathological variants (Nucleotide/Amino acid change) | References |
| ACVRL1 ENSG00000139567 | Alk1 | *(1) Hereditary hemorrhagic telangiectasia syndrome 2 (HHT2; 600376) (AD) | (1) c.1127T > G/p.M376R | Johnson et al., 1996 |
| ACVR1 ENSG00000115170 | Activin A receptor type 1 Alk2 | (1) Fibrodysplasia ossificans progressiva (FOP; 135100) (A/D) | (1) c.617G > A/p.R206H | Shore et al., 2006 |
| TGFBR1 ENSG00000106799 | TGF beta receptor type1 Alk5 | (1) Loeys-Dietz syndrome 1 (LDS1; 609192). (2) Multiple self-healing squamous epithelioma (MSSE; 132800) | (1) c.559C > T/p.T200I | Loeys et al., 2005 Ferguson-Smith et al., 1971 |
| BMPR1A ENSG00000107779 | Bone Morphogenetic Protein Receptor Type 1A Alk3 | (1) Juvenile polyposis syndrome (JPS; 174900) (A/D). (2) Polyposis syndrome, mixed hereditary 2 (HMPS2; 610069) (A/D) | (1) c.715C > T/p. Q239Term (2) c.127_137del11/p.L43T(fs*24) | Howe et al., 2001 Cao et al., 2006 |
| BMPR1B ENSG00000138696 | Bone Morphogenetic Protein Receptor Type 1B Alk6 | (1) Acromesomelic dysplasia, Demirhan type (AMDD; 609441) (A/R). (2) Brachydactyly A2 (BDA2; 112600) (A/D) (3) Brachydactyly A1, D (BDA1D; 616849) (A/D) | (1) c.361_368delGGACCTAT/p.G121T (fs*13) (2) c.1457G > A/p.R486Q (3) c.975A > C/p.K325N | Demirhan et al., 2005 Lehmann et al., 2003 Racacho et al., 2015 |
| TGFBR2 ENSG00000163513 | Transforming growth factor beta receptor 2 | (1) Loeys-Dietz syndrome 2 (LDS2; 610168). (2) Hereditary non-polyposis colorectal cancer 6 (HNPCC6; 614331) (AD) | c.859T > C/p.W28R c.1063G > A/p. A355T | Boileau et al., 1993 Markowitz et al., 1995 |
| BMPR2 ENSG00000204217 | Bone Morphogenetic Protein Receptor Type 2 | *(1) Pulmonary hypertension, primary, 1 (PPH1;17860) (AD) (2) Pulmonary venoocclusive disease 1; (PVOD1;265450) (AD) | (1) c.218C > G/p.S73Term. (2) c.727G > T/p.E243Term | Lane et al., 2000 Machado et al., 2001 |
| ACVR2B ENSG00000114739 | Activin A receptor type 2B | (1) Visceral heterotaxia4 (HTX4; 613751) (AR). | (1) c.119G > A/p.R40H | Kosaki et al., 1999 |
| AMHR2 ENSG00000135409 | Anti-Mullerian Hormone Receptor Type 2 | (1) Persistent Muellerian duct syndrome type 2 (PMDS2; 261550) (AR) | (1) c.118G > T/p.G40Term | Imbeaud et al., 1995 |
| ENG ENSG00000106991 | Endoglin | *(1) Hereditary hemorrhagic telangiectasia syndrome 1 (HHT1; 187300) (AD) | (1) (Trp196Term/c.587G > A) | McAllister et al., 1994 |
| BMP1 ENSG00000168487 | Bone Morphogenetic Protein 1 | (1) Osteogenesis imperfecta 13 (OI13; 614856) | (1) c.747C > G/p.F249L | Martínez-Glez et al., 2012 |
| BMP2 ENSG00000125845 | Bone Morphogenetic Protein 2 | (1) Brachydactyly A2 (BDA2;112600) (A/D) (2) Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies (SSFSC; 617877) (A/D) | (1) (Duplication)5547 bp, ∼110 kb downstream of gene (2) c.79G > T/p.E27Term | Dathe et al., 2009 Tan et al., 2017 |
| BMP4 ENSG00000125378 | Bone Morphogenetic Protein 4 | (1) Microphthalmia, Syndromic 6 (A/D) (MCOPS6; 607932) (2) orofacial cleft 11 (OFC11; 600625) | (1) c.278A > G/p.E93G (2) c.485G > A/p.R162Q | Bakrania et al., 2008 Suzuki et al., 2009 |
| BMP9/GDF2 ENSG00000263761 | Morphogenetic Protein9/Growth Differentiation Factor 2 | (1) Hereditary hemorrhagic telangiectasia type5 (HHT5; 615506) (AD) | c.76C > T/p.q26Term. | Wang et al., 2016 |
| GDF1 ENSG00000130283 | Growth Differentiation Factor 1 | (1) Congenital heart defects, multiple types, 6 (CHTD6; 613854) (AD). (2) Right atrial isomerism (RAI; 208530) | (1) c.203G > A/p.R68H (2) c.1322T > C/L441P | Karkera et al., 2007 Eronen et al., 2004 |
| GDF3 ENSG00000184344 | Growth Differentiation Factor 3 | (1) Klippel-feil syndrome 3 (KFS3; 613702) (AD). (2) Microphthalmia, isolated, 7 (MCOP7; 613704) (AD). (3) Microphthalmia, isolated, with Coloboma 6 (MCOPCB6; 613703) (AD). | (1) c.796C > T/p.R266C (2) c.914T > C/p.R195Q (3) c820C > T/p R274W | Ye et al., 2010 |
| GDF5 ENSG00000125965 | Growth Differentiation Factor 5 | (1) Acromesomelic chondrodysplasia Hunter-Thomson type (AMDH;201250) (AR). (2) Acromesomelic chondrodysplasia, Grebe type (AMDG; 200700) (AR) (3) Brachydactyly C (BDC;113100) (AD and AR) (4) Du Pan syndrome (DUPANS; 228900) (AR) (5) Symphalangism, proximal 1B (SYM1B; 615298) (6) Multiple synostoses syndrome 2 (SYNS2; 610017). (7) Brachydactyly A2 (BDA2; 112600). (8) Osteoarthritis 5 (OS5; 612400) (9) Brachydactyly A1, C (BDA1C; 615072) | (1/2) c.1199G > A/p.C400Y (3) c.122delG/p.(Gly41Aspfs*46) (4) c.1322T > C/p.L441P (5) c.1313G > T/p.R438L (7) c.1139G > A/p.R380Q (8) c.-275C > T (Regulatory) (9) c.1195C > T/p.R399C | Thomas et al., 1997 Polinkovsky et al., 1997 Faiyaz-Ul-Haque et al., 2002 Seemann et al., 2005 Plöger et al., 2008 Miyamoto et al., 2007,Byrnes et al., 2010 |
| TGFb1 ENSG00000105329 | Transforming Growth Factor Beta 1 | (1) Camurati-Engelmann disease (CAEND; 131300) (2) Inflammatory bowel disease, immunodeficiency and encephalopathy (IBDIMDE; 618213) | (1) c.652C > T/p.R218C (2) c.328C > T/p.R110C | Kinoshita et al., 2000 Kotlarz et al., 2018 |
| TGFb2 ENSG00000092969 | Transforming Growth Factor Beta2 | (1) Loeys-Dietz syndrome 4 LDS4; 614816 (AD) | (1) c.297C > A/p.Y99Term. | Lindsay et al., 2012 |
| TGFb3 ENSG00000119699 | Transforming Growth Factor Beta | (1) Loeys-Dietz syndrome 4 (LDS5; 615582) (AD) (2) Arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970) | (1) c.1226G > A/p.C409Y (2) c.-30G > A (Regulatory) | Rienhoff et al., 2013 Rampazzo et al., 2003; Beffagna et al., 2005 |
| SMAD3 ENSG00000166949 | SMAD Family Member | (1) Loeys-Dietz syndrome 3 (LDS3; 613795) (AD) | (1) c.782C > T/p.T261I | van de Laar et al., 2011 |
| SMAD4 ENSG00000141646 | SMAD Family Member | (1) Juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia syndrome (JPS; 174900) (AD) (2) (JP/HHT) (JPHT, 175050) (AD), (3) Myhre syndrome (MYHRS; 139210) | (1) c.1042_1043delGT/p.(Val348Tyrfs*3) (2) c.1157G > A/p.G386D (3) c.1500A > G/p.I500M | Howe et al., 1998 Burger et al., 2002 Le Goff et al., 2011 |
| SMAD6 ENSG00000137834 | SMAD Family Member | (1) Aortic valve disease (AOVD2; 614823) (2) Craniosynostosis (CRS7; 617439) (3) Radioulnar synostosis (RUS; 179300) | (1) c.1244C > T/p.P415L (2) c.968C > T/p.P323L (3) c.461G > A/p.G154D | Tan et al., 2012 Timberlake et al., 2016 Yang et al., 2019 |
| SMAD8/9 ENSG00000120693 | SMAD Family Member | (1) Primary pulmonary hypertension 2 (PPH2; 615342) | (1) c.606C > A/p.C202* | Shintani et al., 2009 |
The table lists all SMAD-regulated components of the TGFβ signaling pathway and associated monogenic diseases. Components with no identified association are (ACVR1B, ACVR1C, ACVR2A, TGFBR3, INHBA, Inhibin subunits A, B, BB and C, BMP 3, 5, 6, 7 and 10, GDF7, SMAD 1, 2, 5 and 7). Genetic diseases found to have a possible ERAD pathology are denoted with an asterisk*. AR, autosomal recessive; AD, autosomal dominant.