Table 1.
Genetic defects in the cardiovascular (CV) system
| Protein (gene name) | Age of death | CV phenotype, animal model | Human genetic CV disorder | References |
|---|---|---|---|---|
| TGF-β1 (TGFB1) | E8.5–adult | Owing to gene modifier, ranging from embryonic lethal with (yolk sac) vascular defects to postnatal lethality, caused by autoimmune disease | No CV malformations | Letterio et al. 1994; Goumans and Mummery 2000; Tang et al. 2005 |
| TGF-β2 (TGFB2) | P0 | Defect in cardiac septation and valve remodeling | Loeys–Dietz syndrome type 4; syndromic TAA disorder; Kawasaki disease | Sanford et al. 1997; Azhar et al. 2011; Shimizu et al. 2011; Lindsay et al. 2012; Kruithof et al. 2013; Leutermann et al. 2014 |
| TGF-β3 (TGFB3) | P0 | Defect in pulmonary development and cleft palate. No CV disease | Unknown | Kaartinen et al. 1995; Proetzel et al. 1995 |
| BMP-9 (BMP9) | Viable | Defects in lymphatic drainage, retina vascularization, and valve maturation | Vascular anomaly similar to HHT | Ricard et al. 2012; Levet et al. 2013; Wooderchak-Donahue et al. 2013 |
| TβRII (TGFBR2) | E10.5 | Abnormal development of yolk sac vasculature and capillary vessel formation in the embryo | Loeys–Dietz syndrome types 1 and 2; MFS | Oshima et al. 1996; Loeys et al. 2005, 2006; Stheneur et al. 2008 |
| BMPRII (BMPR2) | E6.5–E9.5 | Defect in mesoderm induction; heterogenic: pulmonary hypertension | PAH; HHT | Beppu et al. 2000, 2004; Lane et al. 2000; Soubrier et al. 2013 |
| TβRI/ ALK-5 (TGFBR1) | E10.5 | Abnormal angiogenesis, impaired EC migration, and fibronectin production | Loeys–Dietz syndrome type 1 | Larsson et al. 2001; Loeys et al. 2005, 2006 |
| ALK-1 (ACVRL1) | E11.5 | Abnormal angiogenesis, impaired differentiation, and SMC recruitment | HHT-2; PAH | Johnson et al. 1995; Oh et al. 2000; Urness et al. 2000; Fujiwara et al. 2008; Soubrier et al. 2013 |
| Endoglin (ENG) | E10.5–11.5 | Angiogenesis defect, arrested remodeling and SMC development, cardiac defects; heterogenic: HHT | HHT-1 | McAllister et al. 1994; Bourdeau et al. 1999; Li et al. 1999; Arthur et al. 2000 |
| TβRIII/ betaglycan (TGFBR3) | E16.5–P0 | Defect in compaction of ventricular wall and cardiac septation | Unknown | Stenvers et al. 2003 |
| Smad1 (SMAD1) | E9.5 | No allantois formed; disorganized vessels | Unknown | Lechleider et al. 2001 |
| Smad3 (SMAD3) | Viable | Accelerated wound healing; aortic aneurysm | Aneurysm-osteoarthritis syndrome | Ashcroft et al. 1999; van de Laar et al. 2011; van der Linde et al. 2012; Tan et al. 2013; Wischmeijer et al. 2013 |
| Smad4 (SMAD4) | <E7.5 | Gastrulation defect, defect in visceral endoderm differentiation | Myhre syndrome, HHT | Sirard et al. 1998; Yang et al. 1998; Piccolo et al. 2014 |
| Smad5 (SMAD5) | E9.5–10.5 | Defect in angiogenesis, ectopic vascularization | No CV syndrome | Chang et al. 1999, 2000; Yang et al. 1999 |
| Smad6 (SMAD6) | Cardiovascular abnormalities, defect in endocardial cushion formation | BAV | Galvin et al. 2000 | |
| Fibrillin-1 (FBN1) | P0 | Aortic aneurysm and rupture, impaired pulmonary function. | MFS1 | Carta et al. 2006 |
| Fibrillin-2 (FBN2) | Viable | No CV defects | No CV syndrome | Arteaga-Solis et al. 2011 |
| Fibrillin-1/2 (FBN1/2) | E14.5–16.5 | Defects in fiber formation of aortic wall, aortic aneurysms | No CV syndrome | Carta et al. 2006 |
| LTBP-1 (LTBP1) | P0 | Persistent truncus arteriosus and aortic arch defects | No CV syndrome | Todorovic et al. 2007 |
| LTBP-3 (LTBP3) | Thoracic aneurism | No CV syndrome | Zilberberg et al. 2015 | |
| LTBP-4 (LTBP4) | P9-14 | Pulmonary emphysema and cardiomyopathy | ARCL1C | Bultmann-Mellin et al. 2015 |
| LTBP-4S | Adult | Cardiomyopathy | ARCL1C | Sterner-Kock et al. 2002 |
| Thrombo-spondin-1 (THBS1) | 4 wk | Cerebral hemorrhages | No CV syndrome | Crawford et al. 1998 |
TAA, Thoracic aortic aneurysm; HHT, hereditary hemorrhagic telangiectasia; PAH, pulmonary arterial hypertension; EC, endothelial cell; SMCs, smooth muscle cells; BAV, bicuspid aortic valve; MFS, Marfan syndrome; ARCL1C, autosomal-recessive cutis laxa type IC.