SMAD6-deficiency in human genetic disorders

Abstract

SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, SMAD6-deficiency has been associated with three distinctive human congenital conditions, i.e., congenital heart diseases, including left ventricular obstruction and conotruncal defects, craniosynostosis and radioulnar synostosis. Intriguingly, a similar spectrum of heterozygous loss-of-function variants has been reported to cause these clinically distinct disorders without a genotype–phenotype correlation. Even identical nucleotide changes have been described in patients with either a cardiovascular phenotype, craniosynostosis or radioulnar synostosis. These findings suggest that the primary pathogenic variant alone cannot explain the resultant patient phenotype. In this review, we summarise clinical and (patho)genetic (dis)similarities between these three SMAD6-related conditions, compare published Madh6 mouse models, in which the importance and impact of the genetic background with respect to the observed phenotype is highlighted, and elaborate on the cellular key mechanisms orchestrated by SMAD6 in the development of these three discrete inherited disorders. In addition, we discuss future research needed to elucidate the pathogenetic mechanisms underlying these diseases in order to improve their molecular diagnosis, advance therapeutic strategies and facilitate counselling of patients and their families.

Whole Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families with Early Onset Complications

“…SMAD6 encodes an inhibitor of bone morphogenic protein signaling and is highly expressed in cardiac valves and the aortic root (23,24). SMAD6 mutations have been described in 3-9% of individuals with BAV and TAA, including predicted loss of function mutations that are similar to the frameshifts and indel that we identified in 3 EBAV probands (25,26). The SMAD6 mutant phenotype frequently includes other left ventricular obstructive lesions, such as coarctation and HLHS, as well as conotruncal defects, and these variable phenotypes are recapitulated in mice with knockout of the SMAD6 analog Madh6 (23,26–28).…”

“…SMAD6 mutations have been described in 3-9% of individuals with BAV and TAA, including predicted loss of function mutations that are similar to the frameshifts and indel that we identified in 3 EBAV probands (25,26). The SMAD6 mutant phenotype frequently includes other left ventricular obstructive lesions, such as coarctation and HLHS, as well as conotruncal defects, and these variable phenotypes are recapitulated in mice with knockout of the SMAD6 analog Madh6 (23,26–28). There is some evidence that SMAD6 functions downstream of NOTCH1 signaling to regulate endothelial cell motility and adhesion (28).…”

Early mechanisms of aortic failure in a zebrafish model for thoracic aortic dissection and rupture

“…Other features include arterial tortuosity, mitral valve prolapse and craniofacial characteristics 2,9 . Pathogenic variants in SMAD6 are associated with craniosynostosis 10 , radio-ulnar synostosis 11 or congenital heart disease including bicuspid aortic valve 12 with or without TAAD 13 and Shone complex with a hypoplastic ascending aorta and arch 14 . Biallelic variants in SMAD6 underly more complex cardiovascular phenotypes 15 .…”

Reciprocal suppression between TGFβ signaling and TNF stimulation finetunes the macrophage inflammatory response

“…6 The established feedback inhibitors of the TGFβ signaling pathway include inhibitory Smad (I-Smad) Smad7, Smad6, E3 ubiquitin protein ligases Smurf1/2, and other RING/U-box type E3 ubiquitin ligases that bind to Smad3 and Smad4 to induce their degradation. [5][6][7][8][9] The role of TGFβ is complicated and context dependent. For example, TGFβ is involved in both proinflammatory and suppressive immune responses, such as its distinct roles in different T cell subsets and differentiation stages, as well as in inflammatory reaction of myeloid cells in different stimulatory conditions.…”

“…In addition to the canonical SMAD signaling, TGFβ can also regulate downstream cellular response via non‐Smad pathways, such as the MAPK pathway 6 . The established feedback inhibitors of the TGFβ signaling pathway include inhibitory Smad (I‐Smad) Smad7, Smad6, E3 ubiquitin protein ligases Smurf1/2, and other RING/U‐box type E3 ubiquitin ligases that bind to Smad3 and Smad4 to induce their degradation 5–9 . The role of TGFβ is complicated and context dependent.…”