SMAD3 – Familial Thoracic Aortic Aneurysm and Dissection

Heterozygous haploinsufficiency of SMAD3 has been implicated in autosomal dominant familial thoracic aortic aneurysm and aortic dissection (PMID:22803640). A small interstitial deletion of chromosome 15 disrupting SMAD3 was identified in a boy presenting with mild intellectual disability (HP:0001256) and atypical behavior (HP:0000708), along with features of aneurysms-osteoarthritis syndrome; the identical deletion segregated in two additional affected relatives across three generations (PMID:22803640). This copy number variant underscores a haploinsufficiency mechanism, and only a single family (one proband, two relatives) has been described to date. Although specific nucleotide breakpoints were not provided, analogous SMAD3 missense variants such as c.589A>T (p.Asn197Tyr) have demonstrated functional impairment in other contexts.

SMAD3 is a receptor-regulated Smad critical for TGF-β pathway signaling; phosphorylation at C-terminal serines enables heteromeric complex formation with Smad4 and nuclear translocation. In vitro phosphorylation assays and dominant-negative mutation studies confirm that disruption of SMAD3 function impairs TGF-β–mediated transcriptional responses, including extracellular matrix gene regulation (PMID:9346966; PMID:9688538). These experimental data are concordant with the clinical phenotype of thoracic aortic aneurysm and dissection arising from reduced SMAD3 activity. Collectively, the association between SMAD3 and familial thoracic aortic aneurysm and dissection is supported by limited clinical evidence and moderate functional data. Additional case series or unrelated families are needed to upgrade the clinical validity. Key take-home: SMAD3 haploinsufficiency should be included in genetic evaluation and risk assessment for thoracic aortic aneurysm and dissection.

References

• Clinical genetics • 2013 • An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a three-generation family at serious risk for aortic dissection. PMID:22803640
• The Journal of biological chemistry • 1997 • Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. PMID:9346966
• FEBS letters • 1998 • A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3, and has a dominant negative effect on TGF-beta signals. PMID:9688538

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