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Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation

Huay L Tan1, Elise Glen, Ana Töpf

  • 1Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Human Mutation
|January 26, 2012
PubMed

Insights

Rare genetic variants in SMAD6, a bone morphogenetic protein (BMP) signaling inhibitor, predispose individuals to congenital cardiovascular malformations (CVM). This study identifies specific SMAD6 mutations impacting BMP signaling, linking them to CVM development.

Area of Science:

  • Genetics
  • Cardiovascular Biology
  • Developmental Biology

Background:

  • Congenital cardiovascular malformation (CVM) has a familial predisposition, but causative genetic factors remain largely unknown.
  • The bone morphogenetic protein (BMP) signaling pathway plays a critical role in cardiac development.

Purpose of the Study:

  • To investigate rare variants in BMP signaling pathway genes for association with CVM.
  • To identify specific genetic variants in SMAD6 that may predispose to CVM.

Main Methods:

  • Sequencing of BMPR1A, BMPR2, and SMAD6 genes in sporadic CVM cases.
  • In vitro functional assays to assess the impact of identified SMAD6 variants on BMP signaling.
  • Transcriptional reporter assays and osteogenic response assays were utilized.

Main Results:

  • Three nonsynonymous variants (p.C484F, p.P415L, p.A325T) were identified in the SMAD6 gene.
  • SMAD6 variants p.C484F and p.P415L demonstrated significantly reduced activity in inhibiting BMP signaling.
  • The p.C484F variant showed a diminished capacity to inhibit BMP-induced osteogenic response.

Conclusions:

  • Low-frequency deleterious variants in SMAD6 are associated with an increased risk of CVM.
  • This study provides the first evidence linking genetic variations in SMAD6 to a human disease phenotype.

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