Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation

Hum Mutat. 2012 Apr;33(4):720-7. doi: 10.1002/humu.22030. Epub 2012 Feb 14.


Congenital cardiovascular malformation (CVM) exhibits familial predisposition, but most of the specific genetic factors involved are unknown. Postulating that rare variants in genes in critical cardiac developmental pathways predispose to CVM, we systematically surveyed three genes of the bone morphogenetic protein (BMP) signaling pathway for novel variants. Exonic, splice site, and untranslated regions of BMPR1A, BMPR2, and SMAD6 genes were sequenced in 90 unrelated sporadic cases of CVM. One nonsynonymous variant (p.C484F) with predicted functional impact was found in the MAD homology 2 domain of SMAD6, an intracellular inhibitor of BMP signaling. Sequencing this domain in an additional 346 cases of CVM yielded two further nonsynonymous variants (p.P415L and p.A325T). Functional effects of all three SMAD6 mutations were investigated using BMP signaling assays in vitro. Two SMAD6 variants (p.C484F and p.P415L) had significantly (P < 0.05) lower activity than wild-type SMAD6 in inhibiting BMP signaling in a transcriptional reporter assay. In addition, the p.C484F variant had a significantly (P < 0.05) lower capacity to inhibit an osteogenic response to BMP signaling. We conclude that low-frequency deleterious variants in SMAD6 predispose to CVM. This is the first report of a human disease phenotype related to genetic variation in SMAD6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / metabolism
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Cardiovascular Abnormalities / genetics*
  • Cell Line
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Humans
  • Mice
  • Mutation*
  • Signal Transduction
  • Smad6 Protein / chemistry
  • Smad6 Protein / genetics*
  • Smad6 Protein / metabolism
  • United Kingdom


  • Bone Morphogenetic Proteins
  • SMAD6 protein, human
  • Smad6 Protein
  • BMPR1A protein, human
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II
  • Alkaline Phosphatase