Lookup NU author(s): Dr Elise Glen,
Dr Ana Topf,
Dr Darroch Hall,
Dr John O'Sullivan,
Dr Christopher Wren,
Dr Peter Avery,
Professor Rick Lewis,
Professor Helen Arthur,
Professor Judith Goodship,
Professor Bernard Keavney
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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. Hum Mutat 33:720727, 2012. (c) 2012 Wiley Periodicals, Inc.
Author(s): Tan HL, Glen E, Topf A, Hall D, O'Sulliyan JJ, Sneddon L, Wren C, Avery P, Lewis RJ, ten Dijke P, Arthur HM, Goodship JA, Keavney BD
Publication type: Article
Publication status: Published
Journal: Human Mutation
Print publication date: 14/02/2012
ISSN (print): 1059-7794
ISSN (electronic): 1098-1004
Publisher: John Wiley & Sons, Inc.
Altmetrics provided by Altmetric