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PMID:22275001

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Citation

Tan, HL, Glen, E, Töpf, A, Hall, D, O'Sullivan, JJ, Sneddon, L, Wren, C, Avery, P, Lewis, RJ, ten Dijke, P, Arthur, HM, Goodship, JA and Keavney, BD (2012) Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Hum. Mutat. 33:720-7

Abstract

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.

Links

PubMed PMC3492913 Online version:10.1002/humu.22030

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SMAD6

involved_in

GO:0030514: negative regulation of BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD6

involved_in

GO:0030514: negative regulation of BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

part_of:(GO:0003180)

Seeded From UniProt

complete

HUMAN:SMAD6

involved_in

GO:0003180: aortic valve morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD6

involved_in

GO:0045668: negative regulation of osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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