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Hum Mutat. 2013 Sep;34(9):1221-5. doi: 10.1002/humu.22360. Epub 2013 Jun 18.

Rare nonconservative LRP6 mutations are associated with metabolic syndrome.

Author information

1
Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.

Abstract

A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.

KEYWORDS:

LRP6; coronary artery disease; metabolic syndrome; mutation

PMID:
23703864
PMCID:
PMC3745535
DOI:
10.1002/humu.22360
[Indexed for MEDLINE]
Free PMC Article

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