These authors contributed equally to this work.
Rare Nonconservative LRP6 Mutations Are Associated with Metabolic Syndrome
Article first published online: 18 JUN 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 9, pages 1221–1225, September 2013
How to Cite
Singh, R., Smith, E., Fathzadeh, M., Liu, W., Go, G.-W., Subrahmanyan, L., Faramarzi, S., McKenna, W. and Mani, A. (2013), Rare Nonconservative LRP6 Mutations Are Associated with Metabolic Syndrome. Hum. Mutat., 34: 1221–1225. doi: 10.1002/humu.22360
Communicated by Elizabeth F. Neufeld
Contract Grant Sponsor: NIH (1R01HL094574, 5R01HL094784).
- Issue published online: 14 AUG 2013
- Article first published online: 18 JUN 2013
- Accepted manuscript online: 22 MAY 2013 10:31AM EST
- Manuscript Accepted: 7 MAY 2013
- Manuscript Received: 11 MAR 2013
- NIH. Grant Numbers: 1R01HL094574, 5R01HL094784
- metabolic syndrome;
- coronary artery disease
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.