LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors

Department of Internal Medicine, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510, USA.
Science (Impact Factor: 31.48). 04/2007; 315(5816):1278-82. DOI: 10.1126/science.1136370
Source: PubMed

ABSTRACT Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.

Download full-text


Available from: Arya Mani, Mar 12, 2014
  • Source
    • "Reciprocally , rare loss-of-function (LoF) LRP5 mutations lead to osteoporosis (Ai et al., 2005; Gong et al., 2001), which, in a study of 12 affected probands from two families, was coupled with an increased prevalence of T2D (Saarinen et al., 2010). Finally, rare inactivating missense mutations in LRP6 result in autosomal dominant CVD, features of the metabolic syndrome, and osteoporosis (Mani et al., 2007; Singh et al., 2013). Prompted by these and the aforementioned GWAS findings (Heid et al., 2010), we sought to determine the role of LRP5 in human WAT biology and fat distribution. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Metabolism 02/2015; 21(2):262-72. DOI:10.1016/j.cmet.2015.01.009 · 16.75 Impact Factor
  • Source
    • "Strikingly, all three novel mutations reside in the second propeller domain (Fig. 2C), which has a critical role in ligand binding. The previously identified R611C allele resides in second EGF domain [Go and Mani, 2012; Mani et al., 2007]. The crystal structure of LRP6 has revealed the importance of intermolecular interactions between EGF and propeller domain for the tertiary structure of the protein. "
    [Show abstract] [Hide abstract]
    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 2000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which co-segregated 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. . This article is protected by copyright. All rights reserved.
    Human Mutation 09/2013; 34(9). DOI:10.1002/humu.22360 · 5.05 Impact Factor
  • Source
    • "The protein regulates WNT and BMP signaling pathways by competing with LRP5 and LRP6 ligand-binding of importance for bone formation as well as limb and kidney development [12]. The binding of Wnt proteins to LRPs regulates osteoblast function [1] and mutations in the Wnt coreceptor LRP5 gene is associated with Osteoporosis-pseudoglioma syndrome [2] [7] [11] [16] whereas mutations in the LRP6 gene has been linked to bone mineral density changes in humans [14]. Furthermore, it has been shown that LRP4 interacts with agrin to regulate also postsynaptic and presynaptic differentiation of the neuromuscular junction [6] [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cenani-Lenz syndrome (CLS) is a rare autosomal recessive developmental disorder of the limbs. The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes accompanied by radioulnar synostosis. The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement. CLS was recently associated with mutations in the low-density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling. We have identified a large consanguineous Pakistani pedigree with 9 members affected by CLS. The affected individuals present with a consistent expression of the syndrome restricted to the limbs and kidneys. Symptoms from the lower limb are mild or absent and there were no radioulnar synostosis or craniofacial involvement. Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation c.2858T>C (p.L953P) in the LRP4 gene. The mutation is located in a region encoding the highly conserved low-density lipoprotein receptor repeat class B domain of LRP4. Our findings add to the genotype-phenotype correlations in CLS and support kidney anomalies as a frequent associated feature.
    European journal of medical genetics 05/2013; DOI:10.1016/j.ejmg.2013.04.007 · 1.49 Impact Factor