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: 33.61). 04/2007; 315(5816):1278-82. DOI: 10.1126/science.1136370
Source: PubMed


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.

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Available from: Arya Mani, Mar 12, 2014
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    • "Study of the crystal structure of the LRP6 has shown that R611C substitution results in relaxation of the EGF2 domain (Cheng et al., 2011), determine which can explain its reduced affinity for ligands. We have previously shown that the LRP6 R611C mutation causes reduced, but not a complete ablation of LRP6 signaling, and signaling can be rescued by high levels of ligand (Mani et al., 2007). To determine whether activation of LRP6 would reduce the growth factor levels in LRP6 R611C mice aorta, recombinant mouse (rm) Wnt3a was administrated to LRP6 R611C and WT mice on alternate days for 3 weeks. "
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    ABSTRACT: Mutations in Wnt-signaling coreceptor LRP6 have been linked to coronary artery disease (CAD) by unknown mechanisms. Here, we show that reduced LRP6 activity in LRP6(R611C) mice promotes loss of vascular smooth muscle cell (VSMC) differentiation, leading to aortic medial hyperplasia. Carotid injury augmented these effects and led to partial to total vascular obstruction. LRP6(R611C) mice on high-fat diet displayed dramatic obstructive CAD and exhibited an accelerated atherosclerotic burden on LDLR knockout background. Mechanistically, impaired LRP6 activity leads to enhanced non-canonical Wnt signaling, culminating in diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration to LRP6(R611C) mice improved LRP6 activity, led to TCF7L2-dependent VSMC differentiation, and rescued post-carotid-injury neointima formation. These findings demonstrate the critical role of intact Wnt signaling in the vessel wall, establish a causal link between impaired LRP6/TCF7L2 activities and arterial disease, and identify Wnt signaling as a therapeutic target against CAD.
    Full-text · Article · Oct 2015 · Cell Reports
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    • "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. "
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    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.
    Full-text · Article · Feb 2015 · Cell Metabolism
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    • "For example, we observe that WNT1 inducible signaling pathway protein 2 (Wisp2) is differentially expressed and is directly under regulation of ERα. While Wnt/β-catenin signaling, both canonical and non-canonical, has been implicated in cardiac function [33]–[35], there has been no direct evidence for the cross talk between these two key pathways (ERα and Wnt/β-catenin). As mentioned earlier in methods section, to understand how Wnt Signaling may be affected by the absence of ERα, we relaxed the FDR thresholding and subjected the data to Compare Experiment Workflow in MetaCore. "
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    ABSTRACT: Estrogen exerts diverse biological effects in multiple tissues in both animals and humans. Much of the accumulated knowledge on the role of estrogen receptor (ER) in the heart has been obtained from studies using ovariectomized mice, whole body ER gene knock-out animal models, ex vivo heart studies, or from isolated cardiac myocytes. In light of the wide systemic influence of ER signaling in regulating a host of biological functions in multiple tissues, it is difficult to infer the direct role of ER on the heart. Therefore, we developed a mouse model with a cardiomyocyte-specific deletion of the ERα allele (cs-ERα-/-). Male and female cs-ERα-/- mice with age/sex-matched wild type controls were examined for differences in cardiac structure and function by echocardiogram and differential gene expression microarray analysis. Our study revealed sex-differences in structural parameters in the hearts of cs-ERα-/- mice, with minimal functional differences. Analysis of microarray data revealed differential variations in the expression of 208 genes affecting multiple transcriptional networks. Furthermore, we report sex-specific differences in the expression of 56 genes. Overall, we developed a mouse model with cardiac-specific deletion of ERα to characterize the role of ERα in the heart independent of systemic effects. Our results suggest that ERα is involved in controlling the expression of diverse genes and networks in the cardiomyocyte in a sex-dependent manner.
    Full-text · Article · Jul 2014 · PLoS ONE
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