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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    • "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.
    Cell Metabolism 02/2015; 21(2):262-72. DOI:10.1016/j.cmet.2015.01.009 · 17.57 Impact Factor
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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.
    PLoS ONE 07/2014; 9(7):e101900. DOI:10.1371/journal.pone.0101900 · 3.23 Impact Factor
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    • "Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis result in sclerosteosis and osteoporosis, respectively. Mani et al. have shown that a single missense mutation in low-density lipoprotein receptor-related protein 6, the coreceptor for the Wnt signaling pathway, is genetically linked to osteoporosis as well as DM, dyslipoproteinemia, and coronary artery disease [60]. In addition, several studies have documented that T-cell-specific transcription factor- (TCF-) 4, the partner of β-catenin in the canonical Wnt signaling pathway, is the strongest T2DM susceptibility gene [61–63]. "
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    ABSTRACT: It is well established that osteoporosis and diabetes are prevalent diseases with significant associated morbidity and mortality. Patients with diabetes mellitus have an increased risk of bone fractures. In type 1 diabetes, the risk is increased by ∼6 times and is due to low bone mass. Despite increased bone mineral density (BMD), in patients with type 2 diabetes the risk is increased (which is about twice the risk in the general population) due to the inferior quality of bone. Bone fragility in type 2 diabetes, which is not reflected by bone mineral density, depends on bone quality deterioration rather than bone mass reduction. Thus, surrogate markers and examination methods are needed to replace the insensitivity of BMD in assessing fracture risks of T2DM patients. One of these methods can be trabecular bone score. The aim of the paper is to present the present state of scientific knowledge about the osteoporosis risk in diabetic patient. The review also discusses the possibility of problematic using the study conclusions in real clinical practice.
    International Journal of Endocrinology 06/2014; 2014(3):820615. DOI:10.1155/2014/820615 · 1.95 Impact Factor
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