High bone density due to a mutation in LDL-receptor-related protein 5
High bone density due to a mutation in LDL-receptor-related protein 5
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DOI：
10.1056/nejmoa013444
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发表时间：
2002-05-16
影响因子：
158.5
通讯作者：
Lifton, RP
中科院分区：
文献类型：
--
作者：
Boyden, LM;Mao, JH;Lifton, RP
背景：骨质疏松症是一个主要的公共卫生问题，其原因尚不清楚。低密度脂蛋白受体相关蛋白5（LRP 5）基因的功能缺失突变，在Wnt信号通路中起作用，已被证明可导致骨质疏松症-假glioma.Methods：我们对一个常染色体显性遗传综合征家系进行了遗传和生化分析，该家系的特征是高骨密度、宽而深的下颌骨和腭隆凸。遗传分析显示，该综合征与染色体11 q12 -13（连锁几率>1百万比1）连锁，这是一个包含LRP 5的区间。受影响的亲属成员在这个基因中有一个突变，在密码子171处用缬氨酸取代甘氨酸（LRP 5（V171））。这种突变在家族中与性状分离，在对照组中不存在。正常的甘氨酸存在于所谓的螺旋桨基序中，该基序从果蝇到人类都高度保守。受影响的受试者的骨吸收标志物正常，而骨形成标志物如骨钙素显著升高。纤连蛋白的水平也升高，纤连蛋白是Wnt（一种发育蛋白）信号传导的已知靶点。体外研究表明，另一种蛋白Dickkopf-1（Dkk-1）对Wnt信号传导的正常抑制在LRP 5（V171）存在的情况下是有缺陷的，这导致了由于未对抗的Wnt活性而增加的信号传导。LRP 5（V171）突变导致骨密度高，下颌骨和腭隆凸增厚，通过削弱Wnt途径的正常拮抗剂的作用，从而增加Wnt信号传导。这些发现证明了LRP 5功能改变在高骨量中的作用，并指出Dkk是预防或治疗骨质疏松症的潜在靶点。
Background: Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma.Methods: We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus.Results: Genetic analysis revealed linkage of the syndrome to chromosome 11q12-13 (odds of linkage, >1 million to 1), an interval that contains LRP5. Affected members of the kindred had a mutation in this gene, with valine substituted for glycine at codon 171 (LRP5(V171)). This mutation segregated with the trait in the family and was absent in control subjects. The normal glycine lies in a so-called propeller motif that is highly conserved from fruit flies to humans. Markers of bone resorption were normal in the affected subjects, whereas markers of bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5(V171) and that this resulted in increased signaling due to unopposed Wnt activity.Conclusions: The LRP5(V171) mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling. These findings demonstrate the role of altered LRP5 function in high bone mass and point to Dkk as a potential target for the prevention or treatment of osteoporosis.