Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density
Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density
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DOI：
10.1086/368277
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发表时间：
2003-03-01
影响因子：
9.8
通讯作者：
Van Hul, W
中科院分区：
文献类型：
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作者：
Van Wesenbeeck, L;Cleiren, E;Van Hul, W
骨是一种动态组织，受骨形成和骨吸收平衡过程的影响。不平衡可引起骨骼病变，骨密度增加。近年来，已经确定了几个导致这种硬化性骨疾病的基因。低密度脂蛋白受体相关蛋白5 （LRP5）基因已被证明参与骨质疏松-假性胶质瘤综合征和高骨量表型，并被证明是脊椎动物峰值骨量的重要调节因子。我们对10个不同骨密度增加的家庭或分离患者的LRP5基因进行了突变分析，包括骨内膜肥大症、Van Buchem病、常染色体显性骨硬化和i型骨质疏松症。LRP5基因的直接测序显示了19个序列变异。其中13个被证实为多态性，但6个新的错义突变（D111Y、G171R、A214T、A214V、A242T和T253I）最有可能引起疾病。与先前报道的导致高骨量表型的突变（G171V）一样，所有突变都位于该基因的氨基末端部分，位于第一个表皮生长因子样结构域之前。这些结果表明，尽管可以做出不同的诊断，但骨密度增加主要影响长骨和颅骨皮质的情况通常是由LRP5基因突变引起的。对各种突变的作用进行功能分析，以评估是否所有突变都引起相同的致病机制。
Bone is a dynamic tissue that is subject to the balanced processes of bone formation and bone resorption. Imbalance can give rise to skeletal pathologies with increased bone density. In recent years, several genes underlying such sclerosing bone disorders have been identified. The LDL receptor-related protein 5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma syndrome and the high-bone-mass phenotype and turned out to be an important regulator of peak bone mass in vertebrates. We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are most likely disease causing. Like the previously reported mutation (G171V) that causes the high-bone-mass phenotype, all mutations are located in the aminoterminal part of the gene, before the first epidermal growth factor-like domain. These results indicate that, despite the different diagnoses that can be made, conditions with an increased bone density affecting mainly the cortices of the long bones and the skull are often caused by mutations in the LRP5 gene. Functional analysis of the effects of the various mutations will be of interest, to evaluate whether all the mutations give rise to the same pathogenic mechanism.