Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density

被引:427
作者
Van Wesenbeeck, L
Cleiren, E
Gram, J
Beals, RK
Bénichou, O
Scopelliti, D
Key, L
Renton, T
Bartels, C
Gong, YQ
Warman, ML
de Vernejoul, MC
Bollerslev, J
Van Hul, W
机构
[1] Univ Antwerp, Dept Med Genet, B-2610 Antwerp, Belgium
[2] Ribe Cty Hosp, Dept Med, Esbjerg, Denmark
[3] Oregon Hlth Sci Univ, Dept Orthoped & Rehabil, Portland, OR 97201 USA
[4] Hop Lariboisiere, INSERM, U349, F-75475 Paris, France
[5] Santo Spirito Hosp, Dept Maxillofacial Surg, Rome, Italy
[6] Univ S Carolina, Dept Pediat Endocrinol, Charleston, SC USA
[7] Guys Dent Inst, Dept Oral & Maxillofacial Surg, London, England
[8] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA
[9] Univ Oslo, Rikshosp, Dept Endocrinol, N-0027 Oslo, Norway
关键词
D O I
10.1086/368277
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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页码:763 / 771
页数:9
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