Six Novel Missense Mutations in the LDL Receptor-Related Protein 5 ( LRP5) Gene in Different Conditions with an Increased Bone Density

• Published in: American journal of human genetics Vol. 72; no. 3; pp. 763 - 771
• Main Authors: Van Wesenbeeck, Liesbeth, Cleiren, Erna, Gram, Jeppe, Beals, Rodney K., Bénichou, Olivier, Scopelliti, Domenico, Key, Lyndon, Renton, Tara, Bartels, Cindy, Gong, Yaoqin, Warman, Matthew L., de Vernejoul, Marie-Christine, Bollerslev, Jens, Van Hul, Wim
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.03.2003; University of Chicago Press; The American Society of Human Genetics
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Biological and medical sciences; Bone Density - genetics; Bone Diseases - genetics; Diseases of the osteoarticular system; Humans; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Molecular Sequence Data; Mutation, Missense; Osteoporosis - genetics; Receptors, LDL - genetics; Sequence Alignment; Sequence Homology, Amino Acid; Vertebrates; Human; Family study; Pathogenesis; Endosteal hyperostosis; Diseases of the osteoarticular system; Clinical form; Genetic determinism; Genetic disease; Lipoprotein LDL; Phenotype; Missense mutation; Osteopetrosis; Cortical hyperostosis; Autosomal character; Osteosclerosis; Skull; Dominant character; Bone mineral density; Receptor protein; Van Buchem hyperostosis; Osteochondrodysplasia; Long bone; Biological receptor
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/368277

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.