Missense mutations in LRP5 are not a common cause of idiopathic osteoporosis in adult men

Introduction: Mutations in the LDL receptor-related protein 5 (LRP5) gene have been associated with extreme bone phenotypes, which makes LRP5 a plausible candidate gene for idiopathic osteoporosis (10). Materials and Methods: In 66 men with 10, all 23 exons and exon-intron boundaries of the LRP5 gene were screened for mutations, and functional analyses were performed for those that were putatively involved in the phenotype. Results: Mutation analysis in the IO probands revealed five missense mutations, of which 1067C > T (S356L), 1364C > T (S455L), and 4609G > A (A1537T) were of potential functional significance because they were located in highly conserved regions of LRP5 and not found in a control panel. Segregation analysis in the respective families could not exclude their possible causality for IO. Furthermore, functional analyses clearly showed an inhibitory effect of mutations 1067C > T and 1364C > T on Wnt signal transduction. These effects are most likely caused by impaired LRP5 synthesis in the case of 1067C > T and failure of protein trafficking to the cell surface for 1364C > T. Conclusions: For 2 of 66 10 probands, a mutation in the LRP5 gene with proven functionality was found. The findings indicate that carrying an LRP5 mutation is a risk factor for 10, but that overall, 10 in men is infrequently underlied by such a mutation.