High bone density due to a mutation in LDL-receptor-related protein 5.

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 (LRP5V171 ). 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 bo...