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 bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5V171 and that this resulted in increased signaling due to unopposed Wnt activity.
Conclusions: The LRP5V171 mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling. These findings demonstrate the role of altered LRP5 function in high bone mass and point to Dkk as a potential target for the prevention or treatment of osteoporosis.