High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5

Osteoporosis can be caused by a loss-of-function mutation in the gene for low-density lipoprotein receptor–related protein 5 ( LRP5 ). In this study, the authors, reasoning that a gain-of-function mutation in the same gene might be associated with high bone density, performed biochemical and genetic analyses of a kindred with high bone density, a prominent mandible, and torus palatinus. Genetic analysis revealed an LRP5 mutation, the substitution of valine for glycine at codon 171, that segregated with the clinical findings. In vitro studies demonstrated that the defect in LRP5 resulted in changes in signaling events with other molecules that normally interact with this receptor-related protein, resulting in increased bone density. Osteoporosis can be caused by a loss-of-function mutation in the LRP5 gene. This study identifies a gain-of-function mutation in the same gene. Osteoporosis is a major public health problem, and its prevalence is increasing. 1 – 3 In the United States, nearly 1 million fractures occur annually in people over the age of 65 years, the majority of which are due to osteoporosis. 1 , 4 Osteoporotic fractures are associated with substantial morbidity, and the estimated rate of death in the first year after a hip fracture is 25 to 30 percent. 5 , 6 Bone mass, a major determinant of the risk of osteoporotic fracture, increases during childhood and adolescence, reaching a peak at about the age of 20 years. 7 Twin and family studies indicate that genetic . . .