Genetic Tales of Gain and Loss

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Science  30 Nov 2001:
Vol. 294, Issue 5548, pp. 1791
DOI: 10.1126/science.294.5548.1791c

Bone tissue in adults is continuously degraded and rebuilt. As we age, this delicate balance becomes tipped in favor of degradation, which can render bones brittle and prone to fracture—a common and debilitating condition known as osteoporosis. By studying rare inherited disorders that affect bone mass early in life, researchers hope to learn more about the molecular mechanisms that regulate bone remodeling and ultimately to apply that information to the design of drugs for osteoporosis and other common bone diseases.

This strategy has led to the discovery of a gene critical to the bone remodeling process, different alleles of which can cause loss or gain of bone mass. Studying families with osteoporosis-pseudoglioma syndrome (OPPG), a recessively inherited disorder in which children exhibit low bone mass, Gong et al. identified causative mutations in LPR5, a gene encoding a protein related to the low-density lipoprotein receptor. The LPR5 protein regulates the growth and/or differentiation of osteoblasts (the cells that rebuild bone) through the Wnt signaling pathway, and the mutations in the OPPG patients appear to cause loss of protein function. In complementary work, Little et al. found that a family with exceptionally high bone mass, a trait inherited in a dominant fashion, carries a missense mutation in the same gene. The resulting amino acid change is predicted to alter interactions of LPR5 with other proteins, leading to a gain of protein function. The fact that sequence alterations in LPR5 can produce a spectrum of bone phenotypes indicates that this protein and the Wnt pathway through which it acts may be exciting targets for the development of new therapeutics.—PAK

Cell107, 513 (2001); Am. J. Hum. Genet., in press.

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