A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait

Randall D. Little, John P. Carulli, Richard G. Del Mastro, Josée Dupuis, Mark Osborne, Colleen Folz, Susan P. Manning, Pamela M. Swain, Shan Chuan Zhao, Brenda Eustace, Michelle M. Lappe, Lia Spitzer, Susan Zweier, Karen Braunschweiger, Youssef Benchekroun, Xintong Hu, Ronald Adair, Linda Chee, Michael G. Fitzgerald, Craig TuligAnthony Caruso, Nia Tzellas, Alicia Bawa, Barbara Franklin, Shannon McGuire, Xavier Nogues, Gordon Gong, Kristina M. Allen, Anthony Anisowicz, Arturo J. Morales, Peter T. Lomedico, Susan M. Recker, Paul Van Eerdewegh, Robert R. Recker, Mark L. Johnson

Research output: Contribution to journalArticlepeer-review

1082 Scopus citations


Osteoporosis is a complex disease that affects ≤10 million people in the United States and results in 1.5 million fractures annually. In addition, the high prevalence of osteopenia (low bone mass) in the general population places a large number of people at risk for developing the disease. In an effort to identify genetic factors influencing bone density, we characterized a family that includes individuals who possess exceptionally dense bones but are otherwise phenotypically normal. This high-bone-mass trait (HBM) was originally localized by linkage analysis to chromosome 11q12-13. We refined the interval by extending the pedigree and genotyping additional markers. A systematic search for mutations that segregated with the HBM phenotype uncovered an amino acid change, in a predicted β-propeller module of the low-density lipoprotein receptor-related protein 5 (LRP5), that results in the HBM phenotype. During analysis of ≤1,000 individuals, this mutation was observed only in affected individuals from the HBM kindred. By use of in situ hybridization to rat tibia, expression of LRP5 was detected in areas of bone involved in remodeling. Our findings suggest that the HBM mutation confers a unique osteogenic activity in bone remodeling, and this understanding may facilitate the development of novel therapies for the treatment of osteoporosis.

Original languageEnglish (US)
Pages (from-to)11-19
Number of pages9
JournalAmerican journal of human genetics
Issue number1
StatePublished - 2002

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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