1. A Mutation in the LDL Receptor–Related Protein 5 Gene Results in the Autosomal Dominant High–Bone-Mass Trait
- Author
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Robert R. Recker, Colleen Folz, Mark Osborne, Richard G. Del Mastro, Arturo Morales, Nia Tzellas, Gordon Gong, Josée Dupuis, Susan P. Manning, Xintong Hu, Linda Chee, Craig Tulig, Anthony Anisowicz, Brenda K. Eustace, Alicia Bawa, Xavier Nogués, John P. Carulli, Susan Zweier, Kristina Allen, Shan Chuan Zhao, Michael Fitzgerald, Ronald Adair, Shannon M. McGuire, Peter T. Lomedico, Paul Van Eerdewegh, Pamela Marie Swain, Susan M. Recker, Anthony Caruso, Youssef Benchekroun, Karen Braunschweiger, Barbara Franklin, Randall D. Little, Michelle M. Lappe, Lia Spitzer, and Mark L. Johnson
- Subjects
Genetic Markers ,Male ,Models, Molecular ,Bone density ,Bone disease ,Genetic Linkage ,Osteoporosis ,Population ,Biology ,Bone and Bones ,Bone remodeling ,Bone Density ,medicine ,Genetics ,Humans ,Genetics(clinical) ,RNA, Messenger ,education ,Genetics (clinical) ,Alleles ,In Situ Hybridization ,LDL-Receptor Related Proteins ,Genes, Dominant ,Sequence Tagged Sites ,education.field_of_study ,Haplotype ,LRP5 ,Articles ,Organ Size ,medicine.disease ,Physical Chromosome Mapping ,Pedigree ,Protein Structure, Tertiary ,Osteopenia ,Phenotype ,Haplotypes ,Mutation ,Female - Abstract
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.
- Published
- 2002
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