title: A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.
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 beta-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.
authors.affiliation: Department of Human Genetics, Genome Therapeutics Corporation, Waltham, MA 02453, USA. rlittle@genomecorp.com
authors.forename: Randall D
authors.initials: RD
authors.lastname: Little
authors.forename: John P
authors.initials: JP
authors.lastname: Carulli
authors.forename: Richard G
authors.initials: RG
authors.lastname: Del Mastro
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: Mark
authors.initials: M
authors.lastname: Osborne
authors.forename: Colleen
authors.initials: C
authors.lastname: Folz
authors.forename: Susan P
authors.initials: SP
authors.lastname: Manning
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Swain
authors.forename: Shan-Chuan
authors.initials: SC
authors.lastname: Zhao
authors.forename: Brenda
authors.initials: B
authors.lastname: Eustace
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Lappe
authors.forename: Lia
authors.initials: L
authors.lastname: Spitzer
authors.forename: Susan
authors.initials: S
authors.lastname: Zweier
authors.forename: Karen
authors.initials: K
authors.lastname: Braunschweiger
authors.forename: Youssef
authors.initials: Y
authors.lastname: Benchekroun
authors.forename: Xintong
authors.initials: X
authors.lastname: Hu
authors.forename: Ronald
authors.initials: R
authors.lastname: Adair
authors.forename: Linda
authors.initials: L
authors.lastname: Chee
authors.forename: Michael G
authors.initials: MG
authors.lastname: FitzGerald
authors.forename: Craig
authors.initials: C
authors.lastname: Tulig
authors.forename: Anthony
authors.initials: A
authors.lastname: Caruso
authors.forename: Nia
authors.initials: N
authors.lastname: Tzellas
authors.forename: Alicia
authors.initials: A
authors.lastname: Bawa
authors.forename: Barbara
authors.initials: B
authors.lastname: Franklin
authors.forename: Shannon
authors.initials: S
authors.lastname: McGuire
authors.forename: Xavier
authors.initials: X
authors.lastname: Nogues
authors.forename: Gordon
authors.initials: G
authors.lastname: Gong
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Allen
authors.forename: Anthony
authors.initials: A
authors.lastname: Anisowicz
authors.forename: Arturo J
authors.initials: AJ
authors.lastname: Morales
authors.forename: Peter T
authors.initials: PT
authors.lastname: Lomedico
authors.forename: Susan M
authors.initials: SM
authors.lastname: Recker
authors.forename: Paul
authors.initials: P
authors.lastname: Van Eerdewegh
authors.forename: Robert R
authors.initials: RR
authors.lastname: Recker
authors.forename: Mark L
authors.initials: ML
authors.lastname: Johnson
mesh_terms: D000483:Alleles; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009929:Organ Size; D010375:Pedigree; D010641:Phenotype; D020161:Physical Chromosome Mapping; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016324:Sequence Tagged Sites
chemical_list: D005819:Genetic Markers; D026502:LDL-Receptor Related Proteins; D012333:RNA, Messenger