A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.
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.
Little
Randall D
RD
Department of Human Genetics, Genome Therapeutics Corporation, Waltham, MA 02453, USA. rlittle@genomecorp.com
Carulli
John P
JP
Del Mastro
Richard G
RG
Dupuis
Josée
J
Osborne
Mark
M
Folz
Colleen
C
Manning
Susan P
SP
Swain
Pamela M
PM
Zhao
Shan-Chuan
SC
Eustace
Brenda
B
Lappe
Michelle M
MM
Spitzer
Lia
L
Zweier
Susan
S
Braunschweiger
Karen
K
Benchekroun
Youssef
Y
Hu
Xintong
X
Adair
Ronald
R
Chee
Linda
L
FitzGerald
Michael G
MG
Tulig
Craig
C
Caruso
Anthony
A
Tzellas
Nia
N
Bawa
Alicia
A
Franklin
Barbara
B
McGuire
Shannon
S
Nogues
Xavier
X
Gong
Gordon
G
Allen
Kristina M
KM
Anisowicz
Anthony
A
Morales
Arturo J
AJ
Lomedico
Peter T
PT
Recker
Susan M
SM
Van Eerdewegh
Paul
P
Recker
Robert R
RR
Johnson
Mark L
ML
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
D005819:Genetic Markers; D026502:LDL-Receptor Related Proteins; D012333:RNA, Messenger