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

R. D. Little, J. P. Carulli, R. G. Del Mastro, J. Dupuis, M. Osborne, C. Folz, S. P. Manning, P. M. Swain, S. C. Zhao, B. Eustace, M. M. Lappe, L. Spitzer, S. Zweier, K. Braunschweiger, Y. Benchekroun, X. Hu, R. Adair, L. Chee, M. G. Fitzgerald, C. Tulig & 15 others A. Caruso, N. Tzellas, A. Bawa, B. Franklin, S. McGuire, X. Nogues, G. Gong, K. M. Allen, A. Anisowicz, A. J. Morales, P. T. Lomedico, S. M. Recker, P. Van Eerdewegh, Robert R. Recker, M. L. Johnson

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)11-19
Number of pages9
JournalAmerican Journal of Human Genetics
Volume70
Issue number1
DOIs
StatePublished - 2002

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Bone and Bones
Mutation
Genes
Low Density Lipoprotein Receptor-Related Protein-5
Osteoporosis
Chromosomes, Human, Pair 13
Bone Remodeling
Metabolic Bone Diseases
Pedigree
Tibia
Bone Density
In Situ Hybridization
Amino Acids

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Little, R. D., Carulli, J. P., Del Mastro, R. G., Dupuis, J., Osborne, M., Folz, C., ... Johnson, M. L. (2002). A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. American Journal of Human Genetics, 70(1), 11-19. https://doi.org/10.1086/338450

A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. / Little, R. D.; Carulli, J. P.; Del Mastro, R. G.; Dupuis, J.; Osborne, M.; Folz, C.; Manning, S. P.; Swain, P. M.; Zhao, S. C.; Eustace, B.; Lappe, M. M.; Spitzer, L.; Zweier, S.; Braunschweiger, K.; Benchekroun, Y.; Hu, X.; Adair, R.; Chee, L.; Fitzgerald, M. G.; Tulig, C.; Caruso, A.; Tzellas, N.; Bawa, A.; Franklin, B.; McGuire, S.; Nogues, X.; Gong, G.; Allen, K. M.; Anisowicz, A.; Morales, A. J.; Lomedico, P. T.; Recker, S. M.; Van Eerdewegh, P.; Recker, Robert R.; Johnson, M. L.

In: American Journal of Human Genetics, Vol. 70, No. 1, 2002, p. 11-19.

Research output: Contribution to journalArticle

Little, RD, Carulli, JP, Del Mastro, RG, Dupuis, J, Osborne, M, Folz, C, Manning, SP, Swain, PM, Zhao, SC, Eustace, B, Lappe, MM, Spitzer, L, Zweier, S, Braunschweiger, K, Benchekroun, Y, Hu, X, Adair, R, Chee, L, Fitzgerald, MG, Tulig, C, Caruso, A, Tzellas, N, Bawa, A, Franklin, B, McGuire, S, Nogues, X, Gong, G, Allen, KM, Anisowicz, A, Morales, AJ, Lomedico, PT, Recker, SM, Van Eerdewegh, P, Recker, RR & Johnson, ML 2002, 'A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait', American Journal of Human Genetics, vol. 70, no. 1, pp. 11-19. https://doi.org/10.1086/338450
Little, R. D. ; Carulli, J. P. ; Del Mastro, R. G. ; Dupuis, J. ; Osborne, M. ; Folz, C. ; Manning, S. P. ; Swain, P. M. ; Zhao, S. C. ; Eustace, B. ; Lappe, M. M. ; Spitzer, L. ; Zweier, S. ; Braunschweiger, K. ; Benchekroun, Y. ; Hu, X. ; Adair, R. ; Chee, L. ; Fitzgerald, M. G. ; Tulig, C. ; Caruso, A. ; Tzellas, N. ; Bawa, A. ; Franklin, B. ; McGuire, S. ; Nogues, X. ; Gong, G. ; Allen, K. M. ; Anisowicz, A. ; Morales, A. J. ; Lomedico, P. T. ; Recker, S. M. ; Van Eerdewegh, P. ; Recker, Robert R. ; Johnson, M. L. / A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. In: American Journal of Human Genetics. 2002 ; Vol. 70, No. 1. pp. 11-19.
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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.",
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T1 - A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait

AU - Little, R. D.

AU - Carulli, J. P.

AU - Del Mastro, R. G.

AU - Dupuis, J.

AU - Osborne, M.

AU - Folz, C.

AU - Manning, S. P.

AU - Swain, P. M.

AU - Zhao, S. C.

AU - Eustace, B.

AU - Lappe, M. M.

AU - Spitzer, L.

AU - Zweier, S.

AU - Braunschweiger, K.

AU - Benchekroun, Y.

AU - Hu, X.

AU - Adair, R.

AU - Chee, L.

AU - Fitzgerald, M. G.

AU - Tulig, C.

AU - Caruso, A.

AU - Tzellas, N.

AU - Bawa, A.

AU - Franklin, B.

AU - McGuire, S.

AU - Nogues, X.

AU - Gong, G.

AU - Allen, K. M.

AU - Anisowicz, A.

AU - Morales, A. J.

AU - Lomedico, P. T.

AU - Recker, S. M.

AU - Van Eerdewegh, P.

AU - Recker, Robert R.

AU - Johnson, M. L.

PY - 2002

Y1 - 2002

N2 - 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.

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