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Cited by 1,282Bone health and osteoporosis researchBone Metabolism and DiseasesAlkaline Phosphatase Research Studies

A Mutation in the LDL Receptor–Related Protein 5 Gene Results in the Autosomal Dominant High–Bone-Mass Trait

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Little, Randall D., Folz, Colleen, Manning, Susan P., Swain, Pamela M., Zhao, Shan-Chuan, Eustace, Brenda, Lappe, Michelle M., Spitzer, Lia +27 more·2002·The American Journal of Human Genetics
DOI 10.1086/338450PMC PMC419982
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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 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.

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  • Wnt signaling is crucial for osteoblast function and for setting bone mass and strength.

    “the critical role for the Wnt signaling pathway in regulating osteoblast function is of particular interest, since it has been shown to play an important role in determining bone mass and strength”

    From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [58]

    The discussion (section 6) reports that LRP5 participates in Wnt signaling and that an LRP5 mutation increases bone mass; it also reports enhanced skeletal strength in transgenic mice. It describes Wnt as important in skeletal differentiation, but does not directly establish that Wnt signaling regulates osteoblast function or itself determines bone mass and strength. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • An LRP5 mutation causing constitutive activation can raise bone density.

    “A mutation of LRP5 that leads to constitutive activation can result in an increase in bone density”

    From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [58]

    Section 6 says the LRP5 gain-of-function mutation described by the authors produces increased bone mass. It does not establish that the mutation causes constitutive activation; its discussion of how the mutation affects protein interactions is tentative. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 5

  1. Electronic-Database Information Accession numbers and URLs for data in this article are as follows: Cyrillic program, http://www.cyrillicsoftware.com/ (for visu- alizing pedigrees) GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for human LRP5 cDNA [accession number AF064548], human LRP5 protein [accession number AAC36467], and mouse LRP5 cDNA [accession number AF064984]) Online Mendelian Inheritance in Man (OMIM), http://www .ncbi.nlm.nih.gov/Omim/ (for HBM or BMND1 [MIM 601884], OPS [MIM 259770], arOP [MIM 259700]), PYCD [MIM 265800], DPD1 [MIM 13100], VBCH [MIM 239100], and melorheostosis [MIM 155950])
  2. Protein Data Bank, http://www.rcsb.org/pdb/ (for LDLR YWTD-EGF domain pair [PDB 1IJQ]) UniGene, http://www.ncbi.nlm.nih.gov/UniGene/ (for Uni- Gene Cluster Hs.116962, CGI-85 [UniGene Cluster Hs.267448], c11orf24 [UniGene Cluster Hs.303025], LRP5 [UniGene Cluster Hs.6347], c11orf23 [UniGene Cluster Hs.180817], MTL5 [UniGene Cluster Hs.121378], GALN [UniGene Cluster Hs.1907], CPT1A [UniGene Cluster Hs.259785], SMBP2 [UniGene Cluster Hs.1521], RTA [UniGene Cluster Hs.118513], [UniGene Cluster Hs.288748], CCND1 [UniGene Cluster Hs.82932], [UniGene Cluster Hs.170932], FGF19 [UniGene Cluster Hs.249200], FGF4 [UniGene Cluster Hs.1755], and FGF3 [UniGene Cluster Hs.37092]) References
  3. Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC (2001) Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Biol 8:499-504
  4. Marks SC Jr, Hermey DC (1996) The structure and devel- opment of bone. In: Bilezikian JP, Raias LG, Rodan GA (eds) Principles of bone biology. Academic Press, San Diego, pp 3-14
  5. Soares MB (1994) In: Adams MD, Fields C, Venter JC (eds) Automated DNA sequencing and analysis. Academic Press, New York, pp 110-114

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Authors
Little, R. D., 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, R. R., Carulli, J. P., Del Mastro, R. G., Dupuis, J., Osborne, M., & Johnson, M. L.
Affiliations
  • Biogen (United States) (US)
  • Takeda (Japan) (JP)
  • Creighton University (US)
Corresponding author
Folz, Colleen
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2002-01
Volume
70
Issue
1
Pages
11-19
ISSN
0002-9297 (ISSN-L)
DOI
10.1086/338450
PMC
PMC419982
OpenAlex
W2002073678
Cited by
1,282
References
1
Citations by year
2026: 8 · 2025: 13 · 2024: 19 · 2023: 26 · 2022: 21 · 2021: 25 · 2020: 41 · 2019: 31 · 2018: 40 · 2017: 49 · 2016: 49 · 2015: 51 · 2014: 64 · 2013: 72 · 2012: 59
FWCI
85.24
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
Keywords
LRP5, autosomal dominant inheritance, osteoporosis, bone mineral density, osteogenic activity, bone remodeling, amino acid substitutions, osteopenia, linkage mapping
MeSH terms
Alleles, Bone and Bones, Female, Genes, Dominant, Genetic Markers, Haplotypes, Humans, Genetic Linkage, Male, Models, Molecular, Mutation, Organ Size, Pedigree, Phenotype, RNA, Messenger, Bone Density, Sequence Tagged Sites, In Situ Hybridization, Protein Structure, Tertiary, Physical Chromosome Mapping, LDL-Receptor Related Proteins

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