CoChat
Sign Up
Cited by 1,591Bone Metabolism and DiseasesWnt/β-catenin signaling in development and cancerBone health and osteoporosis research

High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5

Open access
Boyden, Lynn M., Mao, Junhao, Belsky, Joseph, Mitzner, Lyle, Farhi, Anita, Mitnick, Mary A., Wu, Dianqing, Insogna, Karl +1 more·2002·New England Journal of Medicine
DOI 10.1056/nejmoa013444
Open this paper in CoChat — free accountOpen PDF

Abstract

Background Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma. Methods We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus. Results Genetic analysis revealed linkage of the syndrome to chromosome 11q12-13 (odds of linkage, >1 million to 1), an interval that contains LRP5. Affected members of the kindred had a mutation in this gene, with valine substituted for glycine at codon 171 (LRP5V171). This mutation segregated with the trait in the family and was absent in control subjects. The normal glycine lies in a so-called propeller motif that is highly conserved from fruit flies to humans. Markers of bone resorption were normal in the affected subjects, whereas markers of bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5V171 and that this resulted in increased signaling due to unopposed Wnt activity. Conclusions The LRP5V171 mutation causes high bone density, with a thickened mandible and tor…

Integrity signals

Registry

Crossref · 10.1056/nejmoa013444

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [59]

  • 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 [59]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Boyden, L. M., Mao, J., Belsky, J., Mitzner, L., Farhi, A., Mitnick, M. A., Wu, D., Insogna, K., & Lifton, R. P.
Affiliations
  • Yale University (US)
  • UConn Health (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2002-05-16
Volume
346
Issue
20
Pages
1513-1521
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa013444
OpenAlex
W2086694435
Cited by
1,591
References
3
Citations by year
2026: 17 · 2025: 12 · 2024: 27 · 2023: 31 · 2022: 34 · 2021: 33 · 2020: 51 · 2019: 43 · 2018: 54 · 2017: 68 · 2016: 67 · 2015: 64 · 2014: 92 · 2013: 96 · 2012: 87
FWCI
25.68
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (AG15345, R01AG015345)
  • National Cancer Institute (R01CA085420, CA85420)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR046032, AR-46032)
  • National Center for Research Resources (M01RR000125, RR00125)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords
LRP5, Wnt signaling, DKK1, osteoporosis, autosomal dominant syndrome, torus mandibularis, torus palatinus, osteocalcin, fibronectin, bone formation, bone resorption, genetic linkage, loss-of-function mutations
MeSH terms
Chromosomes, Human, Pair 11, Female, Genes, Dominant, Genotype, Humans, Male, Mandible, Osteogenesis, Palate, Pedigree, Proteins, Proto-Oncogene Proteins, Radiography, Receptors, LDL, Syndrome, Signal Transduction, Biomarkers, Bone Density, Case-Control Studies, Point Mutation, Mutation, Missense, LDL-Receptor Related Proteins, Zebrafish Proteins, Intercellular Signaling Peptides and Proteins, Wnt Proteins, Low Density Lipoprotein Receptor-Related Protein-5

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review