WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta

N Engl J Med. 2013 May 9;368(19):1809-16. doi: 10.1056/NEJMoa1215458.


This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T→G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C→A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Animals
  • Child
  • Female
  • Genes, Dominant
  • Genes, Recessive
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Mutation*
  • Osteogenesis Imperfecta / genetics*
  • Osteoporosis / genetics*
  • Pedigree
  • Wnt1 Protein / genetics*
  • Wnt1 Protein / metabolism
  • Young Adult


  • WNT1 protein, human
  • Wnt1 Protein
  • Wnt1 protein, mouse