WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta

  • N Engl J Med. 2013 May 9;368(19):1809-16. doi: 10.1056/NEJMoa1215458.
Christine M Laine  1 ,  Kyu Sang Joeng ,  Philippe M Campeau ,  Riku Kiviranta ,  Kati Tarkkonen ,  Monica Grover ,  James T Lu ,  Minna Pekkinen ,  Maija Wessman ,  Terhi J Heino ,  Vappu Nieminen-Pihala ,  Mira Aronen ,  Tero Laine ,  Heikki Kröger ,  William G Cole ,  Anna-Elina Lehesjoki ,  Lisette Nevarez ,  Deborah Krakow ,  Cynthia J R Curry ,  Daniel H Cohn ,  Richard A Gibbs ,  Brendan H Lee ,  Outi Mäkitie
Affiliations
  • 1. Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
PMID: 23656646 DOI: 10.1056/NEJMoa1215458
Abstract

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.