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

Affiliation

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.

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