BoneKEy Reports | BoneKEy Watch

WNT1 mutations responsible for rare forms of genetic bone disease

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DOI:10.1038/bonekey.2013.135

A study of two families has explored the phenotypic effects of mutations in the gene encoding WNT1. The first family had several members with severe, dominantly inherited osteoporosis presenting in early life. The second had two daughters, aged 23 and 26 years, with presumed severe osteogenesis imperfecta.

Genetic analysis revealed mutations in WNT1 in both families. In the first, a heterozygous missense mutation was found in the first cysteine of the WNT1 motif, a portion of the gene that is conserved across different species and within the WNT1 family. In the second, a homozygous nonsense mutation in WNT1 was discovered in both affected daughters (the parents were heterozygous). Located in the last exon of WNT1, this led to a truncation of the last 76 amino acids of the WNT1 protein.

Experiments in vitro showed that proteins expressed by both variant forms of WNT1 could not participate in normal canonical WNT signaling. They did not induce bone mineralization or interact with the usual target genes of WNT1. Analysis of the Wnt1 expression pattern in mice revealed clear evidence of expression in the bone marrow, particularly in hematopoietic progenitor cells and in the B-cell lineage.

Editor’s comment: This is the first report to demonstrate that mutations in WNT1 cause severe osteoporosis. The authors also suggest that bone formation may be regulated by a complex interplay between hematopoietic cells and osteocytes, orchestrated by WNT1-mediated signaling.

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