WNT1 Mutations in Early-Onset Osteoporosis and Osteogenesis Imperfecta

: Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, Grover M, Lu JT, Pekkinen M, Wessman M, Heino TJ, Nieminen-Pihala V, Aronen M, Laine T, Kroger H, Cole WG, Lehesjoki AE, Nevarez L, Krakow D, Curry CJR, Cohn DH, Gibbs RA, Lee BH, Makitie O

Publisher: MASSACHUSETTS MEDICAL SOC

: 2013

: New England Journal of Medicine

: NEW ENGLAND JOURNAL OF MEDICINE

: NEW ENGL J MED

: 19

: 368

: 19

: 1809

: 1816

: 8

: 0028-4793

DOI: https://doi.org/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(star). 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.