Mutations in WNT1 Cause Different Forms of Bone Fragility
AMERICAN JOURNAL OF HUMAN GENETICS, vol.92, no.4, pp.565-574, 2013 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 92 Issue: 4
- Publication Date: 2013
- Doi Number: 10.1016/j.ajhg.2013.02.010
- Journal Name: AMERICAN JOURNAL OF HUMAN GENETICS
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Page Numbers: pp.565-574
- Open Archive Collection: AVESIS Open Access Collection
- Dokuz Eylül University Affiliated: Yes
Abstract
We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.