Mutations in WNT1 Cause Different Forms of Bone Fragility

摘要: 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, splice-site nonsense mutation. addition, family affected dominantly inherited early-onset osteoporosis, heterozygous mutation was individuals. Initial functional analysis revealed altered proteins fail to activate canonical LRP5-mediated WNT-regulated β-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating role osteoblast function development. Our finding variants predispose low-bone-mass phenotypes might advance the development more effective therapeutic strategies for forms fragility, as well common age-related osteoporosis.