[PDF][PDF] Mutations in WNT1 cause different forms of bone fragility

K Keupp, F Beleggia, H Kayserili, AM Barnes… - The American Journal of …, 2013 - cell.com
K Keupp, F Beleggia, H Kayserili, AM Barnes, M Steiner, O Semler, B Fischer, G Yigit…
The American Journal of Human Genetics, 2013cell.com
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 …
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 β-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.
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