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Mutations in WNT1 Cause Different Forms of Bone Fragility

2013; Elsevier BV; Volume: 92; Issue: 4 Linguagem: Inglês

10.1016/j.ajhg.2013.02.010

1537-6605

Katharina Keupp, Filippo Beleggia, Hülya Kayserili, Aileen M. Barnes, Magdalena Steiner, Oliver Semler, Björn Fischer‐Zirnsak, Gökhan Yigit, Claudia Y. Janda, Jutta Becker, Stefan Breer, Umut Altunoğlu, Johannes Grünhagen, Peter Krawitz, Jochen Hecht, Thorsten Schinke, Elena Makareeva, Ekkehart Lausch, Tufan Çankaya, José A. Caparrós‐Martín, Pablo Lapunzina, Samia A. Temtamy, Mona Aglan, Bernhard Zabel, Peer Eysel, Friederike Koerber, Sergey Leikin, K. Christopher García, Christian Netzer, Eckhard Schönaü, Víctor L. Ruiz‐Pérez, Stefan Mundlos, Michael Amling, Uwe Kornak, Joan C. Marini, Bernd Wollnik,

Cancer-related gene regulation

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. 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.