Mutations in WNT1 cause different forms of bone fragility

  • Am J Hum Genet. 2013 Apr 4;92(4):565-74. doi: 10.1016/j.ajhg.2013.02.010.
Katharina Keupp  1 ,  Filippo Beleggia ,  Hülya Kayserili ,  Aileen M Barnes ,  Magdalena Steiner ,  Oliver Semler ,  Björn Fischer ,  Gökhan Yigit ,  Claudia Y Janda ,  Jutta Becker ,  Stefan Breer ,  Umut Altunoglu ,  Johannes Grünhagen ,  Peter Krawitz ,  Jochen Hecht ,  Thorsten Schinke ,  Elena Makareeva ,  Ekkehart Lausch ,  Tufan Cankaya ,  José A Caparrós-Martín ,  Pablo Lapunzina ,  Samia Temtamy ,  Mona Aglan ,  Bernhard Zabel ,  Peer Eysel ,  Friederike Koerber ,  Sergey Leikin ,  K Christopher Garcia ,  Christian Netzer ,  Eckhard Schönau ,  Victor L Ruiz-Perez ,  Stefan Mundlos ,  Michael Amling ,  Uwe Kornak ,  Joan Marini ,  Bernd Wollnik
Affiliations
  • 1. Institute of Human Genetics, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
PMID: 23499309 DOI: 10.1016/j.ajhg.2013.02.010
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 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.