2. Academic Validation
  3. Mutations in WNT1 cause different forms of bone fragility

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

Affiliation

  • 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.

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