Mutations in WNT1 Cause Different Forms of Bone Fragility

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• 作者：Katharina Keupp¹ ; ² ; ³ ; Filippo Beleggia¹ ; ² ; ³ ; Hü ; lya Kayserili⁴ ; Aileen M. Barnes⁵ ; Magdalena Steiner⁶ ; Oliver Semler⁷ ; Bjö ; rn Fischer⁶ ; Gö ; khan Yigit¹ ; ² ; ³ ; Claudia Y. Janda⁸ ; Jutta Becker¹ ; Stefan Breer⁹ ; Umut Altunoglu⁴ ; Johannes Grü ; nhagen⁶ ; Peter Krawitz⁶ ; Jochen Hecht¹⁰ ; Thorsten Schinke⁹ ; Elena Makareeva¹¹ ; Ekkehart Lausch¹² ; Tufan Cankaya¹³ ; José ; A. Caparró ; s-Martí ; n¹⁴ ; ¹⁵ ; Pablo Lapunzina¹⁵ ; ¹⁶ ; Samia Temtamy¹⁷ ; Mona Aglan¹⁷ ; Bernhard Zabel¹² ; Peer Eysel¹⁸ ; Friederike Koerber¹⁹ ; Sergey Leikin¹¹ ; K. Christopher Garcia⁸ ; Christian Netzer¹ ; Eckhard Schö ; nau⁷ ; Victor L. Ruiz-Perez¹⁴ ; ¹⁵ ; Stefan Mundlos⁶ ; ²⁰ ; Michael Amling⁹ ; Uwe Kornak⁶ ; ²⁰ ; ^{uwe.kornak@charite.de} ; Joan Marini⁵ ; Bernd Wollnik¹ ; ² ; ³ ; ^{bwollnik@uni-koeln.de}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：4 April, 2013
• 年：2013
• 卷：92
• 期：4
• 页码：565-574
• 全文大小：1017 K

文摘

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 ¦Â-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.