Mutations in WNT1 Cause Different Forms of Bone Fragility

被引：234

作者：

Keupp, Katharina ^{[1
,2
,3
]}

Beleggia, Filippo ^{[1
,2
,3
]}

Kayserili, Hulya ^{[4
]}

Barnes, Aileen M. ^{[5
]}

Steiner, Magdalena ^{[6
]}

Semler, Oliver ^{[7
]}

Fischer, Bjoern ^{[6
]}

Yigit, Goekhan ^{[1
,2
,3
]}

Janda, Claudia Y. ^{[8
,9
]}

Becker, Jutta ^{[1
]}

Breer, Stefan ^{[10
]}

Altunoglu, Umut ^{[4
]}

Gruenhagen, Johannes ^{[6
]}

Krawitz, Peter ^{[6
]}

Hecht, Jochen ^{[11
]}

Schinke, Thorsten ^{[10
]}

Makareeva, Elena ^{[12
]}

Lausch, Ekkehart ^{[13
]}

Cankaya, Tufan ^{[14
]}

Caparros-Martin, Jose A. ^{[15
,16
,17
]}

Lapunzina, Pablo ^{[17
,18
]}

Temtamy, Samia ^{[19
]}

Aglan, Mona ^{[19
]}

Zabel, Bernhard ^{[13
]}

Eysel, Peer ^{[20
]}

Koerber, Friederike ^{[21
]}

Leikin, Sergey ^{[12
]}

Garcia, K. Christopher ^{[8
,9
]}

Netzer, Christian ^{[1
]}

Schoenau, Eckhard ^{[7
]}

Ruiz-Perez, Victor L. ^{[15
,16
,17
]}

Mundlos, Stefan ^{[6
,22
]}

Amling, Michael ^{[10
]}

Kornak, Uwe ^{[6
,22
]}

Marini, Joan ^{[5
]}

Wollnik, Bernd ^{[1
,2
,3
]}

机构：

[1] Univ Cologne, Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany

[2] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany

[3] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

[4] Istanbul Univ, Istanbul Fac Med, Dept Med Genet, TR-34093 Istanbul, Turkey

[5] NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA

[6] Charite, Inst Med Genet & Human Genet, D-13353 Berlin, Germany

[7] Univ Cologne, Childrens Hosp, D-50931 Cologne, Germany

[8] Stanford Univ, Sch Med, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA

[9] Stanford Univ, Sch Med, Howard Hughes Med Inst, Dept Biol Struct, Stanford, CA 94305 USA

[10] Univ Med Ctr Hamburg Eppendorf, Dept Osteol & Biomech, D-20246 Hamburg, Germany

[11] Berlin Brandenburg Ctr Regenerat Therapies, D-13353 Berlin, Germany

[12] NICHHD, Sect Phys Biochem, NIH, Bethesda, MD 20892 USA

[13] Univ Freiburg, Childrens Hosp, Div Genet, D-79106 Freiburg, Germany

[14] Dokuz Eylul Univ, Fac Med, Dept Med Genet, TR-35210 Izmir, Turkey

[15] CSIC, Inst Invest Biomed, E-28029 Madrid, Spain

[16] Univ Autonoma Madrid, Madrid 28029, Spain

[17] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain

[18] Univ Autonoma Madrid, Inst Genet Med & Mol, Inst Invest Hosp Univ La Paz, Madrid 28046, Spain

[19] Natl Res Ctr, Human Genet & Genome Res Div, Cairo 12311, Egypt

[20] Univ Cologne, Dept Orthopaed & Traumat Surg, D-50931 Cologne, Germany

[21] Univ Cologne, Dept Radiol, D-50931 Cologne, Germany

[22] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2013年 / 92卷 / 04期

基金：

美国国家卫生研究院;

关键词：

RECESSIVE OSTEOGENESIS IMPERFECTA; OSTEOPOROSIS-PSEUDOGLIOMA SYNDROME; MINERAL DENSITY; IN-VIVO; IDENTIFICATION; PROTOONCOGENE; METAANALYSIS; DISORDERS; FRACTURE; REVEALS;

D O I：

10.1016/j.ajhg.2013.02.010

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 beta-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.

引用

页码：565 / 574

页数：10

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