Mutations in WNT1 cause different forms of bone fragility
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Mutations in WNT1 cause different forms of bone fragility. / Keupp, Katharina; Beleggia, Filippo; Kayserili, Hülya; Barnes, Aileen M; Steiner, Magdalena; Semler, Oliver; Fischer, Björn; Yigit, Gökhan; Janda, Claudia Y; Becker, Jutta; Breer, Stefan; Altunoglu, Umut; Grünhagen, Johannes; Krawitz, Peter; Hecht, Jochen; Schinke, Thorsten; Makareeva, Elena; Lausch, Ekkehart; Cankaya, Tufan; Caparrós-Martín, José A; Lapunzina, Pablo; Temtamy, Samia; Aglan, Mona; Zabel, Bernhard; Eysel, Peer; Koerber, Friederike; Leikin, Sergey; Garcia, K Christopher; Netzer, Christian; Schönau, Eckhard; Ruiz-Perez, Victor L; Mundlos, Stefan; Amling, Michael; Kornak, Uwe; Marini, Joan; Wollnik, Bernd.
in: AM J HUM GENET, Jahrgang 92, Nr. 4, 04.04.2013, S. 565-74.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mutations in WNT1 cause different forms of bone fragility
AU - Keupp, Katharina
AU - Beleggia, Filippo
AU - Kayserili, Hülya
AU - Barnes, Aileen M
AU - Steiner, Magdalena
AU - Semler, Oliver
AU - Fischer, Björn
AU - Yigit, Gökhan
AU - Janda, Claudia Y
AU - Becker, Jutta
AU - Breer, Stefan
AU - Altunoglu, Umut
AU - Grünhagen, Johannes
AU - Krawitz, Peter
AU - Hecht, Jochen
AU - Schinke, Thorsten
AU - Makareeva, Elena
AU - Lausch, Ekkehart
AU - Cankaya, Tufan
AU - Caparrós-Martín, José A
AU - Lapunzina, Pablo
AU - Temtamy, Samia
AU - Aglan, Mona
AU - Zabel, Bernhard
AU - Eysel, Peer
AU - Koerber, Friederike
AU - Leikin, Sergey
AU - Garcia, K Christopher
AU - Netzer, Christian
AU - Schönau, Eckhard
AU - Ruiz-Perez, Victor L
AU - Mundlos, Stefan
AU - Amling, Michael
AU - Kornak, Uwe
AU - Marini, Joan
AU - Wollnik, Bernd
N1 - Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2013/4/4
Y1 - 2013/4/4
N2 - 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.
AB - 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.
KW - Animals
KW - Base Sequence
KW - Bone Density
KW - Bone and Bones
KW - Cells, Cultured
KW - Child
KW - Child, Preschool
KW - Female
KW - Heterozygote
KW - Humans
KW - Infant, Newborn
KW - LDL-Receptor Related Proteins
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Molecular Sequence Data
KW - Mutation
KW - Osteoblasts
KW - Osteogenesis Imperfecta
KW - Osteoporosis
KW - Pedigree
KW - Phenotype
KW - Pregnancy
KW - Wnt1 Protein
U2 - 10.1016/j.ajhg.2013.02.010
DO - 10.1016/j.ajhg.2013.02.010
M3 - SCORING: Journal article
C2 - 23499309
VL - 92
SP - 565
EP - 574
JO - AM J HUM GENET
JF - AM J HUM GENET
SN - 0002-9297
IS - 4
ER -