title: Mutations in WNT1 cause different forms of bone fragility.
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.
authors.affiliation: Institute of Human Genetics, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Keupp
authors.forename: Filippo
authors.initials: F
authors.lastname: Beleggia
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.forename: Magdalena
authors.initials: M
authors.lastname: Steiner
authors.forename: Oliver
authors.initials: O
authors.lastname: Semler
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.forename: Claudia Y
authors.initials: CY
authors.lastname: Janda
authors.forename: Jutta
authors.initials: J
authors.lastname: Becker
authors.forename: Stefan
authors.initials: S
authors.lastname: Breer
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.forename: Johannes
authors.initials: J
authors.lastname: Grünhagen
authors.forename: Peter
authors.initials: P
authors.lastname: Krawitz
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Tufan
authors.initials: T
authors.lastname: Cankaya
authors.forename: José A
authors.initials: JA
authors.lastname: Caparrós-Martín
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Peer
authors.initials: P
authors.lastname: Eysel
authors.forename: Friederike
authors.initials: F
authors.lastname: Koerber
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
authors.forename: Christian
authors.initials: C
authors.lastname: Netzer
authors.forename: Eckhard
authors.initials: E
authors.lastname: Schönau
authors.forename: Victor L
authors.initials: VL
authors.lastname: Ruiz-Perez
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.forename: Joan
authors.initials: J
authors.lastname: Marini
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
mesh_terms: D000818:Animals; D001483:Base Sequence; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000473:pathology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D026502:LDL-Receptor Related Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D051155:Wnt1 Protein / Q000235:genetics*
chemical_list: D026502:LDL-Receptor Related Proteins; C495247:WNT1 protein, human; D051155:Wnt1 Protein