title: WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta.
abstract: Osteogenesis imperfecta (OI) is a heritable disorder that ranges in severity from death in the perinatal period to an increased lifetime risk of fracture. Mutations in COL1A1 and COL1A2, which encode the chains of type I procollagen, result in dominant forms of OI, and mutations in several other genes result in recessive forms of OI. Here, we describe four recessive-OI-affected families in which we identified causative mutations in wingless-type MMTV integration site family 1 (WNT1). In family 1, we identified a homozygous missense mutation by exome sequencing. In family 2, we identified a homozygous nonsense mutation predicted to produce truncated WNT1. In family 3, we found a nonsense mutation and a single-nucleotide duplication on different alleles, and in family 4, we found a homozygous 14 bp deletion. The mutations in families 3 and 4 are predicted to result in nonsense-mediated mRNA decay and the absence of WNT1. WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD) and the coreceptor low-density lipoprotein-receptor-related protein 5 (LRP5). Biallelic loss-of-function mutations in LRP5 result in recessive osteoporosis-pseudoglioma syndrome with low bone mass, whereas heterozygous gain-of-function mutations result in van Buchem disease with elevated bone density. Biallelic loss-of-function mutations in WNT1 result in a recessive clinical picture that includes bone fragility with a moderately severe and progressive presentation that is not easily distinguished from dominant OI type III.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA. shawnap@uw.edu
authors.forename: Shawna M
authors.initials: SM
authors.lastname: Pyott
authors.forename: Thao T
authors.initials: TT
authors.lastname: Tran
authors.forename: Dru F
authors.initials: DF
authors.lastname: Leistritz
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Pepin
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Mendelsohn
authors.forename: Renee T
authors.initials: RT
authors.lastname: Temme
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.forename: Solaf M
authors.initials: SM
authors.lastname: Elsayed
authors.forename: Ezzat
authors.initials: E
authors.lastname: Elsobky
authors.forename: Ishwar
authors.initials: I
authors.lastname: Verma
authors.forename: Sreelata
authors.initials: S
authors.lastname: Nair
authors.forename: Emily H
authors.initials: EH
authors.lastname: Turner
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D051155:Wnt1 Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: C495247:WNT1 protein, human; D051155:Wnt1 Protein