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  • Title: WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta.
    Author: Pyott SM, Tran TT, Leistritz DF, Pepin MG, Mendelsohn NJ, Temme RT, Fernandez BA, Elsayed SM, Elsobky E, Verma I, Nair S, Turner EH, Smith JD, Jarvik GP, Byers PH.
    Journal: Am J Hum Genet; 2013 Apr 04; 92(4):590-7. PubMed ID: 23499310.
    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.
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