[PDF][PDF] WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta

SM Pyott, TT Tran, DF Leistritz, MG Pepin… - The American Journal of …, 2013 - cell.com
SM Pyott, TT Tran, DF Leistritz, MG Pepin, NJ Mendelsohn, RT Temme, BA Fernandez
The American Journal of Human Genetics, 2013cell.com
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 …
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.
cell.com