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.
Subject(s)
Genes, Recessive/genetics , Mutation/genetics , Osteogenesis Imperfecta/genetics , Wnt1 Protein/genetics , Adult , Child , Child, Preschool , Disease Progression , Female , Humans , Infant , Male , Osteogenesis Imperfecta/pathology , Pedigree , Young AdultABSTRACT
Latent TGFB-binding protein 3 (LTBP3) is known to increase bio-availability of TGFB. A homozygous mutation in this gene has previously been associated with oligodontia and short stature in a single family. We report on two sisters with homozygous truncating mutations in LTBP3. In addition to oligodontia and short stature, both sisters have mitral valve prolapse, suggesting a link between truncating LTBP3 mutations and mitral valve disease mediated through the TGFB pathway.