title: Mutations in WNT1 are a cause of osteogenesis imperfecta.
abstract: BACKGROUND
  Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually due to dominant mutations in COL1A1 or COL1A2. Rare recessive forms of OI, caused by mutations in genes involved in various aspects of bone formation, have been described as well.
  
  
  OBJECTIVE
  To identify the cause of OI in eight children with severe bone fragility and a clinical diagnosis of OI type IV who had had negative results on COL1A1/COL1A2 Sanger sequencing.
  
  
  METHODS
  Whole exome sequencing was performed in genomic DNA samples from all eight individuals.
  
  
  RESULTS
  WNT1 mutations were found in four children from three families. WNT1 was the only gene where mutations were found in all of these four patients. Two siblings from a consanguineous family had a homozygous missense mutation affecting a highly conserved cysteine residue in WNT1 (c.428G>T (p.Cys143Phe)). One girl had a homozygous frameshift deletion (c.287_300del(p.Gln96Profs)). A girl from a third family was compound heterozygous for a frameshift insertion and a missense mutation affecting a conserved amino acid (c.946_949insAACA (p.Ser317Lysfs); c.1063G>T (p.Val355Phe)). All of these children had short stature, low bone density, and severe vertebral compression fractures in addition to multiple long bone fractures in the first years of life. The Wnt signalling pathway is one of the key regulators of osteoblast activity.
  
  
  CONCLUSIONS
  Recessive inactivating mutations in WNT1 are a new cause of OI type IV.
authors: Department of Human Genetics, McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada.
authors: Somayyeh
authors: S
authors: Fahiminiya
authors: Jacek
authors: J
authors: Majewski
authors: John
authors: J
authors: Mort
authors: Pierre
authors: P
authors: Moffatt
authors: Francis H
authors: FH
authors: Glorieux
authors: Frank
authors: F
authors: Rauch
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001842:Bone and Bones / Q000000981:diagnostic imaging*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010375:Pedigree; D011487:Protein Conformation; D011859:Radiography; D017422:Sequence Analysis, DNA; D051155:Wnt1 Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: C495247:WNT1 protein, human; D051155:Wnt1 Protein