title: A mutation in the 5'-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus.
abstract: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ~65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5'-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.-14C>T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.-14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation.
authors.affiliation: Children's Hospital, University of Cologne, 50924 Cologne, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Semler
authors.forename: Lutz
authors.initials: L
authors.lastname: Garbes
authors.forename: Katharina
authors.initials: K
authors.lastname: Keupp
authors.forename: Daniel
authors.initials: D
authors.lastname: Swan
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Jutta
authors.initials: J
authors.lastname: Becker
authors.forename: Sandra
authors.initials: S
authors.lastname: Iden
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Peer
authors.initials: P
authors.lastname: Eysel
authors.forename: Friederike
authors.initials: F
authors.lastname: Koerber
authors.forename: Eckhard
authors.initials: E
authors.lastname: Schoenau
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Christian
authors.initials: C
authors.lastname: Netzer
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D015502:Absorptiometry, Photon; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D018387:Codon, Initiator / Q000235:genetics; D019295:Computational Biology; D004164:Diphosphonates / Q000627:therapeutic use; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D020121:5' Untranslated Regions; D018387:Codon, Initiator; D004164:Diphosphonates; C575746:IFITM5 protein, human; D008565:Membrane Proteins