title: The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; and causes varying phenotypic severity of osteogenesis imperfecta type V.
abstract: BACKGROUND
  The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5' untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V.
  
  
  METHODS
  Sanger sequencing of the IFITM5 5' UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5.
  
  
  RESULTS
  All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone.
  
  
  CONCLUSIONS
  The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.
authors.forename: Syndia
authors.initials: S
authors.lastname: Lazarus
authors.forename: Aideen M
authors.initials: AM
authors.lastname: McInerney-Leo
authors.forename: Fiona A
authors.initials: FA
authors.lastname: McKenzie
authors.forename: Gareth
authors.initials: G
authors.lastname: Baynam
authors.forename: Stephanie
authors.initials: S
authors.lastname: Broley
authors.forename: Barbra V
authors.initials: BV
authors.lastname: Cavan
authors.forename: Craig F
authors.initials: CF
authors.lastname: Munns
authors.forename: Johannes Egbertus Hans
authors.initials: JE
authors.lastname: Pruijs
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Paulien A
authors.initials: PA
authors.lastname: Terhal
authors.forename: Karena
authors.initials: K
authors.lastname: Pryce
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.forename: Gethin
authors.initials: G
authors.lastname: Thomas
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia. e.duncan@uq.edu.au.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D002146:Bony Callus / Q000473:pathology; D002114:Calcinosis / Q000209:etiology; D002648:Child; D018387:Codon, Initiator / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005598:Fractures, Spontaneous / Q000209:etiology; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia; D004204:Joint Dislocations / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010013:Osteogenesis Imperfecta / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011884:Radius; D017422:Sequence Analysis, DNA
chemical_list: D020121:5' Untranslated Regions; D018387:Codon, Initiator; D018076:DNA, Complementary; D012333:RNA, Messenger