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.