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Osteogenesis Imperfecta Type V is an autosomal-dominant bone fragility disorder caused by recurrent mutations in the 5′-UTR of IFITM5, encoding a membrane protein enriched in osteoblasts, that introduce a novel in‐frame start codon and confer a neomorphic function to the protein. Clinically, patients present with hyperplastic callus formation, calcification of interosseous membranes, radial head dislocation and increased susceptibility to fractures with variable expressivity.
The association is supported by at least 69 unrelated probands: two simplex cases with de novo c.-14C>T (p.Met–Ala–Leu–Glu–Pro) variants in the 5′-UTR (PMID:22863195), one neonatal case with c.-9C>A (p.Met–Glu–Pro) (PMID:32383316), seven individuals from five families (PMID:26648832), four Chinese families (PMID:23977282), 42 individuals in a multi-center cohort (PMID:23240094), and 17 individuals from 12 families (PMID:23408678). In three multigenerational pedigrees, c.-14C>T fully cosegregated with disease, with five additional de novo occurrences (PMID:22863190). Variants are heterozygous and exclusively in the 5′-UTR, consistent with autosomal-dominant inheritance and highly penetrant hyperplastic callus phenotype.
Two distinct pathogenic UTR variants have been reported: c.-14C>T (p.Met–Ala–Leu–Glu–Pro) and c.-9C>A (p.Met–Glu–Pro), both creating upstream in-frame start codons that extend IFITM5’s N-terminus by five or three residues, respectively.
In vitro translation assays confirmed preferential usage of the novel upstream start codon over the reference site, producing an N-terminally extended protein (PMID:22863195). A transgenic mouse expressing the mutant IFITM5 under an osteoblast-specific promoter recapitulates OI-V skeletal defects, including delayed mineralization and hyperplastic callus formation (PMID:25251575). Luciferase reporter assays in osteoblastic cells showed that MALEP-IFITM5 activates MEF2, NFATc and NR4A transcriptional pathways, consistent with a gain-of-function mechanism (PMID:35216266). An inducible Ifitm5^flox c.-14C>T mouse model revealed ectopic chondrogenesis, SOX9 upregulation and arrest of osteogenic differentiation in vivo, elucidating the neomorphic pathogenic cascade (PMID:39908237).
Patients uniformly lack dentinogenesis imperfecta but display interosseous membrane calcification (100%), hyperplastic callus in ~65%, radial head dislocation in >50%, blue sclera in ~30% and scoliosis in >50%, with high phenotypic variability even within families. The recurrent UTR mutation accounts for ~4% of OI cases in referral centers and is pathognomonic for OI Type V.
Definitive evidence establishes that heterozygous UTR variants in IFITM5 cause autosomal-dominant Osteogenesis Imperfecta Type V via a neomorphic mechanism. Genetic testing for c.-14C>T and c.-9C>A variants is critical for diagnosis and management of bone fragility and hyperplastic callus formation.
Gene–Disease AssociationDefinitiveApproximately 69 unrelated probands across multiple families with segregation and de novo occurrences; concordant functional data over >10 years Genetic EvidenceStrong69 probands; complete cosegregation in families; de novo occurrences Functional EvidenceStrongIn vitro translation, reporter assays, and multiple mouse models demonstrating neomorphic mechanism and phenotype recapitulation |