IFITM5 – IFITM5-related Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone fragility and recurrent fractures. OI type V presents with autosomal-dominant inheritance, hyperplastic callus formation, interosseous membrane calcification, and radial head dislocation. The IFITM5 gene (encoding BRIL) is specifically expressed in osteoblasts and was linked to OI type V by the discovery of a recurrent heterozygous c.-14C>T variant in the 5′-UTR, which adds five amino acids (MALEP) to the N-terminus of BRIL (PMID:22863190).

Genetic studies show complete cosegregation of c.-14C>T with OI type V in three multigenerational pedigrees and de novo occurrence in five simplex cases (PMID:22863190). In a cohort of 598 OI individuals, IFITM5 variants accounted for 9% of moderate-to-severe cases, confirming its recurrent involvement in OI pathogenesis (PMID:27509835). Additional coding region mutations, notably c.119C>T (p.Ser40Leu), have been reported in sporadic severe OI cases lacking type V features, expanding the phenotypic spectrum (PMID:24293101).

Autosomal-dominant segregation in affected relatives underscores inheritance; at least three additional family members per pedigree carry the c.-14C>T variant, affirming high penetrance (PMID:22863190). To date, over 35 unrelated probands with pathogenic IFITM5 variants have been described, including rare UTR (c.-9C>A) and coding (c.143A>G, p.Asn48Ser) changes linked to atypical bone phenotypes (PMID:32383316; PMID:38681748).

Functional assays demonstrate that the c.-14C>T mutation introduces an upstream in-frame start codon, generating MALEP-IFITM5 protein. This neomorphic protein impairs osteoblast differentiation, reduces mineralization in vitro, and activates MEF2, NFATc, and NR4A transcriptional pathways (PMID:22863195; PMID:35216266).

Mouse models corroborate the neomorphic mechanism: Ifitm5-deficient mice show only mild prenatal bone size reduction without overt OI phenotypes (PMID:20838829), whereas transgenic expression of MALEP-IFITM5 recapitulates OI type V features, including hypomineralization, long bone deformities, and fractures (PMID:25251575).

There is no robust evidence disputing IFITM5’s role in OI type V; instead, coding region variants such as p.Ser40Leu associate with more severe, non-type V phenotypes, highlighting genotype–phenotype correlations within IFITM5 alterations.

Key Take-home: The definitive association of IFITM5 with autosomal-dominant OI, driven by a neomorphic 5′-UTR mutation, supports its inclusion in diagnostic panels and suggests targeted exploration of MALEP-mediated signaling for therapeutic intervention.

References

• American journal of human genetics • 2012 • A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. PMID:22863190
• Journal of bone and mineral research • 2014 • A nonclassical IFITM5 mutation located in the coding region causes severe osteogenesis imperfecta with prenatal onset. PMID:24293101
• Journal of bone and mineral research • 2015 • A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. PMID:25251575
• Journal of bone and mineral metabolism • 2011 • Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. PMID:20838829
• Osteoporosis international • 2016 • DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. PMID:27509835
• International journal of molecular sciences • 2022 • The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts. PMID:35216266
• Bone reports • 2024 • IFITM5-related (type V) osteogenesis imperfecta with evidence of perinatal involvement: A case report. PMID:38681748

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