Osteogenesis imperfecta (OI) is a genetically heterogeneous disorder characterised by bone fragility. Most cases result from dominant mutations in type I collagen, while recessive OI is caused by defects in genes whose products interact with type I collagen. Type V OI has dominant inheritance, with characteristic skeletal findings and mesh-like lamellation on bone histology. It is caused by a unique heterozygous mutation in IFITM5 (c.-14C>T), which encodes BRIL, a transmembrane protein expressed in osteoblasts. The mutation generates a start codon in the 5′-UTR, adding five residues to the BRIL N-terminus. However, the mechanism of type V OI and its relationship with type I collagen is unknown. We identified 8 patients with the IFITM5 (c.-14C(T) mutation. Using cultured osteoblasts from patients with characteristic type V OI, we verified expression and stability of mutant IFITM5 transcripts. In differentiated type V OI primary osteoblasts in culture, IFITM5 expression and BRIL protein level is comparable to control. Both early (ALPL and IBSP) and late (osteopontin and osteocalcin) markers of osteoblast differentiation are increased in type V OI osteoblasts. Mineralisation, assayed by alizarin red staining, was increased in type V OI osteoblasts compared with control. In contrast to other differentiation markers, type V OI osteoblasts have less than half the level of COL1A1 transcripts found in control in mid to late differentiation, with concomitantly decreased collagen protein secretion. Decreased secreted type I collagen underlies decreased crosslinked collagen in matrix, and altered appearance of fibrils deposited in culture. The increased mineralisation and advanced differentiation of type V OI osteoblasts likely underlie the overactive tissue calcification and hypertrophic callus formation seen in affected individuals and demonstrates that type V OI has a gain-of-function mechanism. Decreased type I collagen expression, secretion and matrix incorporation establish type V OI as a collagen-related defect.
Disclosure: The authors declared no competing interests.