A Mutation in the 5′-UTR of IFITM5 Creates an In-Frame Start Codon and Causes Autosomal-Dominant Osteogenesis Imperfecta Type V with Hyperplastic Callus

Abstract

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.

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] On the contrary, here 15/32 families with no mutation in collagen I had a typical type I phenotype, and 25 additional families were excluded on the basis of a negative sequencing result in combination with an unclear clinical phenotype. These individuals may have a COL1A1 null allele caused by a non-exonic mutation missed here; however, another OI-related gene might be causative in some instances.…”

“…Dominant mutations in collagen type I are generally stated to be responsible for 90% of cases, while a plethora of other genes have been associated with non-collagen OI in recent years. [1][2][3][4][5][6][7][8][9][10][11][12][13] Collagen type I, encoded by COL1A1 and COL1A2, constitutes 85% of the organic matrix in skeletal tissue, and forms a framework for mineral deposition, rendering bone the tensile properties needed to withstand torsion and bending powers. Procollagen is a heterotrimer, with a helical 1014-amino acid-long central stretch of two α1-and one α2-chains, which is flanked by globular N-and C-terminal regions.…”

Osteogenesis imperfecta

“…BRIL seems to have a crucial role during bone mineralization. Interestingly, mutations in the gene that encodes BRIL seem to have a gain of function effect if the protein is elongated, inducing increased bone for mation, which leads to hyperplastic callus and ossifica tion of membranes, whereas mutations in the coding regions impair mineralization of bone 86,88 .…”

Effect of high-dose vitamin D supplementation on bone density in youth with osteogenesis imperfecta: A randomized controlled trial

“…This OI type has been diagnosed in about 5% of all OI cases seen in hospitals [1]. In 2012, whole-exome sequencing of an OI type V patient and her parents allowed for the discovery of a de novo mutation within the gene encoding interferon-induced transmembrane protein 5 (IFITM5) [40]. The IFITM5 gene, also known as Bril (bone-restricted interferon-induced transmembrane protein-like protein), is likely implicated in early mineralization but its exact mechanism in relation to collagen has yet to be elucidated [8,40].…”