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A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor.

ABSTRACT: Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, a transmembrane ifitm-like protein most strongly expressed in the skeletal system, and recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. SERPINF1 sequences were normal despite bone histomorphometry consistent with type VI OI and elevated childhood serum alkaline phosphatase. We performed exome sequencing on the proband, both parents, and an unaffected sibling. IFITM5 emerged as the candidate gene from bioinformatics analysis, and was corroborated by membership in a murine bone co-expression network module containing all currently known OI genes. The de novo IFITM5 mutation was confirmed in one allele of the proband, resulting in a p.S40L substitution in the intracellular domain of BRIL but was absent in unaffected family members. IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control in differentiated proband osteoblasts on Western blot and in permeabilized mutant osteoblasts by microscopy. In contrast, SERPINF1 expression was decreased in proband osteoblasts; PEDF was barely detectable in conditioned media of proband cells. Expression and secretion of type I collagen was similarly decreased in proband osteoblasts; the expression pattern of several osteoblast markers largely overlapped reported values from cells with a primary PEDF defect. In contrast, osteoblasts from a typical case of type V OI, with an activating mutation at the 5'-terminus of BRIL, have increased SERPINF1 expression and PEDF secretion during osteoblast differentiation. Together, these data suggest that BRIL and PEDF have a relationship that connects the genes for types V and VI OI and their roles in bone mineralization.

SUBMITTER: Farber CR

PROVIDER: S-EPMC4352343 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor.

Farber Charles R CR Reich Adi A Barnes Aileen M AM Becerra Patricia P Rauch Frank F Cabral Wayne A WA Bae Alison A Quinlan Aaron A Glorieux Francis H FH Clemens Thomas L TL Marini Joan C JC

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20140601 6

Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, a transmembrane ifitm-like protein most strongly expressed in the skeletal system, and recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. SERPINF1 s ...[more]

PMID: 24519609

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Project description:BackgroundOsteogenesis imperfecta (OI) covers a spectrum of bone fragility disorders. OI is classified into five types; however, the genetic causes of OI might hide in pathogenic variants of 20 different genes. Often clinical OI types mimic each other. This sometimes makes it impossible to identify the OI type clinically, which can be a risk for patients. Up to 90% of OI types I-IV are caused by pathogenic variants in the COL1A1/2 genes. OI type V is caused by the c.-14C > T pathogenic variant in the 5'UTR of the IFITM5 gene and is characterized by hyperplastic callus formation and the ossification of interosseous membranes.ResultsIn the current study, we performed IFITM5 5'UTR region mutational analysis using Sanger sequencing on 90 patients who were negative for COL1A1/2 pathogenic variants. We also investigated the phenotypes of five patients with genetically confirmed OI type V. The proportion of OI type V patients in our cohort of all OI patients was 1.48%. In one family, there was a history of OI in at least three generations. Phenotype severity differed from mild to extremely severe among patients, but all patients harbored the same typical pathogenic variant. One patient had no visible symptoms of OI type V and was suspected to have had OI type IV previously. We also identified a case of extremely severe hyperplastic callus in a 15-year-old male, who has hearing loss and brittleness of teeth.ConclusionsOI type V is underlined with some unique clinical features; however, not all patients develop them. The phenotype spectrum might be even broader than previously suspected, including typical OI features: teeth brittleness, bluish sclera, hearing loss, long bones deformities, and joint laxity. We suggest that all patients negative for COL1A1/2 pathogenic variants be tested for the presence of an IFITM5 pathogenic variant, even if they are not expressing typical OI type V symptoms. Further studies on the pathological nature and hyperplastic callus formation mechanisms of OI type V are necessary.

Dataset Information

A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor.

Publications

A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor.

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