부산대학교 도서관

BackgroundOsteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterised by susceptibility to fractures, primarily due to defects in type 1 collagen. The aim of this study is to present a novel OI phenotype and its causative candidate gene.MethodsWhole-exome sequencing and clinical evaluation were performed in five patients from two unrelated families. PHLDB1mRNA expression in blood and fibroblasts was investigated by real-time PCR, and western blot analysis was further performed on skin fibroblasts.ResultsThe common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. We identified biallelic NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del pathogenic variants in PHLDB1in the affected patients, respectively, in the families; parents were heterozygous for these variants. PHLDB1encodes pleckstrin homology-like domain family B member-1 (PHLDB1) protein, which has a role in insulin-dependent Akt phosphorylation. Compared with controls, a decrease in the expression levels of PHLDB1in the blood and skin fibroblast samples was detected. Western blot analysis of cultured fibroblasts further confirmed the loss of PHLDB1.ConclusionTwo biallelic frameshift variants in the candidate gene PHLDB1were identified in independent families with a novel, mild-type, autosomal recessive OI. The demonstration of decreased PHLDB1mRNA expression levels in blood and fibroblast samples supports the hypothesis that PHLDB1pathogenic variants are causative for the observed phenotype.