Exome sequencing with functional follow-up identifies KIF26B as a novel genetic determinant of familial osteoporosis

Abstract

OBJECTIVES: Genetic factors play an important role in osteoporosis pathogenesis. The study aimed to identify the genetic determinants of primary osteoporosis in a Maltese family, and investigate functionality of novel genes and variants using in vitro and in vivo methods.

METHODS: A 2-generation family of 12 relatives (including 7 siblings) aged 34–77 years was recruited. Osteoporosis was defined using DXA scans of the lumbar spine (LS) and hip. The proband had a LS T-score of - 4.0. Exome sequencing was performed on 6 relatives and replication of shortlisted variants was sought in the Malta Osteoporotic Fracture Study (MOFS, n = 1012). In vitro protein expression was analysed by transfecting in COS-7 cells and western blotting, whereas gene knockout consequences in zebrafish were assessed through measurements of BMD by micro-computed tomography, mineralisation rate using Alizarin red staining of the skeleton, and resorption activity by TRAcP staining of regenerating scales.

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