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Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic  WFS1  mutations, but recessive mutations in a second gene,  CISD2 , have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous  CISD2  mutation (c.215A &gt; G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular  CISD2  mutation disturbs cellular Ca 2+  homeostasis with enhanced Ca 2+  flux from the ER to mitochondria and cytosolic Ca 2+  abnormalities in patient-derived fibroblasts. This Ca 2+  dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of  CISD2  mutations and the subsequent development of multisystemic disease.

A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca 2+ homeostasis and ER-mitochondria interactions