Abstract
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 > 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 Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ 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.
Highlights
Wolfram syndrome (WS, OMIM #222300), known historically as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness), is an autosomal recessive disorder characterized by the association of diabetes mellitus and early-onset optic atrophy, which can occur in varying combinations with diabetes insipidus, sensorineural deafness, renal tract abnormalities or neuropsychiatric disorders [1,2]
We identified a novel homozygous CISD2 variant (c.215A > G; p.Asn72Ser) and the corroborative evidence we have provided all point towards its pathogenicity, namely: (i) co-segregation of this variant with affected disease status in a consanguineous family; (ii) the high degree of evolutionary conservation of the Asn amino acid residue located at position 72 in the functionally important cluster-binding domain of the protein; (iii) the absence of the c.215A > G variant in normative SNP and exome databases and; (iv) in silico evidence predicting a disease causing effect based on the induced conformational change of the CISD2 homodimeric protein model
All the patients with CISD2 mutations reported to date have developed peptic ulcer disease and a significant bleeding tendency, suggesting a possible genotypephenotype association that is peculiar to Wolfram syndrome type 2 (WFS2)
Summary
Wolfram syndrome (WS, OMIM #222300), known historically as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness), is an autosomal recessive disorder characterized by the association of diabetes mellitus and early-onset optic atrophy, which can occur in varying combinations with diabetes insipidus, sensorineural deafness, renal tract abnormalities or neuropsychiatric disorders [1,2]. CISD2, which is known as Miner 1 or ERIS, is an integral membrane protein that localizes to the mitochondria-associated ER membranes (MAMs) and the evidence so far suggests a dynamic distribution between the ER and the mitochondrial outer membrane [10] It has a role in maintaining both the structural integrity and the functional cross-talk between the ER and mitochondria, which in turn is crucial for the regulation of glucose homeostasis and insulin sensitivity [11,12]. Unlike Wolframin encoded by WFS1, whose functions have been extensively studied, the biological functions of CISD2 still remain incompletely defined Both proteins seem to share overlapping functions with pivotal roles in regulating intracellular Ca2þ homeostasis, the ER stress response and autophagy [13,14,15]
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