A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions.
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.
Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France.
Cécile
C
Rouzier
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
David
D
Moore
Fédération de Neurologie, Université Pierre et Marie Curie et Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Cécile
C
Delorme
Joint Centre for Applied Electron Microscopy, Nice Sophia-Antipolis University, Nice, France.
Sandra
S
Lacas-Gervais
Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France.
Samira
S
Ait-El-Mkadem
Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France.
Konstantina
K
Fragaki
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
Florence
F
Burté
UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, Paris, France.
Valérie
V
Serre
Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France.
Sylvie
S
Bannwarth
Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France.
Annabelle
A
Chaussenot
UMR 7622 CNRS et UPMC et Fédération de Neurologie, Université Pierre et Marie Curie et Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Martin
M
Catala
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.|Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.|NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK.
Patrick
P
Yu-Wai-Man
Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France.
Véronique
V
Paquis-Flucklinger
D019588:Aging, Premature / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics*; D009896:Optic Atrophy / Q000235:genetics*; D010375:Pedigree; D014929:Wolfram Syndrome / Q000235:genetics
C523851:CISD2 protein, human; D008565:Membrane Proteins; D002118:Calcium