title: A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.
abstract: Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bannwarth
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Ait-El-Mkadem
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Chaussenot
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France.
authors.forename: Emmanuelle C
authors.initials: EC
authors.lastname: Genin
authors.affiliation: 3 Joint Centre for Applied Electron Microscopy, Nice Sophia-Antipolis University, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Fragaki
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Berg-Alonso
authors.affiliation: 4 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kageyama
authors.affiliation: 5 UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.affiliation: 6 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Moore
authors.affiliation: 7 Department of Neurology, Timone Hospital, Marseille Teaching Hospital, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Verschueren
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Rouzier
authors.affiliation: 8 Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), F-75013 Paris, France9 National Reference Centre on Rare Dementias, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Augé
authors.affiliation: 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cochaud
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lespinasse
authors.affiliation: 10 Department of Medical Genetics, Timone Hospital, Marseille Teaching Hospital, France.
authors.forename: Karine
authors.initials: K
authors.lastname: N'Guyen
authors.affiliation: 8 Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), F-75013 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: de Septenville
authors.affiliation: 8 Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), F-75013 Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: 6 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.affiliation: 4 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: 7 Department of Neurology, Timone Hospital, Marseille Teaching Hospital, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.affiliation: 1 IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France 2 Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France paquis@hermes.unice.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype
chemical_list: C554426:CHCHD10 protein, human; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins
keywords: CHCHD10; FTD-ALS; mitochondrial DNA instability; mitochondrial disorder