title: Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.
abstract: Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouet
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Majounie
authors.affiliation: Department of Histology and Pathology, University of Lille Nord de France, Lille University Hospital, 59000 Lille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Deramecourt
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Jacoupy
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422, 75013 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Cormier-Dequaire
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Sidi Mohamed
authors.initials: SM
authors.lastname: Hassoun
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pujol
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Sorana
authors.initials: S
authors.lastname: Ciura
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Erpapazoglou
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Usenko
authors.affiliation: Department of Histology and Pathology, University of Lille Nord de France, Lille University Hospital, 59000 Lille, France.
authors.forename: Claude-Alain
authors.initials: CA
authors.lastname: Maurage
authors.affiliation: Fondation Jean Dausset-CEPH, 75010 Paris, France.
authors.forename: Mourad
authors.initials: M
authors.lastname: Sahbatou
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tübingen, 72074 Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34390 Istanbul, Turkey.
authors.forename: Basar
authors.initials: B
authors.lastname: Bilgic
authors.affiliation: Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34390 Istanbul, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Emre
authors.affiliation: Department of Genetics, Institute for Experimental Medicine, Istanbul University, 34390 Istanbul, Turkey.
authors.forename: Nihan
authors.initials: N
authors.lastname: Erginel-Unaltuna
authors.affiliation: Department of Genetics, Institute for Experimental Medicine, Istanbul University, 34390 Istanbul, Turkey.
authors.forename: Gamze
authors.initials: G
authors.lastname: Guven
authors.affiliation: Institut des Maladies Neurodégénératives, Université de Bordeaux et CHU de Bordeaux, 33000 Bordeaux, France.
authors.forename: François
authors.initials: F
authors.lastname: Tison
authors.affiliation: Pôle Tête-Cou-CETD, Service de Neurologie, Hôpitaux Universitaires, 67000 Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Pôle des Maladies du Système Nerveux, Fédération de Neurologie, Hôpital de la Salpêtrière, 75013 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vidailhet
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422, 75013 Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.affiliation: Neurology Department, CHU de Grenoble, Joseph Fourier University, and INSERM U836, 38000 Grenoble, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Krack
authors.affiliation: Inserm U946, 75010 Paris, France; Université Paris Diderot, Institut Universitaire d'Hématologie, UMR946, 75010 Paris, France.
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Leutenegger
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.affiliation: Hertie Institute for Clinical Brain Research, University of Tübingen and DZNE, German Center for Neurodegenerative Diseases, 72074 Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: Hertie Institute for Clinical Brain Research, University of Tübingen and DZNE, German Center for Neurodegenerative Diseases, 72074 Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Department of Genetics and Cytogenetics, AP-HP, Hôpital de la Salpêtrière, 75013 Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, 91000 Evry, France.
authors.forename: Jean-François
authors.initials: JF
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authors.affiliation: Service de Neurologie CHU Mustapha, 16000 Alger, Algérie.
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authors.affiliation: Movement Disorders Unit, Lille University, Inserm U837, Lille University Hospital, 59000 Lille, France.
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authors.affiliation: Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34390 Istanbul, Turkey; Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
authors.forename: Ebba
authors.initials: E
authors.lastname: Lohmann
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
authors.forename: Edor
authors.initials: E
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authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
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authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France. Electronic address: olga.corti@upmc.fr.
authors.forename: Olga
authors.initials: O
authors.lastname: Corti
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6 UMR S 1127, 75013 Paris, France; Inserm U 1127, 75013 Paris, France; CNRS UMR 7225, 75013 Paris, France; Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; Department of Genetics and Cytogenetics, AP-HP, Hôpital de la Salpêtrière, 75013 Paris, France. Electronic address: alexis.brice@upmc.fr.
authors.forename: Alexis
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mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D003241:Consanguinity; D005260:Female; D020868:Gene Silencing; D018740:Genetic Heterogeneity; D057809:HEK293 Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D063306:Mitophagy / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D014421:Turkey; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D011506:Proteins; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C495324:VPS13C protein, human; C111567:parkin protein