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Lesage, S.* ; Drouet, V.* ; Majounie, E.* ; Deramecourt, V.* ; Jacoupy, M.* ; Nicolas, A.* ; Cormier-Dequaire, F.* ; Hassoun, S.M.* ; Pujol, C.* ; Ciura, S.* ; Erpapazoglou, Z.* ; Usenko, T.* ; Maurage, C.A.* ; Sahbatou, M.* ; Liebau, S.* ; Ding, J.* ; Bilgic, B.* ; Emre, M.* ; Erginel-Unaltuna, N.* ; Guven, G.* ; Tison, F.* ; Tranchant, C.* ; Vidailhet, M.* ; Corvol, J.C.* ; Krack, P.* ; Leutenegger, A.L.* ; Nalls, M.A.* ; Hernandez, D.G.* ; Heutink, P.* ; Gibbs, J.R.* ; Hardy, J.* ; Wood, N.W.* ; Gasser, T.* ; Dürr, A.* ; Deleuze, J.F.* ; Tazir, M.* ; Destée, A.* ; Lohmann, E.* ; Kabashi, E.* ; Singleton, A.* ; Corti, O.* ; Brice, A.* ; International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. ; Lichtner, P.)

Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy.

Am. J. Hum. Genet. 98, 500-513 (2016)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Sequencing Data; Nitric-oxide; Disease; Protein; Mutations; Pink1; Gene; Interact; Association; Clearance
Sprache englisch
Veröffentlichungsjahr 2016
HGF-Berichtsjahr 2016
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 98, Heft: 3, Seiten: 500-513 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
POF Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504091-001
G-500700-001
DOI 10.1016/j.ajhg.2016.01.014
WOS ID WOS:000372383100013
PubMed ID 26942284
Erfassungsdatum 2016-03-07
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