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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 500-513 |
| Number of pages | 14 |
| Journal | American journal of human genetics |
| Volume | 98 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 3 2016 |
Funding
The authors are grateful to the families for their participation in this study. We thank Merle Ruberg for critical reading of the manuscript, the DNA and Cell Bank of ICM, the Plate-Forme d’Imagerie Cellulaire de la Pitié-Salpêtrière (PICPS), and Ebru Özer and Meltem Pak for sample preparation. We are grateful to the Lille brain bank for the gift of a brain (“Lille Neurobank,” BB-0033-00030). This study was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, the Roger de Spoelberch Foundation (R12123DD), the French Academy of Sciences, the French program “Investissements d’avenir” (ANR-10-IAIHU-06), and the European Joint Programme - Neurodegenerative Disease Research (JPND-COURAGE-PD) project. This study was also supported by the Intramural Research Program of the National Institute on Aging and the National Institutes of Neurological Disorders and Stroke, NIH, Department of Health and Human Services (project Z01 AG000958 and by MRC Grant G1100643/1), by the European Social Fund, and by the Ministry of Science, Research, and the Arts, Baden-Württemberg. This work was also supported by the Department of Defense, including grant 10064005/11348001, the French Health Ministry (PHRC), France Parkinson Association, Lille University Hospital (A. Destée), the Atip/Avenir from the National Institute of Health and Medical Research (INSERM), the ANR in association with the ERA-NET E-rare program, the France Alzheimer Association, and a Career Integration Grant from Marie Curie Actions (E.K.). C.P. received a postdoctoral fellowship from the Cognacq-Jay Foundation. S.C. received postdoctoral fellowships from EMBO and AFM-Telethon. The authors are grateful to the families for their participation in this study.We thank Merle Ruberg for critical reading of the manuscript, the DNA and Cell Bank of ICM, the Plate-Forme d''Imagerie Cellulaire de la Pitié-Salpêtrière (PICPS), and Ebru Ö zer and Meltem Pak for sample preparation.We are grateful to the Lille brain bank for the gift of a brain ("Lille Neurobank," BB-0033-00030). This study was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, the Roger de Spoelberch Foundation (R12123DD), the French Academy of Sciences, the French program "Investissements d''avenir" (ANR-10-IAIHU-06), and the European Joint Programme-Neurodegenerative Disease Research (JPND-COURAGE-PD) project. This study was also supported by the Intramural ResearchProgram of the National Institute on Aging and the National Institutes of Neurological Disorders and Stroke, NIH, Department of Health and Human Services (project Z01 AG000958 and by MRC Grant G1100643/1), by the European Social Fund, and by the Ministry of Science, Research, and the Arts, Baden-Württemberg. This work was also supported by the Department of Defense, including grant 10064005/11348001, the French Health Ministry (PHRC), France Parkinson Association, Lille University Hospital (A. Desteé), the Atip/Avenir from the National Institute of Health and Medical Research (INSERM), the ANR in association with the ERA-NET E-rare program, the France Alzheimer Association, and a Career Integration Grant from Marie Curie Actions (E.K.). C.P. received a postdoctoral fellowship from the Cognacq-Jay Foundation. S.C. received postdoctoral fellowships from EMBO and AFM-Telethon.
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)