Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 publication

DOI

10.1016/j.ajhg.2016.01.014

Type

Journal article

Journal

Am J Hum Genet

Publication Date

03/03/2016

Volume

98

Pages

500 - 513

Keywords

Adult, Aged, Animals, COS Cells, Case-Control Studies, Consanguinity, Female, Gene Silencing, Genetic Heterogeneity, HEK293 Cells, Heterozygote, Homozygote, Humans, Male, Middle Aged, Mitophagy, Parkinsonian Disorders, Pedigree, Phenotype, Protein Kinases, Proteins, Reproducibility of Results, Turkey, Ubiquitin-Protein Ligases