Abstract
Objective Our goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation.
Methods We combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation.
Results Here, we report an association of a homozygous variant in CHCHD2, encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman. The CHCHD2 mutation in PD patient fibroblasts causes fragmentation of the mitochondrial reticular morphology and results in reduced oxidative phosphorylation at complex I and complex IV. Although patient cells could maintain a proton motive force, reactive oxygen species production was increased, which correlated with an increased metabolic rate.
Conclusions Our findings implicate CHCHD2 in the pathogenesis of recessive early-onset PD, expanding the repertoire of mitochondrial proteins that play a direct role in this disease.
Glossary
- BCA=
- Bicinchoninic acid;
- DHE=
- dihydroethidium;
- ETC=
- electron transport chain;
- MICOS=
- mitochondrial contact site and cristae organizing system;
- NGS=
- next-generation sequencing;
- OXPHOS=
- oxidative phosphorylation;
- PBS=
- phosphate-buffered saline;
- PD=
- Parkinson disease;
- RCR=
- respiratory control ratio;
- ROS=
- reactive oxygen species;
- WES=
- whole-exome sequencing
Footnotes
↵* These authors contributed equally to the study and share first authorship.
↵§ These authors share senior authorship and are co-corresponding authors.
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing Charge was funded by the Australian Research Council.
- Received February 28, 2018.
- Accepted in final form June 18, 2018.
- Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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