Lee 2018 Neurol Genet
|Lee RG, Sedghi M, Salari M, Shearwood AJ, Stentenbach M, Kariminejad A, Goullee H, Rackham O, Laing NG, Tajsharghi H, Filipovska A (2018) Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction. Neurol Genet 4:e276.|
Abstract: 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.
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.
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.
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.
Labels: MiParea: Respiration, nDNA;cell genetics Pathology: Parkinson's
Organism: Human Tissue;cell: Fibroblast Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV, NS HRR: Oxygraph-2k