ArticlesCHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study
Introduction
Parkinson's disease (MIM 168600), which is caused by the death of dopaminergic neurons in the substantia nigra, is the second most common neurodegenerative disorder. Symptoms mainly involve movement, including resting tremor, rigidity, bradykinesia, and postural instability. Most Parkinson's disease cases are sporadic; only about 11% of patients with Parkinson's disease have one or more first-degree relatives diagnosed with Parkinson's disease.1 Nevertheless, identification of causative genes in rare familial cases can shed new light on the cause of Parkinson's disease. Most monogenic forms of neurodegenerative diseases are autosomal dominant; however, so far, only six genes have been identified for autosomal dominant forms of familial Parkinson's disease.2, 3, 4
Although the exact mechanisms of dopaminergic cell death are still unclear, discovery of causative genes for Parkinson's disease has enabled several processes to be proposed, such as impairments in protein degradation, oxidative stress, and mitochondrial dysfunction.5 We aimed to identify a novel causative gene for familial Parkinson's disease by whole-genome and exome sequencing with next-generation sequencing.
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Study design and participants
Participants were selected from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (CGSPD). The CGSPD bank in the Department of Neurology at Juntendo University School of Medicine (Tokyo, Japan) collects DNA and RNA of patients with typical Parkinson's disease, patients with atypical parkinsonism, and control participants for use in case-control studies, replication studies, and the discovery of novel genetic factors for Parkinson's disease. The CGSPD
Results
The mean age at onset of the participating patients in family A (eight patients) was 55·5 years (SD 4·8; range 48–61). For validation and case-control analysis, we obtained DNA samples from 340 additional index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls (16 hospital staff and 543 volunteers recruited during medical check-ups; table 1).
Using next-generation sequencing, we detected a cumulative total of over 2·3 million
Discussion
In this study, we show that the heterozygous 182C>T (Thr61Ile) mutation in CHCHD2 cosegregated with Parkinson's disease in a Japanese family with autosomal dominant Parkinson's disease. We identified three CHCHD2 variants, none of which was present in controls, and our findings suggest that CHCHD2 is a novel gene for autosomal dominant Parkinson's disease (panel).
CHCHD2 belongs to the CHCHD protein family, which are small proteins (about <18 kDa) containing twin cysteine-x9-cysteine motifs.
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