Elsevier

The Lancet Neurology

Volume 14, Issue 3, March 2015, Pages 274-282
The Lancet Neurology

Articles
CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study

https://doi.org/10.1016/S1474-4422(14)70266-2Get rights and content

Summary

Background

Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes.

Methods

We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles.

Findings

We identified a missense mutation (CHCHD2, 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (−9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48–4·24; p=0·0004) and 4·69 (1·59–13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96–1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping.

Interpretation

CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease.

Funding

Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.

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.

Section snippets

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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