title: CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors: Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Manabu
authors: M
authors: Funayama
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; Training Program of Leaders for Integrated Medical System for Fruitful Healthy-Longevity Society (LIMS), Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Kenji
authors: K
authors: Ohe
authors: Department of Applied Chemistry, National Defense Academy, Yokosuka, Japan.
authors: Taku
authors: T
authors: Amo
authors: Department of Research and Therapeutics for Movement Disorders, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Norihiko
authors: N
authors: Furuya
authors: Department of Cellular and Molecular Neuropathology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Junji
authors: J
authors: Yamaguchi
authors: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Shinji
authors: S
authors: Saiki
authors: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Yuanzhe
authors: Y
authors: Li
authors: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Kotaro
authors: K
authors: Ogaki
authors: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Maya
authors: M
authors: Ando
authors: Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors: Hiroyo
authors: H
authors: Yoshino
authors: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Tomiyama
authors: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Kenya
authors: K
authors: Nishioka
authors: Department of Neurology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan.
authors: Kazuko
authors: K
authors: Hasegawa
authors: Department of Neurology, Tazuke Kofukai Medical Research Institute and Kitano Hospital, Osaka, Japan.
authors: Hidemoto
authors: H
authors: Saiki
authors: Division of Neurology and Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Wataru
authors: W
authors: Satake
authors: Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors: Kaoru
authors: K
authors: Mogushi
authors: Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan.
authors: Ryogen
authors: R
authors: Sasaki
authors: Kii ALS/PDC Research Center, Mie University Graduate School of Regional Innovation Studies, Tsu, Japan.
authors: Yasumasa
authors: Y
authors: Kokubo
authors: Department of Neurology and Medicine, School of Nursing, Suzuka University of Medical Science, Suzuka, Japan.
authors: Shigeki
authors: S
authors: Kuzuhara
authors: Division of Neurology and Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Tatsushi
authors: T
authors: Toda
authors: Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Yoshikuni
authors: Y
authors: Mizuno
authors: Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Cellular and Molecular Neuropathology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Yasuo
authors: Y
authors: Uchiyama
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Kinji
authors: K
authors: Ohno
authors: Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. Electronic address: nhattori@juntendo.ac.jp.
authors: Nobutaka
authors: N
authors: Hattori
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C580880:CHCHD2 protein, human; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors