CHCHD2 and Parkinson's disease—Authors' reply
2015; Elsevier BV; Volume: 14; Issue: 7 Linguagem: Inglês
10.1016/s1474-4422(15)00097-6
ISSN1474-4465
AutoresManabu Funayama, Nobutaka Hattori,
Tópico(s)Neurological diseases and metabolism
ResumoWe thank Jansen and colleagues for their interest in our Article and for replicating the analysis of CHCHD2 variants using a large western European cohort from the International Parkinson's Disease Genomics Consortium (IPDGC). We reported three potentially pathogenic mutations (182C>T, Thr61Ile; 434G>A, Arg145Gln; and 300+5G>A) for autosomal dominant Parkinson's disease.1Funayama M Ohe K Amo T et al.CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.Lancet Neurol. 2015; 14: 274-282Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar Of these mutations, only Thr61Ile was confirmed to cosegregate in two independent families with autosomal dominant Parkinson's disease. The other two mutations were found in only one patient in each family, possibly because we did not have access to samples from other family members. In response to comments from Jansen and colleagues, we searched the Exome Aggregation Consortium (ExAC) database on April 6, 2015, and found 434G>A (Arg145Gln) and 300+5G>A with rare frequencies and only in Asian and Latino populations. Three variants reported by us were not found in the large cohort of the white population from the IPDGC, and the frequencies of risk variants for sporadic Parkinson's disease (rs10043 and rs142444896) were rarer in white than in Japanese populations. This difference suggests that the frequencies of CHCHD2 variants differ between ethnic groups. Interestingly, three novel putative pathogenic variants were noted in the white cohort, suggesting CHCHD2 is a novel, but rare, causal gene for autosomal dominant Parkinson's disease in different populations. We thank Puschmann and colleagues for their prompt investigation of CHCHD2 mutations in the Arkansas family and the Swedish family F-081 with autosomal dominant parkinsonism and essential tremor. We reported one patient with essential tremor carrying the CHCHD2 Thr61Ile mutation1Funayama M Ohe K Amo T et al.CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.Lancet Neurol. 2015; 14: 274-282Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar and obtained information from this patient that his child also had tremor in the upper limb. If the child is diagnosed with essential tremor, the CHCHD2 mutation might be increasing the probability of developing essential tremor. We have no pathological data or samples from patients with CHCHD2 mutations; however, no patients with CHCHD2 mutations showed symptoms of amyotrophic lateral sclerosis or frontotemporal lobar degeneration, so TAR DNA-binding protein 43 pathology might be absent in our patients. Further genetic and functional investigation of CHCHD2 might increase our knowledge of essential tremor and Parkinson's disease. We thank Liu and Li for the meta-analysis using previously reported genome-wide association study (GWAS) data from European patients with Parkinson's or Alzheimer's disease. The frequency of rs816411 was not significantly different between patients with Parkinson's disease and controls in the Japanese GWAS.2Satake W Nakabayashi Y Mizuta I et al.Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease.Nat Genet. 2009; 41: 1303-1307Crossref PubMed Scopus (1036) Google Scholar However, we found two variants (rs10043 and rs142444896) with significantly different frequencies in our cohort.1Funayama M Ohe K Amo T et al.CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.Lancet Neurol. 2015; 14: 274-282Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar This disparity between the GWAS data and our findings is likely to be due to the absence of useful single nucleotide variants in the genotyping arrays used in GWAS studies for investigating the CHCHD2 locus for the risk of Parkinson's disease. As Jansen and colleagues pointed out, the susceptibility for Parkinson's disease conferred by CHCHD2 mutations might be specific to Asian people. Therefore, more detailed genetic analyses in a large Asian cohort are needed. Because CHCHD2 is also reported to be associated with Huntington's disease and hepatocellular carcinoma,3Feyeux M Bourgois-Rocha F Redfern A et al.Early transcriptional changes linked to naturally occurring Huntington's disease mutations in neural derivatives of human embryonic stem cells.Hum Mol Genet. 2012; 21: 3883-3895Crossref PubMed Scopus (56) Google Scholar, 4Song R Yang B Gao X et al.Cyclic adenosine monophosphate response element-binding protein transcriptionally regulates CHCHD2 associated with the molecular pathogenesis of hepatocellular carcinoma.Mol Med Rep. 2015; 11: 4053-4062PubMed Google Scholar further genetic association studies are needed to elucidate the link between CHCHD2 and other diseases. We thank Iqbal and Toft for their comment about the CHCHD2 mutations we reported.1Funayama M Ohe K Amo T et al.CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.Lancet Neurol. 2015; 14: 274-282Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar According to ExAC data (April 6, 2015), three variants were reported for Arg145 (Arg145Gln/Leu/Ter). Although the frequencies of each variant were low, Arg145 might be a hot-spot aminoacid for mutation that is similar to LRRK2 Arg1441Gly/His/Cys.5Kumari U Tan EK LRRK2 in Parkinson's disease: genetic and clinical studies from patients.FEBS J. 2009; 276: 6455-6463Crossref PubMed Scopus (108) Google Scholar We reported two mutations (Arg145Gln and 300+5G>A) in only one patient in a small family.1Funayama M Ohe K Amo T et al.CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.Lancet Neurol. 2015; 14: 274-282Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar The pathogenicity of these mutations in autosomal dominant Parkinson's disease is unclear; however, the splicing abnormality of the 300+5G>A mutation was detected with the exon-trapping vector in vitro.1Funayama M Ohe K Amo T et al.CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.Lancet Neurol. 2015; 14: 274-282Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar This splicing abnormality is due to reduced U1 small-nuclear-ribonucleoprotein-binding. We agree that further functional and genetic studies should help to elucidate the pathogenicity of the CHCHD2 mutations. We thank Foo and colleagues for the replication study of one of the risk variants in CHCHD2 in Chinese patients with Parkinson's disease. We feel that the results of this study provide important evidence that CHCHD2 is not only a causal gene for monogenic autosomal dominant forms of Parkinson's disease, but also a risk factor for sporadic Parkinson's disease, similar to SNCA and LRRK2.6Singleton AB Farrer MJ Bonifati V The genetics of Parkinson's disease: Progress and therapeutic implications.Mov Disord. 2013; 28: 14-23Crossref PubMed Scopus (267) Google Scholar Although the frequency of the rs142444896 (Pro2Leu) variant in East Asian people is higher than in other populations, according to our search of ExAc on May 13, 2015, presence of racial specificity in rs142444896 is not clear. We have to investigate the presence of founder effect of this variant. However, rs142444896 lies within the mitochondrial target sequence of CHCHD2, and Pro2 is highly conserved across species. To elucidate the pathogenicity of this variant for development of Parkinson's disease, we will have to investigate whether the Pro2Leu variant affects the efficiency of import of CHCHD2 into mitochondria. In conclusion, the letters in relation to our report suggest that mutations in CHCHD2 are rare, and might vary by ethnic origin; however, some putative pathogenic and risk variants were found in cohorts other than our original cohort. These findings increase the probability that mutations in CHCHD2 are causal for autosomal dominant Parkinson's disease and a risk factor for sporadic Parkinson's disease. NH reports personal fees from Hisamitsu Pharmaceutical, Dai-Nippon Sumitomo Pharma, Otsuka Pharmaceutical, Novartis Pharma, GlaxoSmithKline, Nippon Boehringer Ingelheim, FP Pharmaceutical, Eisai, Kissei Pharmaceutical, Janssen Pharmaceutical, Nihon Medi-Physics, and Kyowa Hakko-Kirin, outside of this work; grants as sponsors of endowed departments from GlaxoSmithKline, Nippon Boehringer Ingelheim, Dai-Nippon Sumitomo Pharma, Eisai, Kissei Pharmaceutical, Janssen Pharmaceutical, Nihon Medi-Physics, Kyowa Hakko-Kirin, Medtronic, Novartis Pharma, Ono Pharmaceutical, Mitsubishi Tanabe Pharma, Zaiho, Hydrogen Health Medical Labo, ABIST, Melodian, Daiwa, Biogen Idec Japan, Bayer Yakuhin, Nihon Pharmaceutical, Asahi Kasei Medical, and MiZ, outside of this work; and grants as research support from Astellas Pharma, Eisai, FP Pharmaceutical, Shionogi and Company, Merck Sharp Dohme, Daiichi Sankyo, outside of this work. MF reports no competing interests. CHCHD2 and Parkinson's diseaseGenetic discoveries have lent support to the growing consensus that protein aggregation, impairment in oxidative stress, and mitochondrial dysfunction are important pathways in Parkinson's disease.1 In agreement with this hypothesis, Funayama and colleagues2 report an association of CHCHD2, which is suggested to be involved in mitochondrial respiration, with Parkinson's disease in the Japanese population.2 Full-Text PDF CHCHD2 and Parkinson's diseaseFunayama and colleagues recently identified a mutation in the CHCHD2 gene in a large Japanese family with autosomal dominant Parkinson's disease,1 increasing our knowledge about the monogenic causes of this disorder.2,3 They also noted the same mutation (182C>T, Thr61Ile) in another family with autosomal dominant Parkinson's disease; the mutation was detected not only in a man with familial disease but also in his brother, who had developed fine tremor at age 10 years but did not have parkinsonism at 50 years of age. Full-Text PDF CHCHD2 and Parkinson's diseaseParkinson's disease is the second most common neurodegenerative disease in elderly people.1 Results of large-scale genome-wide association studies (GWAS) provided insights into the disease genetics and identified some common susceptibility variants with genome-wide significance (p<5·00 × 10⁻⁸).1 However, these newly identified susceptibility variants have very small risk effects and do not fully account for the underlying genetic risk of Parkinson's disease.2,3 Full-Text PDF CHCHD2 and Parkinson's diseaseFunayama and colleagues reported that mutations in the CHCHD2 gene cause Parkinson's disease.1 Genes causing monogenic forms of Parkinson's disease have been identified in recent years, but in our opinion additional evidence is needed before CHCHD2 can be added to the definitive list. Full-Text PDF CHCHD2 and Parkinson's diseaseFunayama and colleagues1 identified mutations in the CHCHD2 gene that were associated with increased risk of sporadic Parkinson's disease in Japanese patients. We have sequenced all coding exons of CHCHD2 in 99 Chinese patients with early-onset disease (<55 years; mean age at onset 48·3 years [SD 5·8], mean age at sample collection 54·7 years [7·1], 66 males; 23 familial and 76 sporadic) and 99 healthy Chinese controls (mean age 71·9 years [SD 10·8], 60 males). Full-Text PDF CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing studyCHCHD2 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. Full-Text PDF
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