- Email: [email protected]
Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease
Parkinsonism and Related Disorders xxx (2016) 1e2
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Correspondence
Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease
Keywords: Parkinson's disease CHCHD2 Chinese Han Mutation
Parkinson's disease (PD, OMIM 168600) is a common multifactorial neurodegenerative movement disorder characterized by resting tremor, rigidity, slowness of movements, and postural instability. Multi-factors including genetic abnormalities and environmental factors play significant roles in the potential causes of PD. Genetic research in PD has been extremely prolific over the past 2 decades, and more than 21 loci and 16 pathogenic genes involved in familial and sporadic PD have been reported. Recently, three mutations (p.Thr61Ile, p.Arg145Gln and c.300þ5G>A) in the coiledcoil-helix-coiled-coil-helix domain containing 2 gene (CHCHD2; OMIM 616244) were identified in Japanese families with ADPD [1]. Subsequently, p.Thr61Ile mutation was also discovered in a Chinese ADPD pedigree [2], and three putative pathogenic variants (p.Ala32Thr, p.Pro34Leu and p.Ile80Val) were noted in familial and sporadic cases of western European ancestry [3]. To determine the frequency of the CHCHD2 gene in the Chinese PD patients, we performed a direct sequencing analysis of the CHCHD2 gene in our PD patients and normal controls from Mainland China. A total of 245 unrelated Chinese Han patients with PD (male/female: 125/120; age: 65.7 ± 10.4 years; age at onset: 62.3 ± 7.9 years; 110 familial PD and 135 sporadic PD) and 220 gender, age and ethnicity matched normal controls (male/female: 112/108; age: 65.8 ± 10.3 years) from Mainland China were recruited. The study was approved by the Institutional Review Board of the Third Xiangya Hospital, Central South University. All participants or their legally authorized caregivers provided written informed consent. Blood samples were collected, and standard phenol-chloroform extraction method was used to extract DNA. Primers covered all coding regions and exon-intron boundaries of the CHCHD2 gene for polymerase chain reaction (PCR) amplification were designed by using Primer3 (http://primer3.ut.ee/) (Supplementary Table 1). No coding mutation was found in 245 patients with PD. However, we found three known non-coding variants c.e34C>A (rs816407), c.e11G>A (rs200226056) and c.e9T>G (rs10043) in both PD cases and control samples. There was no statistically
significant difference in genotypic distribution or allelic distribution between disease group and normal controls (P ¼ 0.83, P ¼ 0.86, and P ¼ 0.83 for genotypic distribution, respectively; P ¼ 0.60, P ¼ 0.86, and P ¼ 0.60 for allele distribution, respectively) (Table 1). After stratifying by family history, there is still no significant difference in genotypic and allele distributions for three variants between PD groups (familial PD and sporadic PD) and matched controls (Table 1). The CHCHD2 gene, located on chromosome 7p11.2, contains four exons that span 4922 bp encoding a 151-amino acids small protein (<18 kDa) [1]. CHCHD2 localized to the mitochondria intermembrane space via the Mia40 and Erv1 disulphide relay system, suggesting that CHCHD2 may fit into the disease-related network associated with PARK2, PINK1, and FBXO7 [4]. It contains twin cysteine-x9-cysteine motifs, may exhibit largely roles critical for biogenesis and regulation of enzymes in the mitochondrial respiratory chain. Impaired mitochondrial biogenesis and quality control may contribute to PD [5]. Because of the incomplete penetrance of familial PD and late onset of sporadic PD, we screened both familial and sporadic Chinese Han PD patients from Mainland China. Although of great interest, no potentially disease-causing mutations in the CHCHD2 coding region except that three known non-coding variants (rs816407, rs200226056 and rs10043) were identified. No significant association between three variants and risk of PD were found (all P > 0.05), suggesting these variants in the CHCHD2 gene may play little or no role in PD susceptibility in Chinese Han population, which is consistent with the recent studies in PD populations from US, Canada, Europe and China (Supplementary Table 2). However, only one study showed that rs10043 is associated with PD in Japanese population [1], and the inconsistent results may be partially explained by the variable frequencies in different populations, background genotype, environmental factors and genotype-environment interactions, etc. In summary, our study suggests that mutations in the CHCHD2 gene are not likely to be a common cause of PD in Chinese Han population, which seems to be in accordance with recent studies of PD in American, Canadian, part of Chinese and European population. Moreover, mutations in the CHCHD2 gene are rare in both general population and Chinese population with predicted frequencies of less than 0.19% (6/3086) and 0.21% (2/957), respectively (Supplementary Table 3). In addition, other factors involving the CHCHD2 gene such as non-coding mutation, gross exon deletion, rearrangement and change of gene copies can not be excluded in our study. Although the mutation frequency of the CHCHD2 gene is low, further studies to use appropriate CHCHD2 genetic-deficient animal models may shed new light on the genetic factors involved in PD.
http://dx.doi.org/10.1016/j.parkreldis.2016.04.012 1353-8020/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Q. Lu, et al.Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.04.012
2
Correspondence / Parkinsonism and Related Disorders xxx (2016) 1e2
Table 1 Genotypic and allelic frequencies of the CHCHD2 gene variants in PD patients and controls. Variant
Genotype/allele Total PD N (%) FPD N (%) SPD N (%) Controls N (%) All PD vs Controls
rs816407
CC CA AA C A rs200226056 GG GA AA G A rs10043 GG GT TT G T
2 (0.8) 42 (17.1) 201 (82.0) 46 (9.4) 444 (90.6) 240 (98.0) 5 (2.0) 0 485 (99.0) 5 (1.0) 201 (82.0) 42 (17.1) 2 (0.8) 444 (90.6) 46 (9.4)
1 (0.9) 19 (17.3) 90 (81.8) 21 (9.5) 199 (90.5) 107 (97.3) 3 (2.7) 0 217 (98.6) 3 (1.4) 90 (81.8) 19 (17.3) 1 (0.9) 199 (90.5) 21 (9.5)
1 (0.7) 23 (17.0) 111 (82.2) 25 (9.3) 245 (90.7) 133 (98.5) 2 (1.5) 0 268 (99.3) 2 (0.7) 111 (82.2) 23 (17.0) 1 (0.7) 245 (90.7) 25 (9.3)
1 (0.5) 35 (15.9) 184 (83.6) 37 (8.4) 403 (91.6) 216 (98.2) 4 (1.8) 0 436 (99.1) 4 (0.9) 184 (83.6) 35 (15.9) 1 (0.5) 403 (91.6) 37 (8.4)
FPD vs Controls
SPD vs Controls
P values OR (95% CI)
P values OR (95% CI)
P values OR (95% CI)
0.83
NA
0.83
0.90
0.60
0.89 (0.56e1.39) 0.63
0.87 (0.50e1.53) 0.70
0.90 (0.53e1.53)
0.86
1.13 (0.30e4.24) 0.59
1.51 (0.33e6.89) 0.81
0.81 (0.15e4.50)
0.86
1.12 (0.30e4.21) 0.59
1.51 (0.33e6.79) 0.81
0.81 (0.15e4.47)
0.83
NA
NA
NA
0.60
0.89 (0.56e1.39) 0.63
0.83
NA
0.90
0.87 (0.50e1.53) 0.70
NA
0.90 (0.53e1.53)
Abbreviations: PD, Parkinson's disease; N: number; FPD, familial Parkinson's disease; SPD, sporadic Parkinson's disease; OR: odds ratio; CI: confidence interval; NA, not applicable.
Acknowledgements We thank the contributions of the participating members and investigators. This work was supported by New Xiangya Talents Project (H.D.).
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2016.04.012. References [1] M. Funayama, K. Ohe, T. Amo, N. Furuya, J. Yamaguchi, S. Saiki, Y. Li, K. Ogaki, M. Ando, H. Yoshino, H. Tomiyama, K. Nishioka, K. Hasegawa, H. Saiki, W. Satake, K. Mogushi, R. Sasaki, Y. Kokubo, S. Kuzuhara, T. Toda, Y. Mizuno, Y. Uchiyama, K. Ohno, N. Hattori, CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study, Lancet Neurol. 14 (2015) 274e282. [2] C.H. Shi, C.Y. Mao, S.Y. Zhang, J. Yang, B. Song, P. Wu, C.T. Zuo, Y.T. Liu, Y. Ji, Z.H. Yang, J. Wu, Z.P. Zhuang, Y.M. Xu, CHCHD2 gene mutations in familial and sporadic Parkinson's disease, Neurobiol. Aging (2015), http://dx.doi.org/ 10.1016/j.neurobiolaging.2015.10.040. [3] I.E. Jansen, J.M. Bras, S. Lesage, C. Schulte, J.R. Gibbs, M.A. Nalls, A. Brice, N.W. Wood, H. Morris, J.A. Hardy, A.B. Singleton, T. Gasser, P. Heutink, M. Sharma, CHCHD2 and Parkinson's disease, Lancet Neurol. 14 (2015) 678e679. [4] Y. Liu, H.V. Clegg, P.L. Leslie, J. Di, L.A. Tollini, Y. He, T.H. Kim, A. Jin, L.M. Graves, J. Zheng, Y. Zhang, CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation, Cell Death Differ. 22 (2015) 1035e1046. [5] S. Longen, M. Bien, K. Bihlmaier, C. Kloeppel, F. Kauff, M. Hammermeister, B. Westermann, J.M. Herrmann, J. Riemer, Systematic analysis of the twin cx(9)c protein family, J. Mol. Biol. 393 (2009) 356e368.
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China Xiong Deng Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China Zhi Song Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China Yi Guo Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China Department of Medical Information, Information Security and Big Data Research Institute, Central South University, Changsha, China Yan Yang Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China Hao Deng* Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China * Corresponding author. Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Tongzipo Road 138, Changsha, Hunan, 410013, China. E-mail address: [email protected] (H. Deng).
13 January 2016 Qian Lu Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
Please cite this article in press as: Q. Lu, et al.Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.04.012
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Correspondence
Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease
Keywords: Parkinson's disease CHCHD2 Chinese Han Mutation
Parkinson's disease (PD, OMIM 168600) is a common multifactorial neurodegenerative movement disorder characterized by resting tremor, rigidity, slowness of movements, and postural instability. Multi-factors including genetic abnormalities and environmental factors play significant roles in the potential causes of PD. Genetic research in PD has been extremely prolific over the past 2 decades, and more than 21 loci and 16 pathogenic genes involved in familial and sporadic PD have been reported. Recently, three mutations (p.Thr61Ile, p.Arg145Gln and c.300þ5G>A) in the coiledcoil-helix-coiled-coil-helix domain containing 2 gene (CHCHD2; OMIM 616244) were identified in Japanese families with ADPD [1]. Subsequently, p.Thr61Ile mutation was also discovered in a Chinese ADPD pedigree [2], and three putative pathogenic variants (p.Ala32Thr, p.Pro34Leu and p.Ile80Val) were noted in familial and sporadic cases of western European ancestry [3]. To determine the frequency of the CHCHD2 gene in the Chinese PD patients, we performed a direct sequencing analysis of the CHCHD2 gene in our PD patients and normal controls from Mainland China. A total of 245 unrelated Chinese Han patients with PD (male/female: 125/120; age: 65.7 ± 10.4 years; age at onset: 62.3 ± 7.9 years; 110 familial PD and 135 sporadic PD) and 220 gender, age and ethnicity matched normal controls (male/female: 112/108; age: 65.8 ± 10.3 years) from Mainland China were recruited. The study was approved by the Institutional Review Board of the Third Xiangya Hospital, Central South University. All participants or their legally authorized caregivers provided written informed consent. Blood samples were collected, and standard phenol-chloroform extraction method was used to extract DNA. Primers covered all coding regions and exon-intron boundaries of the CHCHD2 gene for polymerase chain reaction (PCR) amplification were designed by using Primer3 (http://primer3.ut.ee/) (Supplementary Table 1). No coding mutation was found in 245 patients with PD. However, we found three known non-coding variants c.e34C>A (rs816407), c.e11G>A (rs200226056) and c.e9T>G (rs10043) in both PD cases and control samples. There was no statistically
significant difference in genotypic distribution or allelic distribution between disease group and normal controls (P ¼ 0.83, P ¼ 0.86, and P ¼ 0.83 for genotypic distribution, respectively; P ¼ 0.60, P ¼ 0.86, and P ¼ 0.60 for allele distribution, respectively) (Table 1). After stratifying by family history, there is still no significant difference in genotypic and allele distributions for three variants between PD groups (familial PD and sporadic PD) and matched controls (Table 1). The CHCHD2 gene, located on chromosome 7p11.2, contains four exons that span 4922 bp encoding a 151-amino acids small protein (<18 kDa) [1]. CHCHD2 localized to the mitochondria intermembrane space via the Mia40 and Erv1 disulphide relay system, suggesting that CHCHD2 may fit into the disease-related network associated with PARK2, PINK1, and FBXO7 [4]. It contains twin cysteine-x9-cysteine motifs, may exhibit largely roles critical for biogenesis and regulation of enzymes in the mitochondrial respiratory chain. Impaired mitochondrial biogenesis and quality control may contribute to PD [5]. Because of the incomplete penetrance of familial PD and late onset of sporadic PD, we screened both familial and sporadic Chinese Han PD patients from Mainland China. Although of great interest, no potentially disease-causing mutations in the CHCHD2 coding region except that three known non-coding variants (rs816407, rs200226056 and rs10043) were identified. No significant association between three variants and risk of PD were found (all P > 0.05), suggesting these variants in the CHCHD2 gene may play little or no role in PD susceptibility in Chinese Han population, which is consistent with the recent studies in PD populations from US, Canada, Europe and China (Supplementary Table 2). However, only one study showed that rs10043 is associated with PD in Japanese population [1], and the inconsistent results may be partially explained by the variable frequencies in different populations, background genotype, environmental factors and genotype-environment interactions, etc. In summary, our study suggests that mutations in the CHCHD2 gene are not likely to be a common cause of PD in Chinese Han population, which seems to be in accordance with recent studies of PD in American, Canadian, part of Chinese and European population. Moreover, mutations in the CHCHD2 gene are rare in both general population and Chinese population with predicted frequencies of less than 0.19% (6/3086) and 0.21% (2/957), respectively (Supplementary Table 3). In addition, other factors involving the CHCHD2 gene such as non-coding mutation, gross exon deletion, rearrangement and change of gene copies can not be excluded in our study. Although the mutation frequency of the CHCHD2 gene is low, further studies to use appropriate CHCHD2 genetic-deficient animal models may shed new light on the genetic factors involved in PD.
http://dx.doi.org/10.1016/j.parkreldis.2016.04.012 1353-8020/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Q. Lu, et al.Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.04.012
2
Correspondence / Parkinsonism and Related Disorders xxx (2016) 1e2
Table 1 Genotypic and allelic frequencies of the CHCHD2 gene variants in PD patients and controls. Variant
Genotype/allele Total PD N (%) FPD N (%) SPD N (%) Controls N (%) All PD vs Controls
rs816407
CC CA AA C A rs200226056 GG GA AA G A rs10043 GG GT TT G T
2 (0.8) 42 (17.1) 201 (82.0) 46 (9.4) 444 (90.6) 240 (98.0) 5 (2.0) 0 485 (99.0) 5 (1.0) 201 (82.0) 42 (17.1) 2 (0.8) 444 (90.6) 46 (9.4)
1 (0.9) 19 (17.3) 90 (81.8) 21 (9.5) 199 (90.5) 107 (97.3) 3 (2.7) 0 217 (98.6) 3 (1.4) 90 (81.8) 19 (17.3) 1 (0.9) 199 (90.5) 21 (9.5)
1 (0.7) 23 (17.0) 111 (82.2) 25 (9.3) 245 (90.7) 133 (98.5) 2 (1.5) 0 268 (99.3) 2 (0.7) 111 (82.2) 23 (17.0) 1 (0.7) 245 (90.7) 25 (9.3)
1 (0.5) 35 (15.9) 184 (83.6) 37 (8.4) 403 (91.6) 216 (98.2) 4 (1.8) 0 436 (99.1) 4 (0.9) 184 (83.6) 35 (15.9) 1 (0.5) 403 (91.6) 37 (8.4)
FPD vs Controls
SPD vs Controls
P values OR (95% CI)
P values OR (95% CI)
P values OR (95% CI)
0.83
NA
0.83
0.90
0.60
0.89 (0.56e1.39) 0.63
0.87 (0.50e1.53) 0.70
0.90 (0.53e1.53)
0.86
1.13 (0.30e4.24) 0.59
1.51 (0.33e6.89) 0.81
0.81 (0.15e4.50)
0.86
1.12 (0.30e4.21) 0.59
1.51 (0.33e6.79) 0.81
0.81 (0.15e4.47)
0.83
NA
NA
NA
0.60
0.89 (0.56e1.39) 0.63
0.83
NA
0.90
0.87 (0.50e1.53) 0.70
NA
0.90 (0.53e1.53)
Abbreviations: PD, Parkinson's disease; N: number; FPD, familial Parkinson's disease; SPD, sporadic Parkinson's disease; OR: odds ratio; CI: confidence interval; NA, not applicable.
Acknowledgements We thank the contributions of the participating members and investigators. This work was supported by New Xiangya Talents Project (H.D.).
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2016.04.012. References [1] M. Funayama, K. Ohe, T. Amo, N. Furuya, J. Yamaguchi, S. Saiki, Y. Li, K. Ogaki, M. Ando, H. Yoshino, H. Tomiyama, K. Nishioka, K. Hasegawa, H. Saiki, W. Satake, K. Mogushi, R. Sasaki, Y. Kokubo, S. Kuzuhara, T. Toda, Y. Mizuno, Y. Uchiyama, K. Ohno, N. Hattori, CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study, Lancet Neurol. 14 (2015) 274e282. [2] C.H. Shi, C.Y. Mao, S.Y. Zhang, J. Yang, B. Song, P. Wu, C.T. Zuo, Y.T. Liu, Y. Ji, Z.H. Yang, J. Wu, Z.P. Zhuang, Y.M. Xu, CHCHD2 gene mutations in familial and sporadic Parkinson's disease, Neurobiol. Aging (2015), http://dx.doi.org/ 10.1016/j.neurobiolaging.2015.10.040. [3] I.E. Jansen, J.M. Bras, S. Lesage, C. Schulte, J.R. Gibbs, M.A. Nalls, A. Brice, N.W. Wood, H. Morris, J.A. Hardy, A.B. Singleton, T. Gasser, P. Heutink, M. Sharma, CHCHD2 and Parkinson's disease, Lancet Neurol. 14 (2015) 678e679. [4] Y. Liu, H.V. Clegg, P.L. Leslie, J. Di, L.A. Tollini, Y. He, T.H. Kim, A. Jin, L.M. Graves, J. Zheng, Y. Zhang, CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation, Cell Death Differ. 22 (2015) 1035e1046. [5] S. Longen, M. Bien, K. Bihlmaier, C. Kloeppel, F. Kauff, M. Hammermeister, B. Westermann, J.M. Herrmann, J. Riemer, Systematic analysis of the twin cx(9)c protein family, J. Mol. Biol. 393 (2009) 356e368.
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China Xiong Deng Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China Zhi Song Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China Yi Guo Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China Department of Medical Information, Information Security and Big Data Research Institute, Central South University, Changsha, China Yan Yang Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China Hao Deng* Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China * Corresponding author. Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Tongzipo Road 138, Changsha, Hunan, 410013, China. E-mail address: [email protected] (H. Deng).
13 January 2016 Qian Lu Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
Please cite this article in press as: Q. Lu, et al.Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.04.012