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VPS35 Asp620Asn and EIF4G1 Arg1205His mutations are rare in Parkinson disease from Southwest China
Neurobiology of Aging 34 (2013) 1709.e7e1709.e8
Contents lists available at SciVerse ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
VPS35 Asp620Asn and EIF4G1 Arg1205His mutations are rare in Parkinson disease from Southwest China YongPing Chen a, Ke Chen a, Wei Song a, XuePing Chen a, Bei Cao a, Rui Huang a, Bi Zhao a, XiaoYan Guo a, JeanMarc Burgunder a, b, JianPeng Li a, Hui-Fang Shang a, * a b
Department of Neurology and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, SiChuan University, Chengdu, Sichuan, China Department of Neurology, University of Bern, Bern, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2012 Received in revised form 1 November 2012 Accepted 4 November 2012 Available online 20 December 2012
The Asp620Asn mutation in the vacuolar protein sorting protein 35 (VPS35) gene and the Arg1205His mutation in the eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) gene were identified in autosomal dominant late-onset familial and sporadic Parkinson disease (PD) patients in a Caucasian population. However, the frequencies of these 2 mutations among Chinese PD patients are unknown. We examined these mutations in a large cohort consisting of 609 PD patients and 600 healthy control subjects from Southwest China. Our results suggest that the Asp620Asn mutation in VPS35 and the Arg1205His mutation in EIF4G1 do not play a role in PD in the Southwest China population. The novel Arg1205Cys mutation in EIF4G1 detected in the current study should be further studied among other Asian patients. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Parkinson disease VPS35 gene Asp620Asn mutation EIF4G1 gene Arg1205His mutation
1. Introduction Parkinson disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is characterized by tremors, rigidity, bradykinesia, and postural instability. Multiple genetic and environmental factors are believed to contribute to the development of PD. Recently, the vacuolar protein sorting protein 35 gene (VPS35), and the eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1) were reported to be associated with autosomal dominant (AD) PD (Fujioka and Wszolek, 2012). The Asp620Asn mutation in the VPS35 gene and the Arg1205His mutation in the EIF4G1 gene have only been identified in large families with dominant late-onset PD. A total of 13 ADPD families with the Asp620Asn mutation in VPS35 have been found in Austria, Switzerland, the United States, Tunisia, Israel, and France (Lesage et al., 2012; Sheerin, et al., 2012; Vilarino-Guell et al., 2011; Zimprich et al., 2011). The Arg1205His missense mutation in EIF4G1 was identified in familial and sporadic PD patients from France, the United States, Canada, Ireland, Italy, and Tunisia (Chartier-Harlin, et al., 2011). However, the frequencies of these 2 mutations
among Chinese PD patients are unknown. Hence, we performed a large-scale case-control study that included 609 PD patients and 600 healthy control subjects to identify the frequency of the Asp620Asn mutations in VPS35 and Arg1205His in EIF4G1 in a Chinese population from Southwest China. 2. Methods A total of 609 PD patients (including 37 familial cases and 572 sporadic cases) diagnosed according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria, and 600 healthy control subjects matched in sex, age, and area of residence from Southwest China were included. Polymerase chain reactionrestriction fragment length polymorphism analysis was performed to identify the mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 in all patients and control subjects. The polymerase chain reaction-restriction fragment length polymorphism results were confirmed through direct sequencing.
3. Results * Corresponding author at: Department of Neurology, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China. Tel.: þ0086 18980602127; fax: þ0086 028 85423550. E-mail address: [email protected] (H.-F. Shang). 0197-4580/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2012.11.003
No mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 were detected in our study. However, a novel Arg1205Cys mutation (c.3613C / T) was identified in a late-onset sporadic PD patient
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Y. Chen et al. / Neurobiology of Aging 34 (2013) 1709.e7e1709.e8
(Supplementary Fig. 1A, B, and C), which was absent in the 600 healthy control subjects. 4. Discussion In the current study, we found no mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 in a large sample of Chinese PD patients from Southwest China. However, we found a novel Arg1205Cys (c.3613C / T) mutation in EIF4G1 in a late-onset sporadic PD patient. The inconsistent findings between previous studies and our present study were probably influenced by various factors. First, these 2 mutants were rare among PD patients. In 2 multicenter studies, only 2 PD families with Asp620Asn were found among 860 PD patients (Zimprich et al., 2011), and 4 families with this mutation were identified among 4326 patients (Vilarino-Guell et al., 2011). In the current study, we have only included 609 PD patients. Ethnic factors also play an important role in the diversity of the mutation frequencies; the highest is 1.67% in Yemenite Jews (2/120), followed by 1.2% in France (3/246), 0.5% in Tunisia (1/199), 0% in Canada, Norway, Poland, Ireland, Taiwan (Vilarino-Guell et al., 2011), and Germany (Zimprich, et al., 2011). From this perspective, our sample is sufficiently large for detecting the Asp620Asn mutation if its frequency among our patients were the same as that in Yemenite Jews or the French. Second, Parkinson disease-17 and Parkinson disease-18, caused by mutations of VPS35 and EIF4G1, are both late-onset ADPD. However, in our study, the patients with a definite family history and the late-onset form of ADPD are too few (18 patients). This number is less than that in a previous study (160 familial PD cases) that found only 1 patient with this mutation (Sheerin, et al., 2012). Our results suggest mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 do not play an important role in Chinese PD patients. Moreover, the finding of a novel Arg2015Cys variant in EIF4G1 in 1 sporadic PD patient is of unknown pathogenicity considering the absence of segregation data. Disclosure statement The authors have no conflicts of interest to disclose.
Acknowledgements The authors thank the patients for their participation in the study. The study was supported by the National Science Fund of China (Grant No. 30973149) and the Science and Technology Bureau Fund of Sichuan Province (No. 2010SZ0069). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neurobiolaging. 2012.11.003. References Chartier-Harlin, M.C., Dachsel, J.C., Vilarino-Guell, C., Lincoln, S.J., Lepretre, F., Hulihan, M.M., Kachergus, J., Milnerwood, A.J., Tapia, L., Song, M.S., Le Rhun, E., Mutez, E., Larvor, L., Duflot, A., Vanbesien-Mailliot, C., Kreisler, A., Ross, O.A., Nishioka, K., Soto-Ortolaza, A.I., Cobb, S.A., Melrose, H.L., Behrouz, B., Keeling, B.H., Bacon, J.A., Hentati, E., Williams, L., Yanagiya, A., Sonenberg, N., Lockhart, P.J., Zubair, A.C., Uitti, R.J., Aasly, J.O., Krygowska-Wajs, A., Opala, G., Wszolek, Z.K., Frigerio, R., Maraganore, D.M., Gosal, D., Lynch, T., Hutchinson, M., Bentivoglio, A.R., Valente, E.M., Nichols, W.C., Pankratz, N., Foroud, T., Gibson, R.A., Hentati, F., Dickson, D.W., Destee, A., Farrer, M.J., 2011. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am. J. Hum. Genet. 89, 398e406. Fujioka, S., Wszolek, Z.K., 2012. Update on genetics of parkinsonism. Neurodegener. Dis. 10, 257e260. Lesage, S., Condroyer, C., Klebe, S., Honore, A., Tison, F., Brefel-Courbon, C., Durr, A., Brice, A., 2012. Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology 78, 1449e1450. Sheerin, U.M., Charlesworth, G., Bras, J., Guerreiro, R., Bhatia, K., Foltynie, T., Limousin, P., Silveira-Moriyama, L., Lees, A., Wood, N., 2012. Screening for VPS35 mutations in Parkinson’s disease. Neurobiol. Aging 33, 838.e1e838.e5. Vilarino-Guell, C., Wider, C., Ross, O.A., Dachsel, J.C., Kachergus, J.M., Lincoln, S.J., Soto-Ortolaza, A.I., Cobb, S.A., Wilhoite, G.J., Bacon, J.A., Behrouz, B., Melrose, H.L., Hentati, E., Puschmann, A., Evans, D.M., Conibear, E., Wasserman, W.W., Aasly, J.O., Burkhard, P.R., Djaldetti, R., Ghika, J., Hentati, F., Krygowska-Wajs, A., Lynch, T., Melamed, E., Rajput, A., Rajput, A.H., Solida, A., Wu, R.M., Uitti, R.J., Wszolek, Z.K., Vingerhoets, F., Farrer, M.J., 2011. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162e167. Zimprich, A., Benet-Pages, A., Struhal, W., Graf, E., Eck, S.H., Offman, M.N., Haubenberger, D., Spielberger, S., Schulte, E.C., Lichtner, P., Rossle, S.C., Klopp, N., Wolf, E., Seppi, K., Pirker, W., Presslauer, S., Mollenhauer, B., Katzenschlager, R., Foki, T., Hotzy, C., Reinthaler, E., Harutyunyan, A., Kralovics, R., Peters, A., Zimprich, F., Brucke, T., Poewe, W., Auff, E., Trenkwalder, C., Rost, B., Ransmayr, G., Winkelmann, J., Meitinger, T., Strom, T.M., 2011. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168e175.
Contents lists available at SciVerse ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
VPS35 Asp620Asn and EIF4G1 Arg1205His mutations are rare in Parkinson disease from Southwest China YongPing Chen a, Ke Chen a, Wei Song a, XuePing Chen a, Bei Cao a, Rui Huang a, Bi Zhao a, XiaoYan Guo a, JeanMarc Burgunder a, b, JianPeng Li a, Hui-Fang Shang a, * a b
Department of Neurology and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, SiChuan University, Chengdu, Sichuan, China Department of Neurology, University of Bern, Bern, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2012 Received in revised form 1 November 2012 Accepted 4 November 2012 Available online 20 December 2012
The Asp620Asn mutation in the vacuolar protein sorting protein 35 (VPS35) gene and the Arg1205His mutation in the eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) gene were identified in autosomal dominant late-onset familial and sporadic Parkinson disease (PD) patients in a Caucasian population. However, the frequencies of these 2 mutations among Chinese PD patients are unknown. We examined these mutations in a large cohort consisting of 609 PD patients and 600 healthy control subjects from Southwest China. Our results suggest that the Asp620Asn mutation in VPS35 and the Arg1205His mutation in EIF4G1 do not play a role in PD in the Southwest China population. The novel Arg1205Cys mutation in EIF4G1 detected in the current study should be further studied among other Asian patients. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Parkinson disease VPS35 gene Asp620Asn mutation EIF4G1 gene Arg1205His mutation
1. Introduction Parkinson disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is characterized by tremors, rigidity, bradykinesia, and postural instability. Multiple genetic and environmental factors are believed to contribute to the development of PD. Recently, the vacuolar protein sorting protein 35 gene (VPS35), and the eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1) were reported to be associated with autosomal dominant (AD) PD (Fujioka and Wszolek, 2012). The Asp620Asn mutation in the VPS35 gene and the Arg1205His mutation in the EIF4G1 gene have only been identified in large families with dominant late-onset PD. A total of 13 ADPD families with the Asp620Asn mutation in VPS35 have been found in Austria, Switzerland, the United States, Tunisia, Israel, and France (Lesage et al., 2012; Sheerin, et al., 2012; Vilarino-Guell et al., 2011; Zimprich et al., 2011). The Arg1205His missense mutation in EIF4G1 was identified in familial and sporadic PD patients from France, the United States, Canada, Ireland, Italy, and Tunisia (Chartier-Harlin, et al., 2011). However, the frequencies of these 2 mutations
among Chinese PD patients are unknown. Hence, we performed a large-scale case-control study that included 609 PD patients and 600 healthy control subjects to identify the frequency of the Asp620Asn mutations in VPS35 and Arg1205His in EIF4G1 in a Chinese population from Southwest China. 2. Methods A total of 609 PD patients (including 37 familial cases and 572 sporadic cases) diagnosed according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria, and 600 healthy control subjects matched in sex, age, and area of residence from Southwest China were included. Polymerase chain reactionrestriction fragment length polymorphism analysis was performed to identify the mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 in all patients and control subjects. The polymerase chain reaction-restriction fragment length polymorphism results were confirmed through direct sequencing.
3. Results * Corresponding author at: Department of Neurology, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China. Tel.: þ0086 18980602127; fax: þ0086 028 85423550. E-mail address: [email protected] (H.-F. Shang). 0197-4580/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2012.11.003
No mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 were detected in our study. However, a novel Arg1205Cys mutation (c.3613C / T) was identified in a late-onset sporadic PD patient
1709.e8
Y. Chen et al. / Neurobiology of Aging 34 (2013) 1709.e7e1709.e8
(Supplementary Fig. 1A, B, and C), which was absent in the 600 healthy control subjects. 4. Discussion In the current study, we found no mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 in a large sample of Chinese PD patients from Southwest China. However, we found a novel Arg1205Cys (c.3613C / T) mutation in EIF4G1 in a late-onset sporadic PD patient. The inconsistent findings between previous studies and our present study were probably influenced by various factors. First, these 2 mutants were rare among PD patients. In 2 multicenter studies, only 2 PD families with Asp620Asn were found among 860 PD patients (Zimprich et al., 2011), and 4 families with this mutation were identified among 4326 patients (Vilarino-Guell et al., 2011). In the current study, we have only included 609 PD patients. Ethnic factors also play an important role in the diversity of the mutation frequencies; the highest is 1.67% in Yemenite Jews (2/120), followed by 1.2% in France (3/246), 0.5% in Tunisia (1/199), 0% in Canada, Norway, Poland, Ireland, Taiwan (Vilarino-Guell et al., 2011), and Germany (Zimprich, et al., 2011). From this perspective, our sample is sufficiently large for detecting the Asp620Asn mutation if its frequency among our patients were the same as that in Yemenite Jews or the French. Second, Parkinson disease-17 and Parkinson disease-18, caused by mutations of VPS35 and EIF4G1, are both late-onset ADPD. However, in our study, the patients with a definite family history and the late-onset form of ADPD are too few (18 patients). This number is less than that in a previous study (160 familial PD cases) that found only 1 patient with this mutation (Sheerin, et al., 2012). Our results suggest mutations of Asp620Asn in VPS35 and Arg1205His in EIF4G1 do not play an important role in Chinese PD patients. Moreover, the finding of a novel Arg2015Cys variant in EIF4G1 in 1 sporadic PD patient is of unknown pathogenicity considering the absence of segregation data. Disclosure statement The authors have no conflicts of interest to disclose.
Acknowledgements The authors thank the patients for their participation in the study. The study was supported by the National Science Fund of China (Grant No. 30973149) and the Science and Technology Bureau Fund of Sichuan Province (No. 2010SZ0069). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neurobiolaging. 2012.11.003. References Chartier-Harlin, M.C., Dachsel, J.C., Vilarino-Guell, C., Lincoln, S.J., Lepretre, F., Hulihan, M.M., Kachergus, J., Milnerwood, A.J., Tapia, L., Song, M.S., Le Rhun, E., Mutez, E., Larvor, L., Duflot, A., Vanbesien-Mailliot, C., Kreisler, A., Ross, O.A., Nishioka, K., Soto-Ortolaza, A.I., Cobb, S.A., Melrose, H.L., Behrouz, B., Keeling, B.H., Bacon, J.A., Hentati, E., Williams, L., Yanagiya, A., Sonenberg, N., Lockhart, P.J., Zubair, A.C., Uitti, R.J., Aasly, J.O., Krygowska-Wajs, A., Opala, G., Wszolek, Z.K., Frigerio, R., Maraganore, D.M., Gosal, D., Lynch, T., Hutchinson, M., Bentivoglio, A.R., Valente, E.M., Nichols, W.C., Pankratz, N., Foroud, T., Gibson, R.A., Hentati, F., Dickson, D.W., Destee, A., Farrer, M.J., 2011. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am. J. Hum. Genet. 89, 398e406. Fujioka, S., Wszolek, Z.K., 2012. Update on genetics of parkinsonism. Neurodegener. Dis. 10, 257e260. Lesage, S., Condroyer, C., Klebe, S., Honore, A., Tison, F., Brefel-Courbon, C., Durr, A., Brice, A., 2012. Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology 78, 1449e1450. Sheerin, U.M., Charlesworth, G., Bras, J., Guerreiro, R., Bhatia, K., Foltynie, T., Limousin, P., Silveira-Moriyama, L., Lees, A., Wood, N., 2012. Screening for VPS35 mutations in Parkinson’s disease. Neurobiol. Aging 33, 838.e1e838.e5. Vilarino-Guell, C., Wider, C., Ross, O.A., Dachsel, J.C., Kachergus, J.M., Lincoln, S.J., Soto-Ortolaza, A.I., Cobb, S.A., Wilhoite, G.J., Bacon, J.A., Behrouz, B., Melrose, H.L., Hentati, E., Puschmann, A., Evans, D.M., Conibear, E., Wasserman, W.W., Aasly, J.O., Burkhard, P.R., Djaldetti, R., Ghika, J., Hentati, F., Krygowska-Wajs, A., Lynch, T., Melamed, E., Rajput, A., Rajput, A.H., Solida, A., Wu, R.M., Uitti, R.J., Wszolek, Z.K., Vingerhoets, F., Farrer, M.J., 2011. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162e167. Zimprich, A., Benet-Pages, A., Struhal, W., Graf, E., Eck, S.H., Offman, M.N., Haubenberger, D., Spielberger, S., Schulte, E.C., Lichtner, P., Rossle, S.C., Klopp, N., Wolf, E., Seppi, K., Pirker, W., Presslauer, S., Mollenhauer, B., Katzenschlager, R., Foki, T., Hotzy, C., Reinthaler, E., Harutyunyan, A., Kralovics, R., Peters, A., Zimprich, F., Brucke, T., Poewe, W., Auff, E., Trenkwalder, C., Rost, B., Ransmayr, G., Winkelmann, J., Meitinger, T., Strom, T.M., 2011. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168e175.