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GIGYF2 Asn56Ser mutation is rare in Chinese Parkinson's disease patients
Neuroscience Letters 463 (2009) 172–175
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
GIGYF2 Asn56Ser mutation is rare in Chinese Parkinson’s disease patients Yu Zhang a,1 , Lan Zheng a,1 , Ting Zhang a , Ying Wang a , Qin Xiao a , Qin-Zhou Fei a , Pei-Jing Cui a , Li Cao a,∗ , Sheng-Di Chen a,b,∗∗ a
Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Science (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China b
a r t i c l e
i n f o
Article history: Received 18 January 2009 Received in revised form 12 July 2009 Accepted 23 July 2009 Keywords: Parkinson’s disease GIGYF2 Asn56Ser Chinese
a b s t r a c t Grb10-Interacting GYF Protein-2 gene (GIGYF2) has been suggested as a candidate gene for PARK11 locus since seven different GIGYF2 missense mutations were identified in familial Parkinson’s disease (PD) patients of European descent. To evaluate the frequency and distribution of GIGYF2 Asn56Ser mutation in Chinese PD patients, we analyzed 469 patients with PD from mainland China, including 36 cases with familial PD and 433 cases with sporadic PD. A total of 451 subjects without neurological disorders from the same region in China were set as a control group. The result showed that the GIGYF2 Asn56Ser mutation was not present in all subjects. Our finding suggests that the GIGYF2 Asn56Ser mutation is rare in Chinese PD patients. © 2009 Elsevier Ireland Ltd. All rights reserved.
Parkinson’s disease (PD) is a common neurodegenerative movement disorder affecting approximately 2% of the population above 65 years of age [8]. In China, about 1.7 million people (age ≥55 years) are afflicted with this disorder [19,27]. The classic clinical features of PD include resting tremor, bradykinesia, rigidity and postural instability. Pathologically, PD is characterized by selective degeneration of dopaminergic neurons of the substantia nigra pars compacta and the presence of intracytoplasmic inclusions known as Lewy bodies in the surviving neurons. Although the cause of PD remains unknown, increasing evidences indicate that multiple genetic risk factors contribute to its development. The identification of genetic risk factors of PD would improve our understanding of its etiopathogenesis and develop new therapeutic approaches to this disease. Up to date, 14 chromosome loci (PARK1–PARK14) associated with familial PD have been reported. LRRK2, ˛-synuclein, UCHL1, and NR4A2 are associated with autosomal dominant familial PD; while Parkin, PINK1, DJ-1, and ATP13A2 are associated with autosomal recessive familial PD [3,4,6,11,12,16,18,20–22,24,25]. The PARK11 was initially identified by whole-genome linkage analysis in a population of PD patients and located on chromosome 2q36-
∗ Corresponding author. ∗∗ Corresponding author at: Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Tel.: +86 21 6445 7249; fax: +86 21 6445 7249. E-mail addresses: [email protected] (L. Cao), chen [email protected] (S.-D. Chen). 1 These authors contributed equally to this work as joint first authors. 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.07.067
37 between microsatellite markers D2S396 and D2S338. Further statistical analysis revealed a significant correlation of the genes between those two markers in PARK11 locus and PD [4,15–17]. Recently, Lautier et al. [9] sequenced all 27 coding exons of the GIGYF2 gene in 123 Italian and 126 French patients with familial PD, and 131 Italian and 96 French controls. Seven different GIGYF2 missense mutations were observed in 12 unrelated PD patients (4.8%), but not in the controls. Among these mutations, the Asn56Ser (c.167A>G) has the highest allele frequency (0.8%), which was observed in 4 unrelated PD patients (1 Italian and 3 French) [9]. In order to identify the frequency and distribution of GIGYF2 Asn56Ser mutation in Chinese PD patients, we conducted a genetic analysis of the Asn56Ser mutation in 469 PD patients and 451 controls in a Chinese population from mainland China. A total of 469 patients with PD were enrolled from the outpatient clinic of Department of Neurology in Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. Among these patients, based on the published criteria for PD [7], 36 patients were diagnosed with familial PD (defined as having at least one first-degree relative with PD in the family) and 433 patients were diagnosed with sporadic idiopathic PD. Patients with secondary Parkinsonism or Parkinson-plus syndrome were excluded from this study. 451 control subjects without neurological disorders were collected from the same outpatient clinic with the same ethnic background. The institutional ethics committees approved this study and informed consents for the participation in the study were obtained from all subjects. Genomic DNA from peripheral blood was extracted using the standardized phenol/chlorine extraction method. The Asn56Ser
Table 1 General characteristics of case control dataset. Sample characteristics
At least one first-degree relative affected (%) Only father affected in familial PD (%) Only mother affected in familial PD (%) Both parents affected in familial PD (%) Only siblings affected in familial PD (%) Only progeny affected in familial PD (%) At least one parent and one sibling affected in familial PD (%) At least one parent and one progeny affected in familial PD (%) At least one parent, one sibling and one progeny affected in familial PD (%) At least one sibling and one progeny affected in familial PD (%) Scores UPDRS PART I mentation (rage)a UPDRS PART II ADL (rage)a UPDRS PART III Motor (rage)a UPDRS PART IV complications (rage)a Hoehn and Yahr staging (rage)a Schwab and England daily life activity (rage)a Population with Asn56Ser/Asn457Thr mutation (n)
Italian [9]
PD (n = 469)
Control (n = 451)
PD (n = 123)
57.0 ± 11.4 (14–88) 61.8 ± 11.2 (15–88) 220/249
58.9 ± 17.0 (20–81) 238/213
53 ± 12 N.A. 54/69
French [9] Control (n = 131)
69 ± 9 75/56
PD (n = 126)
48 ± 12 N.A. 63/63
Portuguese [1] Control (n = 96)
64 ± 9 61/35
American [1]
PD (n = 267)
Control (n = 451)
PD (n = 462)
55 ± 12.7 65 ± 11.6 N.A.
66 ± 12.2 (24–89) N.A.
N.A. N.A. N.A.
10.72
100
100
29.21
32.17
30.77 13.46 1.92 25 0
25.6 24.0 0.8 44.6 0
33.9 32.2 0.9 1.7 6.0
N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A.
23.08
5.0
18.3
N.A.
N.A.
1.93
0
4.4
N.A.
N.A.
3.85
0
1.7
N.A.
N.A.
0
0
0.9
N.A.
N.A.
2.2 ± 1.8 (0–9) 13.4 ± 6.7 (0–38) 20.8 ± 12.8 (1–85) 3.2 ± 2.8 (0–14) 2.0 ± 0.8 (0–5) 78.3 ± 15.7% (10–100%)
N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A.
0/0
0/0
1/2
0/0
3/1
0/0
0/0
0/0
0/0
Control (n = 460)
N.A. 235/225
Y. Zhang et al. / Neuroscience Letters 463 (2009) 172–175
General information Average onset age (rage) yra Average study age (rage) yra Sex ratio (F/M)
Chinese
0/0
N.A.: not applicable. a Data are mean ± SD.
173
174
Y. Zhang et al. / Neuroscience Letters 463 (2009) 172–175
(c.167A>G) genotype was determined by PCR-restriction fragment length polymorphism (PCR-RFLP) assays. A 281-bp fragment containing Asn56Ser mutation site was PCR amplified using forward primer 5 -CTGATACTTTGAGATAGTAGGAT-3 and reverse mismatched primer 5 -TCTTTTCCTACTTTCTTAGCATG-3 . The amplification products, digested overnight with Sph I (Takara, Japan) at 37 ◦ C, were separated by electrophoresis in 6% nondenaturing polyacrylamide gel and visualized by silver staining. The homozygote Asn56Ser (c.167A>G) mutant and the heterozygous Asn56Ser (c.167A>G) mutant were expected to yield 2 fragments (262 and 19 bp) and 3 fragments (281, 262, and 19 bp) respectively, whereas the wild type remained uncut as a 281 bp fragment. Sequencing confirmed wild type of the exon 2 of GIGYF2 and wild type of the exon 14 of LRRK2 gene carrying Sph I site were used as negative and positive control in each experiment. A total of 920 individuals (PD n = 469, controls n = 451) were screened in this study. The 469 PD patients consist of 249 males and 220 females. Their average study age is 61.8 ± 11.2 years, ranging from 15 to 88 years. The average onset age is 57.0 ± 11.4 years, ranging from 14 to 88 years. The 451 control subjects consist of 213 males and 238 females. Their average study age is 58.9 ± 17.0 years, ranging from 20 to 81 years. There is no statistically significant difference in the age and gender between patients and controls (P > 0.05) (Table 1). GIGYF2 Asn56Ser mutation was not detected in any of the 469 PD patients or 451 controls by PCR-RELP. Moreover, in order to exclude the possibility of other mutations in the GIGYF2 gene in those subjects, we screened Asn457Thr mutation whose allele frequency was second to Asn56Ser. However, we failed to find any Asn457Thr mutation in our subjects either. GIGYF2 has been described as a candidate PD-associate gene at PARK11 locus by Lautier et al. [9] in their recent study. They screened the pathogenic mutations in GIGYF2 gene in 249 familial PD patients and 237 controls. Seven different GIGYF2 missense mutations associated with PD were reported [9]. However, in a previous study by Bras et al. [1], neither GIGYF2 Asn56Ser nor Asn457Thr mutation was detected after the screening of 724 PD patients and 911 controls from two different populations. The result of our study is similar to that of Bras et al. [1]. None of the subjects in our study bears GIGYF2 Asn56Ser and Asn457Thr mutation (Table 1). In recent months, the results of several other studies on the association of GIGYF2 and PD were published [13,14,23,26,28]. Although new variants were found in different populations, there were no solid evidences supporting GIGYF2 as a PD causative gene. The difference between the results of Lautier et al. [9] and ours might have several explanation. The differences in genetic background might be the major reason contributing to this inconsistency. For example, the frequency of LRRK2 G2019S mutation was higher among Caucasians PD patients, but rare among Asian. On the contrary, the frequency of LRRK2 G2385R various was higher among Asian PD patients, but absent among Caucasians [2,5,10]. On the other hand, the founder effect in Caucasian might help to explain the absence of these two mutations in Chinese. Furthermore, the difference in the number of relatives with PD might account for this inconsistency. To our knowledge, this is the first study that assesses the frequency of the GIGYF2 Asn56Ser mutation in a relatively large cohort of Chinese PD patients. On the basis of our results obtained from screening 469 PD patients and 451 controls, we found that GIGYF2 Asn56Ser mutation is rare in Chinese PD patients. Multi-centre clinical cooperative studies involving larger number of subjects is expected to verify whether the GIGYF2 Asn56Ser mutation is associated with PD and whether the GIGYF2 gene is a candidate gene for PARK11.
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Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
GIGYF2 Asn56Ser mutation is rare in Chinese Parkinson’s disease patients Yu Zhang a,1 , Lan Zheng a,1 , Ting Zhang a , Ying Wang a , Qin Xiao a , Qin-Zhou Fei a , Pei-Jing Cui a , Li Cao a,∗ , Sheng-Di Chen a,b,∗∗ a
Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Science (CAS) and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China b
a r t i c l e
i n f o
Article history: Received 18 January 2009 Received in revised form 12 July 2009 Accepted 23 July 2009 Keywords: Parkinson’s disease GIGYF2 Asn56Ser Chinese
a b s t r a c t Grb10-Interacting GYF Protein-2 gene (GIGYF2) has been suggested as a candidate gene for PARK11 locus since seven different GIGYF2 missense mutations were identified in familial Parkinson’s disease (PD) patients of European descent. To evaluate the frequency and distribution of GIGYF2 Asn56Ser mutation in Chinese PD patients, we analyzed 469 patients with PD from mainland China, including 36 cases with familial PD and 433 cases with sporadic PD. A total of 451 subjects without neurological disorders from the same region in China were set as a control group. The result showed that the GIGYF2 Asn56Ser mutation was not present in all subjects. Our finding suggests that the GIGYF2 Asn56Ser mutation is rare in Chinese PD patients. © 2009 Elsevier Ireland Ltd. All rights reserved.
Parkinson’s disease (PD) is a common neurodegenerative movement disorder affecting approximately 2% of the population above 65 years of age [8]. In China, about 1.7 million people (age ≥55 years) are afflicted with this disorder [19,27]. The classic clinical features of PD include resting tremor, bradykinesia, rigidity and postural instability. Pathologically, PD is characterized by selective degeneration of dopaminergic neurons of the substantia nigra pars compacta and the presence of intracytoplasmic inclusions known as Lewy bodies in the surviving neurons. Although the cause of PD remains unknown, increasing evidences indicate that multiple genetic risk factors contribute to its development. The identification of genetic risk factors of PD would improve our understanding of its etiopathogenesis and develop new therapeutic approaches to this disease. Up to date, 14 chromosome loci (PARK1–PARK14) associated with familial PD have been reported. LRRK2, ˛-synuclein, UCHL1, and NR4A2 are associated with autosomal dominant familial PD; while Parkin, PINK1, DJ-1, and ATP13A2 are associated with autosomal recessive familial PD [3,4,6,11,12,16,18,20–22,24,25]. The PARK11 was initially identified by whole-genome linkage analysis in a population of PD patients and located on chromosome 2q36-
∗ Corresponding author. ∗∗ Corresponding author at: Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Tel.: +86 21 6445 7249; fax: +86 21 6445 7249. E-mail addresses: [email protected] (L. Cao), chen [email protected] (S.-D. Chen). 1 These authors contributed equally to this work as joint first authors. 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.07.067
37 between microsatellite markers D2S396 and D2S338. Further statistical analysis revealed a significant correlation of the genes between those two markers in PARK11 locus and PD [4,15–17]. Recently, Lautier et al. [9] sequenced all 27 coding exons of the GIGYF2 gene in 123 Italian and 126 French patients with familial PD, and 131 Italian and 96 French controls. Seven different GIGYF2 missense mutations were observed in 12 unrelated PD patients (4.8%), but not in the controls. Among these mutations, the Asn56Ser (c.167A>G) has the highest allele frequency (0.8%), which was observed in 4 unrelated PD patients (1 Italian and 3 French) [9]. In order to identify the frequency and distribution of GIGYF2 Asn56Ser mutation in Chinese PD patients, we conducted a genetic analysis of the Asn56Ser mutation in 469 PD patients and 451 controls in a Chinese population from mainland China. A total of 469 patients with PD were enrolled from the outpatient clinic of Department of Neurology in Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. Among these patients, based on the published criteria for PD [7], 36 patients were diagnosed with familial PD (defined as having at least one first-degree relative with PD in the family) and 433 patients were diagnosed with sporadic idiopathic PD. Patients with secondary Parkinsonism or Parkinson-plus syndrome were excluded from this study. 451 control subjects without neurological disorders were collected from the same outpatient clinic with the same ethnic background. The institutional ethics committees approved this study and informed consents for the participation in the study were obtained from all subjects. Genomic DNA from peripheral blood was extracted using the standardized phenol/chlorine extraction method. The Asn56Ser
Table 1 General characteristics of case control dataset. Sample characteristics
At least one first-degree relative affected (%) Only father affected in familial PD (%) Only mother affected in familial PD (%) Both parents affected in familial PD (%) Only siblings affected in familial PD (%) Only progeny affected in familial PD (%) At least one parent and one sibling affected in familial PD (%) At least one parent and one progeny affected in familial PD (%) At least one parent, one sibling and one progeny affected in familial PD (%) At least one sibling and one progeny affected in familial PD (%) Scores UPDRS PART I mentation (rage)a UPDRS PART II ADL (rage)a UPDRS PART III Motor (rage)a UPDRS PART IV complications (rage)a Hoehn and Yahr staging (rage)a Schwab and England daily life activity (rage)a Population with Asn56Ser/Asn457Thr mutation (n)
Italian [9]
PD (n = 469)
Control (n = 451)
PD (n = 123)
57.0 ± 11.4 (14–88) 61.8 ± 11.2 (15–88) 220/249
58.9 ± 17.0 (20–81) 238/213
53 ± 12 N.A. 54/69
French [9] Control (n = 131)
69 ± 9 75/56
PD (n = 126)
48 ± 12 N.A. 63/63
Portuguese [1] Control (n = 96)
64 ± 9 61/35
American [1]
PD (n = 267)
Control (n = 451)
PD (n = 462)
55 ± 12.7 65 ± 11.6 N.A.
66 ± 12.2 (24–89) N.A.
N.A. N.A. N.A.
10.72
100
100
29.21
32.17
30.77 13.46 1.92 25 0
25.6 24.0 0.8 44.6 0
33.9 32.2 0.9 1.7 6.0
N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A.
23.08
5.0
18.3
N.A.
N.A.
1.93
0
4.4
N.A.
N.A.
3.85
0
1.7
N.A.
N.A.
0
0
0.9
N.A.
N.A.
2.2 ± 1.8 (0–9) 13.4 ± 6.7 (0–38) 20.8 ± 12.8 (1–85) 3.2 ± 2.8 (0–14) 2.0 ± 0.8 (0–5) 78.3 ± 15.7% (10–100%)
N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A.
N.A. N.A. N.A. N.A. N.A. N.A.
0/0
0/0
1/2
0/0
3/1
0/0
0/0
0/0
0/0
Control (n = 460)
N.A. 235/225
Y. Zhang et al. / Neuroscience Letters 463 (2009) 172–175
General information Average onset age (rage) yra Average study age (rage) yra Sex ratio (F/M)
Chinese
0/0
N.A.: not applicable. a Data are mean ± SD.
173
174
Y. Zhang et al. / Neuroscience Letters 463 (2009) 172–175
(c.167A>G) genotype was determined by PCR-restriction fragment length polymorphism (PCR-RFLP) assays. A 281-bp fragment containing Asn56Ser mutation site was PCR amplified using forward primer 5 -CTGATACTTTGAGATAGTAGGAT-3 and reverse mismatched primer 5 -TCTTTTCCTACTTTCTTAGCATG-3 . The amplification products, digested overnight with Sph I (Takara, Japan) at 37 ◦ C, were separated by electrophoresis in 6% nondenaturing polyacrylamide gel and visualized by silver staining. The homozygote Asn56Ser (c.167A>G) mutant and the heterozygous Asn56Ser (c.167A>G) mutant were expected to yield 2 fragments (262 and 19 bp) and 3 fragments (281, 262, and 19 bp) respectively, whereas the wild type remained uncut as a 281 bp fragment. Sequencing confirmed wild type of the exon 2 of GIGYF2 and wild type of the exon 14 of LRRK2 gene carrying Sph I site were used as negative and positive control in each experiment. A total of 920 individuals (PD n = 469, controls n = 451) were screened in this study. The 469 PD patients consist of 249 males and 220 females. Their average study age is 61.8 ± 11.2 years, ranging from 15 to 88 years. The average onset age is 57.0 ± 11.4 years, ranging from 14 to 88 years. The 451 control subjects consist of 213 males and 238 females. Their average study age is 58.9 ± 17.0 years, ranging from 20 to 81 years. There is no statistically significant difference in the age and gender between patients and controls (P > 0.05) (Table 1). GIGYF2 Asn56Ser mutation was not detected in any of the 469 PD patients or 451 controls by PCR-RELP. Moreover, in order to exclude the possibility of other mutations in the GIGYF2 gene in those subjects, we screened Asn457Thr mutation whose allele frequency was second to Asn56Ser. However, we failed to find any Asn457Thr mutation in our subjects either. GIGYF2 has been described as a candidate PD-associate gene at PARK11 locus by Lautier et al. [9] in their recent study. They screened the pathogenic mutations in GIGYF2 gene in 249 familial PD patients and 237 controls. Seven different GIGYF2 missense mutations associated with PD were reported [9]. However, in a previous study by Bras et al. [1], neither GIGYF2 Asn56Ser nor Asn457Thr mutation was detected after the screening of 724 PD patients and 911 controls from two different populations. The result of our study is similar to that of Bras et al. [1]. None of the subjects in our study bears GIGYF2 Asn56Ser and Asn457Thr mutation (Table 1). In recent months, the results of several other studies on the association of GIGYF2 and PD were published [13,14,23,26,28]. Although new variants were found in different populations, there were no solid evidences supporting GIGYF2 as a PD causative gene. The difference between the results of Lautier et al. [9] and ours might have several explanation. The differences in genetic background might be the major reason contributing to this inconsistency. For example, the frequency of LRRK2 G2019S mutation was higher among Caucasians PD patients, but rare among Asian. On the contrary, the frequency of LRRK2 G2385R various was higher among Asian PD patients, but absent among Caucasians [2,5,10]. On the other hand, the founder effect in Caucasian might help to explain the absence of these two mutations in Chinese. Furthermore, the difference in the number of relatives with PD might account for this inconsistency. To our knowledge, this is the first study that assesses the frequency of the GIGYF2 Asn56Ser mutation in a relatively large cohort of Chinese PD patients. On the basis of our results obtained from screening 469 PD patients and 451 controls, we found that GIGYF2 Asn56Ser mutation is rare in Chinese PD patients. Multi-centre clinical cooperative studies involving larger number of subjects is expected to verify whether the GIGYF2 Asn56Ser mutation is associated with PD and whether the GIGYF2 gene is a candidate gene for PARK11.
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