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Wang C.,Capital Medical University | Wang C.,Beijing Institute for Brain Disorders Parkinsons Disease Center | Wang C.,Fujian Medical University | Xu Y.,University of Sichuan | And 10 more authors.
Neurobiology of Aging | Year: 2014

CAG expansion within the exon 1 of ataxin-2 (ATXN2) gene responsible for spinocerebellar ataxia-2 (SCA2) has been reported to cause pure parkinsonism and other neurodegenerative disorders. However, it remains unclear whether CAG expansion is the only cause for SCA2 and its clinical alternatives, and whether extra mutations exist to modify the phenotypic diversity. To address this, we have conducted fine genetic mapping and exome sequencing for a large Chinese SCA2 pedigree predominantly manifesting parkinsonism (called SCA2-P). In addition, we compared the CAG expansions between the SCA2-P and 16 SCA2 families presenting as pure ataxia (SCA2-A). As a result, CAG repeat expansions, ranging from 37 to 40 copies, were detected among 10 affected and 8 nonsymptomatic members of the SCA2-P family. The CAG repeats in the diseased alleles were interrupted by CAA in the 3′-end. In contrast, CAG expansion ranging from 36 to 54 without CAA interruption was detected in all probands of the SCA2-A families. Genetic mapping located the SCA2-P pedigree on 12q24.21, which spans the ATXN2 gene. Exome sequencing for 3 patients and 1 normal member revealed no extra mutations in this family. In addition, by genotyping single-nucleotide polymorphisms around SCA2 locus, we have excluded the existence of haplotypes predisposing different patterns of CAG expansion. These results demonstrate that the ATXN2 CAG expansion is the sole causative mutation responsible for SCA2-P, and that genetic modifiers may not be the major cause of the phenotypic diversity of SCA2. © 2014 Elsevier Inc. All rights reserved. Source


Wang C.,Capital Medical University | Xu Y.,University of Sichuan | Feng X.,National Human Genome Center in Beijing | Ma J.,Capital Medical University | And 4 more authors.
Neurobiology of aging | Year: 2015

CAG expansion within the exon 1 of ataxin-2 (ATXN2) gene responsible for spinocerebellar ataxia-2 (SCA2) has been reported to cause pure parkinsonism and other neurodegenerative disorders. However, it remains unclear whether CAG expansion is the only cause for SCA2 and its clinical alternatives, and whether extra mutations exist to modify the phenotypic diversity. To address this, we have conducted fine genetic mapping and exome sequencing for a large Chinese SCA2 pedigree predominantly manifesting parkinsonism (called SCA2-P). In addition, we compared the CAG expansions between the SCA2-P and 16 SCA2 families presenting as pure ataxia (SCA2-A). As a result, CAG repeat expansions, ranging from 37 to 40 copies, were detected among 10 affected and 8 nonsymptomatic members of the SCA2-P family. The CAG repeats in the diseased alleles were interrupted by CAA in the 3'-end. In contrast, CAG expansion ranging from 36 to 54 without CAA interruption was detected in all probands of the SCA2-A families. Genetic mapping located the SCA2-P pedigree on 12q24.21, which spans the ATXN2 gene. Exome sequencing for 3 patients and 1 normal member revealed no extra mutations in this family. In addition, by genotyping single-nucleotide polymorphisms around SCA2 locus, we have excluded the existence of haplotypes predisposing different patterns of CAG expansion. These results demonstrate that the ATXN2 CAG expansion is the sole causative mutation responsible for SCA2-P, and that genetic modifiers may not be the major cause of the phenotypic diversity of SCA2. Copyright © 2015 Elsevier Inc. All rights reserved. Source


Wang C.,Capital Medical University | Wang C.,Key Laboratory on Neurodegenerative Disease of Ministry of Education | Wang C.,Key Laboratory on Parkinsons Disease of Beijing | Wang C.,Fujian Medical University | And 10 more authors.
Neurobiology of Aging | Year: 2013

Genome-wide association and large-scale replication studies have linked Parkinson's disease (PD) to a locus on 4p15 encompassing a single gene encoding bone marrow stromal cell antigen 1 (BST1). To screen for causative mutations of BST1 in PD, we have directly sequenced all the 9 exons of BST1 in a Chinese cohort consisting of 524 PD cases and 527 controls. As a result, 6 known and 1 novel single-nucleotide polymorphisms (SNPs) were identified in exons 1, 3, 4, 7, and 9. However, none of these SNPs were associated with PD. The data, together with previous reports, suggested that the association between BST1 and PD might be determined by the noncoding sequences of the gene. © 2013 Elsevier Inc. Source


Wang C.,Capital Medical University | Ma H.,Capital Medical University | Feng X.,National Human Genome Center in Beijing | Xie S.,National Human Genome Center in Beijing | And 2 more authors.
Brain Research | Year: 2010

Mutations in the parkin gene have been identified as one of the important genetic factors for the etiology of PD. However, pathogenicities of parkin mutations, especially of those heterozygotes, remain controversial, possibly due to confusions caused by the "mixed" effects of all types of mutations. Here we report a study on the independent effects of exonic deletions/duplications (or dosage mutations) on the risk for and clinical profiles of PD in a Chinese cohort consisting of 29 autosomal-recessive early-onset parkinsonism (AREP) families and 173 patients with sporadic early-onset Parkinson's disease (EOPD). Detected simultaneously by multiplex PCR/denaturing high-performance liquid chromatography and real-time quantitative PCR analysis, heterozygous or homozygous dosage mutations were identified in exons 2-7 of parkin. The overall frequency of these mutations for both types of EOPD patients (8.91%, 18/202) was significantly higher than that of the controls (0%, 0/54) (p = 0.03), and heterozygous mutations were more frequent in the AREP probands (17.2%, 5/29) than in the controls (0%) (p = 0.004) and the sporadic EOPD cases (3.5%, 6/173) (p = 0.01). AREP patients with dosage mutations had significantly younger age at onset (AAO) (p = 0.000) and were more likely to present as bradykinesia and complicated with dystonia or dyskinesia compared with those without mutations. Sporadic EOPD patients with dosage mutations do not have an earlier AAO but are more likely to present as tremor and bradykinesia. These data suggested that dosage mutations alone can increase the risk for both sporadic and familial EOPD and affect their clinical aspects, but might contribute to a greater degree to familial EOPD. © 2010 Elsevier B.V. All rights reserved. Source

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