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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

Dan X.,Capital Medical University | Dan X.,Key Laboratory on Neurodegenerative Disorders of Ministry of Education | Dan X.,Key Laboratory on Parkinsons Disease of Beijing | Wang C.,Capital Medical University | And 13 more authors.
Neurobiology of Aging | Year: 2014

Variants of the MAPT gene have been suggested to be associated with Parkinson's disease (PD) and to modify the risk for leucine-rich repeat kinase 2 (LRRK2) Parkinsonism. However, this has not been confirmed in Asians with ethnicity-specific variants of MAPT and LRRK2. In this study, Asian-specific LRRK2 p.G2385R variant and IVS1+124 C>G, a functional single-nucleotide polymorphism located in the MAPT promoter region, were genotyped in 561 Chinese PD patients and 556 control subjects. Allelic and genotypic frequencies of the 2 variants were compared between cases and control subjects independently and in combination. As a result, the LRRK2 p.G2385R variant alone was associated with an increased risk for PD (Odds ratio, 1.86; 95% confidence intervals, 1.08-3.19; p=0.014), whereas MAPT IVS1+124 C>G was not (p= 0.34). However, the coexistence of MAPT IVS1+124C>G significantly enhanced the LRRK2 G2385R-conferred risk for PD (Odds ratio, 2.30; 95% confidence intervals, 1.14-4.54; p= 0.012). These results provide further evidence supporting the interaction between MAPT and LRRK2 genes, which increases the susceptibility to PD in Chinese individuals. © 2014 Elsevier Inc. 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

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