title: Linkage analysis and whole-exome sequencing exclude extra mutations responsible for the parkinsonian phenotype of spinocerebellar ataxia-2.
abstract: 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.
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China; Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders Parkinson's Disease Center, Beijing, China; Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China.
authors.forename: Chaodong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Xu
authors.affiliation: National Human Genome Center in Beijing, Beijing, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China; Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders Parkinson's Disease Center, Beijing, China.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ma
authors.affiliation: National Human Genome Center in Beijing, Beijing, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Bei-Sha
authors.initials: BS
authors.lastname: Tang
authors.affiliation: Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China; Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders Parkinson's Disease Center, Beijing, China; Key Laboratory on Neurodegenerative Disease of Ministry of Education, Beijing, China; Key Laboratory on Parkinson's Disease of Beijing, Beijing, China. Electronic address: pbchan90@gmail.com.
authors.forename: Piu
authors.initials: P
authors.lastname: Chan
mesh_terms: D000328:Adult; D000067528:Ataxins; D059472:Exome / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D055815:Young Adult
chemical_list: D000067528:Ataxins; D009419:Nerve Tissue Proteins
keywords: Linkage analysis; Mutation; Parkinsonism; Spinocerebellar ataxia-2; Whole-exome sequencing