title: The Potential Mutation of GAK Gene in the Typical Sporadic Parkinson's Disease from the Han Population of Chinese Mainland.
abstract: The genetic factors about the pathogenesis of sporadic Parkinson's disease (sPD) is not completely clear at present; therefore, we performed a genome-wide association study, high-throughput sequencing analysis (HTPSA) of all cyclin G-associated kinase (GAK) exons, loss-of-function assessment, and sorting intolerant from tolerant analysis of HTPSA data in 250 typical sPD and 250 controls, which found 55 candidate single nucleotide polymorphisms (SNPs). To further explore these SNPs, we sequenced the 30 most strongly associated SNPs in the 460 typical sPD cases and the 525 controls. All subjects were from the Han population of Chinese mainland and excluded the toxic exposure, the heavy coffee drinking, and the early- and late-onset sPD. The minor allele frequencies (MAFs) at c.3824T>G, c.3794T>C, and c.3819G>A were higher in the control. The TG of c.3824T>G, the TC of c.3794T>C, and the AG of c.3819G>A were associated with the decreased risk of sPD. The subjects carrying the minor C allele of c.3794T>C or the minor A allele of c.3819G>A exhibited a decreased risk of sPD. c.3824T>G negatively affected the binding affinity of heat shock protein 70 (HSP70). c.3794T>C increased the surface area exposed to substrates. c.3819G>A most likely reduced the expression level of GAK. Our data suggest that the multiple SNPs of GAK synergistically participate in the pathogenesis of sPD through multiple pathways.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.|Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Hanyi
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Human Genetics, Institute of Translational Medicine, Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Huiting
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Neurology, The Affiliated Union Hospital of Huazhong Technological University, Wuhan, 430006, Hubei, China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, the First Clinical Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Biochemistry and Molecular Biology, the First Clinical Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Department of Neurology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, Guangzhou, 510080, Guangdong, China. xiong715@126.com.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China. 13767015770@163.com.
authors.forename: Renshi
authors.initials: R
authors.lastname: Xu
mesh_terms: D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002681:China; D017124:Conserved Sequence / Q000235:genetics; D003710:Demography; D005006:Ethnicity / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014176:Protein Biosynthesis; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Allele; Chinese Han population; Cyclin G-associated kinase; Genotype; Sporadic Parkinson’s disease