title: ATP13A2 variability in Taiwanese Parkinson's disease.
abstract: Mutations in ATP13A2 have been reported to associate with Parkinson's disease (PD). This study investigates the contribution of genetic variants in ATP13A2 to Taiwanese PD. ATP13A2 cDNA fragments from 65 early onset PD (onset <50 years) were sequenced. The identified variants were validated in a cohort of PD (n = 493) and ethnically matched controls (n = 585). A novel heterozygous G1014S, located at the conserved seventh transmembrane domain of ATP13A2 protein, was identified in an early onset PD patient, which was absent in 585 normal controls. Additionally, a reported heterozygous A746T was found in two PD patients and four controls. The clinical features and 99mTc-TRODAT-1 single photon emission computed tomography (SPECT) image of the patients carrying G1014S and A746T were similar to that of idiopathic PD. One normal control with A746T showed an asymmetric reduction of 99mT TRODAT-1 uptake in the right striatum. Under oxidative stress or apoptotic stimulus, lymphoblastoid cells carrying either A764T or G1014S showed increased caspase 3 activity compared with the controls. The rates of decay for G1014S and A746T proteins were more or less reduced in cycloheximide chase experiment. In silico modeling of G1014S exhibited a more stable feature than wild-type, and G1014S is mislocalized mainly in the intralysosomal space, which is coherent with the prediction of prohibiting N-myristoylation and membrane association. We therefore hypothesize that rare variants of ATP13A2 may contribute to PD susceptibility in Taiwan. The role played by ATP13A2 variants in PD remains to be clarified.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang-Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Lin
authors.forename: Hsueh-Fen
authors.initials: HF
authors.lastname: Juan
authors.forename: Fen-Ju
authors.initials: FJ
authors.lastname: Hu
authors.forename: Ya-Chin
authors.initials: YC
authors.lastname: Hsiao
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chang
authors.forename: Chih-Ying
authors.initials: CY
authors.lastname: Chao
authors.forename: I-Cheng
authors.initials: IC
authors.lastname: Chen
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lee
authors.forename: Tsu-Wei
authors.initials: TW
authors.lastname: Wang
authors.forename: Ya-Tang
authors.initials: YT
authors.lastname: Chen
authors.forename: Yi-Tsun
authors.initials: YT
authors.lastname: Chen
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D017422:Sequence Analysis, DNA; D013624:Taiwan
chemical_list: C514983:ATP13A2 protein, human; D012333:RNA, Messenger; D053148:Caspase 3; D006180:Proton-Translocating ATPases