title: ATP13A2 variability in Parkinson disease.
abstract: Recessively inherited mutations in ATP13A2 result in Kufor-Rakeb syndrome (KRS), whereas genetic variability and elevated ATP13A2 expression have been implicated in Parkinson disease (PD). Given this background, ATP13A2 was comprehensively assessed to support or refute its contribution to PD. Sequencing of ATP13A2 exons and intron-exon boundaries was performed in 89 probands with familial parkinsonism from Tunisia. The segregation of mutations with parkinsonism was subsequently assessed within pedigrees. The frequency of genetic variants and evidence for association was also examined in 240 patients with nonfamilial PD and 372 healthy controls. ATP13A2 mRNA expression was also quantified in brain tissues from 38 patients with nonfamilial PD and 38 healthy subjects from the United States. Sequencing analysis revealed 37 new variants; seven missense, six silent, and 24 that were noncoding. However, no single ATP13A2 mutation segregated with familial parkinsonism in either a dominant or recessive manner. Four markers showed marginal association with nonfamilial PD, prior to correction for multiple testing. ATP13A2 mRNA expression was marginally decreased in PD brains compared with tissue from control subjects. In conclusion, neither ATP13A2 genetic variability nor quantitative gene expression in brain appears to contribute to familial parkinsonism or nonfamilial PD.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Carles
authors.initials: C
authors.lastname: Vilariño-Güell
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lincoln
authors.forename: Samia
authors.initials: S
authors.lastname: Ben Yahmed
authors.forename: Mounir
authors.initials: M
authors.lastname: Kefi
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.forename: Mary M
authors.initials: MM
authors.lastname: Hulihan
authors.forename: Hua
authors.initials: H
authors.lastname: Chai
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Diehl
authors.forename: Rim
authors.initials: R
authors.lastname: Amouri
authors.forename: Alex
authors.initials: A
authors.lastname: Rajput
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Lefkos T
authors.initials: LT
authors.lastname: Middleton
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gibson
authors.forename: Faycal
authors.initials: F
authors.lastname: Hentati
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002531:Cerebellum / Q000378:metabolism; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013378:Substantia Nigra / Q000378:metabolism; D014416:Tunisia
chemical_list: C514983:ATP13A2 protein, human; D006180:Proton-Translocating ATPases