Vilariño-Güell Carles, Soto Alexandra I, Lincoln Sarah J, Ben Yahmed Samia, Kefi Mounir, Heckman Michael G, Hulihan Mary M, Chai Hua, Diehl Nancy N, Amouri Rim, Rajput Alex, Mash Deborah C, Dickson Dennis W, Middleton Lefkos T, Gibson Rachel A, Hentati Faycal, Farrer Matthew J
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
Hum Mutat. 2009 Mar;30(3):406-10. doi: 10.1002/humu.20877.
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.
ATP13A2基因的隐性遗传突变会导致库福尔-拉凯布综合征（KRS），而基因变异性和ATP13A2表达升高与帕金森病（PD）有关。基于这一背景，对ATP13A2进行了全面评估，以支持或反驳其对帕金森病的影响。对来自突尼斯的89例家族性帕金森病先证者进行了ATP13A2外显子和内含子-外显子边界的测序。随后在家族谱系中评估突变与帕金森病的分离情况。还在240例非家族性帕金森病患者和372例健康对照中检测了基因变异的频率和关联证据。对来自美国的38例非家族性帕金森病患者和38例健康受试者的脑组织中的ATP13A2 mRNA表达也进行了定量分析。测序分析发现了37个新变异；7个错义变异、6个沉默变异和24个非编码变异。然而，没有一个ATP13A2突变以显性或隐性方式与家族性帕金森病分离。在进行多重检验校正之前，有4个标记与非家族性帕金森病有边缘关联。与对照组组织相比，帕金森病患者脑组织中的ATP13A2 mRNA表达略有下降。总之，无论是ATP13A2基因变异性还是脑中的定量基因表达似乎都与家族性帕金森病或非家族性帕金森病无关。
