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dc.contributor.authorPuschmann, Andreas
dc.contributor.authorFiesel, Fabienne C
dc.contributor.authorCaulfield, Thomas R
dc.contributor.authorHudec, Roman
dc.contributor.authorAndo, Maya
dc.contributor.authorTruban, Dominika
dc.contributor.authorHou, Xu
dc.contributor.authorOgaki, Kotaro
dc.contributor.authorHeckman, Michael G
dc.contributor.authorJames, Elle D
dc.contributor.authorSwanberg, Maria
dc.contributor.authorJimenez-Ferrer, Itzia
dc.contributor.authorHansson, Oskar
dc.contributor.authorOpala, Grzegorz
dc.contributor.authorSiuda, Joanna
dc.contributor.authorBoczarska-Jedynak, Magdalena
dc.contributor.authorFriedman, Andrzej
dc.contributor.authorKoziorowski, Dariusz
dc.contributor.authorRudzinska-Bar, Monika
dc.contributor.authorAasly, Jan O
dc.contributor.authorLynch, Timothy
dc.contributor.authorMellick, George D
dc.contributor.authorMohan, Megha
dc.contributor.authorSilburn, Peter A
dc.contributor.authorSanotsky, Yanosh
dc.contributor.authorVilarino-Guell, Carles
dc.contributor.authorFarrer, Matthew J
dc.contributor.authorChen, Li
dc.contributor.authorDawson, Valina L
dc.contributor.authorDawson, Ted M
dc.contributor.authorWszolek, Zbigniew K
dc.contributor.authorRoss, Owen A
dc.contributor.authorSpringer, Wolfdieter
dc.date.accessioned2017-08-31T12:30:40Z
dc.date.available2017-08-31T12:30:40Z
dc.date.issued2017
dc.identifier.issn0006-8950
dc.identifier.doi10.1093/brain/aww261
dc.identifier.urihttp://hdl.handle.net/10072/100614
dc.description.abstractIt has been postulated that heterozygous mutations in recessive Parkinson’s genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson’s disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson’s disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson’s disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherOxford University Press
dc.relation.ispartofpagefrom1
dc.relation.ispartofpageto20
dc.relation.ispartofjournalBrain
dc.subject.fieldofresearchGenome Structure and Regulation
dc.subject.fieldofresearchSystems Biology
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchPsychology and Cognitive Sciences
dc.subject.fieldofresearchcode060407
dc.subject.fieldofresearchcode060114
dc.subject.fieldofresearchcode11
dc.subject.fieldofresearchcode17
dc.titleHeterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc/4.0/
dc.description.versionPublished
gro.rights.copyright© The Author(s) 2016. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
gro.hasfulltextFull Text
gro.griffith.authorSilburn, Peter A.
gro.griffith.authorMellick, George
gro.griffith.authorMohan, Megha


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