Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism

Research output: Contribution to journalArticle


SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It 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.


  • Fabienne C Fiesel
  • Thomas R Caulfield
  • Roman Hudec
  • Maya Ando
  • Dominika Truban
  • Xu Hou
  • Kotaro Ogaki
  • Michael G. Heckman
  • Elle D James
  • Grzegorz Opala
  • Joanna Siuda
  • Magdalena Boczarska-Jedynak
  • Andrzej Friedman
  • Dariusz Koziorowski
  • Jan O. Aasly
  • Timothy Lynch
  • George D. Mellick
  • Megha Mohan
  • Peter A. Silburn
  • Yanosh Sanotsky
  • Carles Vilariño-Güell
  • Matthew J. Farrer
  • Li Chen
  • Valina L Dawson
  • Ted M. Dawson
  • Zbigniew K Wszolek
  • Owen A. Ross
  • Wolfdieter Springer
External organisations
  • Skåne University Hospital
  • Mayo Clinic Florida
  • Medical University of Silesia
  • Medical University of Warsaw
  • Norwegian University of Science and Technology
  • University College Dublin
  • Griffith University
  • University of Queensland
  • Lviv Regional Clinical Hospital
  • University of British Columbia
  • Adrienne Helis Malvin Medical Research Foundation
  • Johns Hopkins University School of Medicine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
  • Neurosciences


  • Journal Article
Original languageEnglish
Pages (from-to)98-117
Issue number1
Publication statusPublished - 2017 Jan
Publication categoryResearch

Related research output

Maria Swanberg & Itzia Jimenez-Ferrer, 2018 Dec 21, Parkinson’s Disease : Pathogenesis and Clinical Aspects. Stoker, T. B. & Greenland, J. C. (eds.). Brisbane (AU): Codon Publications, p. 27-44

Research output: Chapter in Book/Report/Conference proceedingBook chapter

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