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


ABSTRACT: 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.

SUBMITTER: Puschmann A 

PROVIDER: S-EPMC5379862 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Puschmann Andreas A   Fiesel Fabienne C FC   Caulfield Thomas R TR   Hudec Roman R   Ando Maya M   Truban Dominika D   Hou Xu X   Ogaki Kotaro K   Heckman Michael G MG   James Elle D ED   Swanberg Maria M   Jimenez-Ferrer Itzia I   Hansson Oskar O   Opala Grzegorz G   Siuda Joanna J   Boczarska-Jedynak Magdalena M   Friedman Andrzej A   Koziorowski Dariusz D   Rudzińska-Bar Monika M   Aasly Jan O JO   Lynch Timothy T   Mellick George D GD   Mohan Megha M   Silburn Peter A PA   Sanotsky Yanosh Y   Vilariño-Güell Carles C   Farrer Matthew J MJ   Chen Li L   Dawson Valina L VL   Dawson Ted M TM   Wszolek Zbigniew K ZK   Ross Owen A OA   Ross Owen A OA   Springer Wolfdieter W  

Brain : a journal of neurology 20161102 1


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  ...[more]

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