Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
(2017) In Brain 140(1). p.98-117- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2017-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Journal Article
- in
- Brain
- volume
- 140
- issue
- 1
- pages
- 98 - 117
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85018383742
- wos:000392710500018
- pmid:27807026
- ISSN
- 1460-2156
- DOI
- 10.1093/brain/aww261
- language
- English
- LU publication?
- yes
- id
- 951e000a-d661-45e6-b046-dedac7c44f41
- date added to LUP
- 2017-02-20 14:00:45
- date last changed
- 2025-02-03 10:37:25
@article{951e000a-d661-45e6-b046-dedac7c44f41, abstract = {{<p>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.</p>}}, author = {{Puschmann, Andreas and Fiesel, Fabienne C and Caulfield, Thomas R and Hudec, Roman and Ando, Maya and Truban, Dominika and Hou, Xu and Ogaki, Kotaro and Heckman, Michael G. and James, Elle D and Swanberg, Maria and Jimenez Ferrer Carrillo, Itzia and Hansson, Oskar and Opala, Grzegorz and Siuda, Joanna and Boczarska-Jedynak, Magdalena and Friedman, Andrzej and Koziorowski, Dariusz and Aasly, Jan O. and Lynch, Timothy and Mellick, George D. and Mohan, Megha and Silburn, Peter A. and Sanotsky, Yanosh and Vilariño-Güell, Carles and Farrer, Matthew J. and Chen, Li and Dawson, Valina L and Dawson, Ted M. and Wszolek, Zbigniew K and Ross, Owen A. and Springer, Wolfdieter}}, issn = {{1460-2156}}, keywords = {{Journal Article}}, language = {{eng}}, number = {{1}}, pages = {{98--117}}, publisher = {{Oxford University Press}}, series = {{Brain}}, title = {{Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism}}, url = {{http://dx.doi.org/10.1093/brain/aww261}}, doi = {{10.1093/brain/aww261}}, volume = {{140}}, year = {{2017}}, }