dc.contributor.author | Mencacci, NE | en_US |
dc.contributor.author | Isaias, IU | en_US |
dc.contributor.author | Reich, MM | en_US |
dc.contributor.author | Ganos, C | en_US |
dc.contributor.author | Plagnol, V | en_US |
dc.contributor.author | Polke, JM | en_US |
dc.contributor.author | Bras, J | en_US |
dc.contributor.author | Hersheson, J | en_US |
dc.contributor.author | Stamelou, M | en_US |
dc.contributor.author | Pittman, AM | en_US |
dc.contributor.author | Noyce, AJ | en_US |
dc.contributor.author | Mok, KY | en_US |
dc.contributor.author | Opladen, T | en_US |
dc.contributor.author | Kunstmann, E | en_US |
dc.contributor.author | Hodecker, S | en_US |
dc.contributor.author | Münchau, A | en_US |
dc.contributor.author | Volkmann, J | en_US |
dc.contributor.author | Samnick, S | en_US |
dc.contributor.author | Sidle, K | en_US |
dc.contributor.author | Nanji, T | en_US |
dc.contributor.author | Sweeney, MG | en_US |
dc.contributor.author | Houlden, H | en_US |
dc.contributor.author | Batla, A | en_US |
dc.contributor.author | Zecchinelli, AL | en_US |
dc.contributor.author | Pezzoli, G | en_US |
dc.contributor.author | Marotta, G | en_US |
dc.contributor.author | Lees, A | en_US |
dc.contributor.author | Alegria, P | en_US |
dc.contributor.author | Krack, P | en_US |
dc.contributor.author | Cormier-Dequaire, F | en_US |
dc.contributor.author | Lesage, S | en_US |
dc.contributor.author | Brice, A | en_US |
dc.contributor.author | Heutink, P | en_US |
dc.contributor.author | Gasser, T | en_US |
dc.contributor.author | Lubbe, SJ | en_US |
dc.contributor.author | Morris, HR | en_US |
dc.contributor.author | Taba, P | en_US |
dc.contributor.author | Koks, S | en_US |
dc.contributor.author | Majounie, E | en_US |
dc.contributor.author | Raphael Gibbs, J | en_US |
dc.contributor.author | Singleton, A | en_US |
dc.contributor.author | Hardy, J | en_US |
dc.contributor.author | Klebe, S | en_US |
dc.contributor.author | Bhatia, KP | en_US |
dc.contributor.author | Wood, NW | en_US |
dc.contributor.author | International Parkinson’s Disease Genomics Consortium and UCL-exomes consortium | en_US |
dc.date.accessioned | 2018-05-09T16:22:13Z | |
dc.date.issued | 2014-09 | en_US |
dc.date.submitted | 2018-04-10T08:04:02.984Z | |
dc.identifier.other | 10.1093/brain/awu179 | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/37203 | |
dc.description | "This is the peer reviewed version of the following article: Mencacci et al. 2014. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers, which has been published in final form at Brain, Volume 137, Issue 9, 1 September 2014, Pages 2480–2492, https://doi.org/10.1093/brain/awu179. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions." | en_US |
dc.description.abstract | GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease. | en_US |
dc.description.sponsorship | This study was supported by the Wellcome Trust/Medical Research Council (MRC) Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium. This project was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the Grigioni Foundation for Parkinson Disease. This work was also supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; project numbers Z01-AG000949-02 and Z01-ES101986. In addition this work was supported by the Department of Defense (award W81XWH-09-2-0128), and the Michael J Fox Foundation for Parkinson’s Disease Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; the Deutsche Forschungsgemeinschaft (SFB 936). This study was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The work was also funded in part by Parkinson's UK (Grants 8047 and J-1101) and the Medical Research Council UK (G0700943, G1100643) for H.R.M and S.J.L. | en_US |
dc.format.extent | 2480 - 2492 | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Brain | en_US |
dc.rights | Creative Commons Attribution License | |
dc.subject | DOPA-responsive-dystonia | en_US |
dc.subject | GCH1 | en_US |
dc.subject | Parkinson’s disease | en_US |
dc.subject | dopamine | en_US |
dc.subject | exome sequencing | en_US |
dc.subject | Adolescent | en_US |
dc.subject | Adult | en_US |
dc.subject | Aged | en_US |
dc.subject | Aged, 80 and over | en_US |
dc.subject | Child | en_US |
dc.subject | Databases, Genetic | en_US |
dc.subject | Europe | en_US |
dc.subject | Female | en_US |
dc.subject | GTP Cyclohydrolase | en_US |
dc.subject | Genetic Variation | en_US |
dc.subject | Heterozygote | en_US |
dc.subject | Humans | en_US |
dc.subject | Male | en_US |
dc.subject | Middle Aged | en_US |
dc.subject | Mutation | en_US |
dc.subject | Parkinson Disease | en_US |
dc.subject | Pedigree | en_US |
dc.subject | Risk | en_US |
dc.subject | United States | en_US |
dc.subject | Young Adult | en_US |
dc.title | Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. | en_US |
dc.type | Article | |
dc.rights.holder | The Author (2014). | |
dc.identifier.doi | 10.1093/brain/awu179 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/24993959 | en_US |
pubs.issue | Pt 9 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 137 | en_US |