Journal
BRAIN
Volume 137, Issue -, Pages 2480-2492Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awu179
Keywords
GCH1; DOPA-responsive-dystonia; Parkinson's disease; dopamine; exome sequencing
Categories
Funding
- Wellcome Trust/Medical Research Council (MRC) Joint Call in Neurodegeneration award [WT089698]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Grigioni Foundation for Parkinson Disease
- Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services [Z01-AG000949-02, Z01-ES101986]
- National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [Z01-AG000949-02, Z01-ES101986]
- Department of Defense [W81XWH-09-2-0128]
- Michael J Fox Foundation for Parkinson's Disease Research
- 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
- Deutsche Forschungsgemeinschaft [SFB 936]
- section of medical genomics, the Prinses Beatrix Fonds
- Forschungszentrum fur Umwelt und Gesundheit - German Federal Ministry of Education, Science, Research, and Technology
- State of Bavaria
- German National Genome Network (NGFNplus, German Ministry for Education and Research) [01GS08134]
- German Federal Ministry of Education and Research (PopGen) [NGFN 01GR0468]
- ERA-NET NEURON [01EW0908]
- Helmholtz Alliance Mental Health in an Ageing Society - Initiative and Networking Fund of the Helmholtz Association [HA-215]
- Wellcome Trust [076113, 085475, 090355]
- Parkinson's UK [8047, J-1101]
- Medical Research Council UK [G0700943, G1100643]
- Department of Health's National Institute for Health Research Biomedical Research Centres funding
- France-Parkinson Association
- French program Investissements d'avenir funding [ANR-10-IAIHU-06]
- EU European Regional Development Fund [3.2.1001.11-0017]
- Estonian Research Council [IUT2-4]
- European Regional Development Fund in the frame of Centre of Excellence for Translational Medicine
- Alzheimers Research UK [ARUK-PhD2014-16] Funding Source: researchfish
- Medical Research Council [MR/L501554/1, MC_G0901330, MC_PC_09003, G108/638, MR/J004758/1, G1100643, G1001253, G0701075, G0700943, G0400000, MC_G1000735, G0802760] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10376] Funding Source: researchfish
- Parkinson's UK [J-0804, F-1201, G-0907, J-1101] Funding Source: researchfish
- MRC [G0701075, G0700943, G108/638, G1001253, MR/J004758/1, MC_PC_09003, G0802760, MC_G1000735, G1100643, G0400000, MC_G0901330] Funding Source: UKRI
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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 ([I-123]N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(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.
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