DRD1 rare variants associated with tardive-like dystonia: A pilot pathway sequencing study in dystonia |
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| Affiliation: | 1. Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;2. Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;3. Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK;4. Department of Neurology, University of Groningen, The Netherlands;3. From the National Laboratory of Biomacromolecules and;4. Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China;1. Oscar-Langendorff-Institute of Physiology, University Medicine Rostock, 18057 Rostock, Germany;2. Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Freie University of Berlin, 14195 Berlin, Germany;3. Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany;1. Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, Oslo 0317, Norway;2. Tampere University, IMT, Tampere Fin-33014, Finland;3. MRC Centre for Regenerative Medicine, SCRM Building, University of Edinburgh, Bioquarter, 5 Little France Drive, Edinburgh EH16 4UU, UK;4. Stem Cell Center, Yale, 10 Amistad 201B, New Haven, CT 06520, USA;5. Norwegian Center for Stem Cell Research, PO Box 1112 Blindern, Oslo 0317, Norway;6. Institute of Immunology, Oslo University Hospital-Rikshospitalet, PO Box 4950 Nydalen, Oslo 0424, Norway;1. Maebashi Institute of Technology, Gunma 371-0816, Japan;2. Department of Environmental Biology and Chemistry, Graduate School of Science and Engineering for Research, University of Toyama, Toyama 930-8555, Japan;1. Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland;2. Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland |
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| Abstract: | The dystonias are a clinical heterogeneous group with a complex genetic background. To gain more insight in genetic risk factors in dystonia we used a pathway sequence approach in patients with an extreme dystonia phenotype (n = 26). We assessed all coding and non-coding variants in candidate genes in D1-like subclass of dopamine receptor genes (DRD1, DRD5) and the synaptic vesicle pathway linked to torsinA (TOR1A, STON2, SNAPIN, KLC1 and THAP1), spanning 96 Kb.Two rare missense variants in DRD1 were found: c.68G>A(p.Arg23His) in the screening group and c.776C>A(p.Ser259Tyr) in an additional screen of 15 selected dystonia patients. Genetic burden analysis of DRD1 rare variants in patients (4.8%) versus European American controls from ESP (0.72%) reveals an OR 5.35 (95% CI 1.29–23.1). No rare missense SNVs in the synaptic vesicle pathway were found. Sequencing of TOR1A showed variant enrichment in haplotype 2, possibly accountable for contradictive results in previous association studies. Two new rare SNVs were detected in THAP1, including a nonsense mutation (p.Gln167Ter) and a splice site variant (c.72-1G>A). Screening for rare SNV of candidate pathways in a phenotype extreme population appears to be a promising alternative method to identify genetic risk factors in complex disorders like primary torsion dystonia. These findings indicate a role for rare genetic variation in dopamine processing genes in dystonia pathophysiology. |
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| Keywords: | Dystonia Pathway sequencing |
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