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- Title
The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway.
- Authors
Lee, Hsien-Yang; Xu, Ying; Huang, Yong; Ahn, Andrew H.; Auburger, Georg W.J.; Pandolfo, Massimo; Kwieciński, Hubert; Grimes, David A.; Lang, Anthony E.; Nielsen, Jorgen E.; Averyanov, Yuri; Servidei, Serenella; Friedman, Andrzej; Bogaert, Patrick Van; Abramowicz, Marc J.; Bruno, Michiko K.; Sorensen, Beatrice F.; Tang, Ling; Fu, Ying-Hui; Ptáček, Louis J.
- Abstract
Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous hyperkinetic attacks that are precipitated by alcohol, coffee, stress and fatigue. We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD in 50 individuals from eight families. The mutations cause changes (Ala to Val) in the N-terminal region of two MR-1 isoforms. The MR-1L isoform is specifically expressed in brain and is localized to the cell membrane while the MR-1S isoform is ubiquitously expressed and shows diffuse cytoplasmic and nuclear localization. Bioinformatic analysis reveals that the MR-1 gene is homologous to the hydroxyacylglutathione hydrolase (HAGH) gene. HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress. Our results suggest a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD. Stress response pathways will be important areas for elucidation of episodic disease genetics where stress is a common precipitant of many common disorders like epilepsy, migraine and cardiac arrhythmias.
- Publication
Human Molecular Genetics, 2004, Vol 13, Issue 24, p3161
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddh330