Human Molecular Genetics Advance Access originally published online on October 20, 2004
Human Molecular Genetics 2004 13(24):3161-3170; doi:10.1093/hmg/ddh330
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved
The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway
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ek1,12,*1Department of Neurology, UCSF, San Francisco, CA, USA, 2Department of Human Genetics, University of Utah, Salt Lake City, UT, USA, 3JW Goethe University Hospital, Frankfurt/M, Germany, 4Erasme Hospital, Brussels, Belgium, 5Department of Neurology, Medical Academy of Warsaw, Warsaw, Poland, 6University of Ottawa, Ottawa Hospital, Division of Neurology, D715, Ottawa, Canada, 7University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada, 8Institute of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark, 9Clinic of Nervous Diseases, Moscow Medical Academy, Moscow, Russia, 10Institute of Neurology, Catholic University, Rome, Italy, 11National Institutes of Health/National Institute of Neurological Diseases and Stroke, Bethesda, MD, USA and 12Howard Hughes Medical Institute, San Francisco, USA
Received August 23, 2004; Accepted October 11, 2004
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.
* To whom correspondence should be addressed at: University of California at San Francisco, Department of Neurology, Box 2922, 1550 4th Street, San Francisco, CA 94143-2922, USA. Email: ptacek{at}itsa.ucsf.edu
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