Human Molecular Genetics Advance Access first published online on October 20, 2004
This version published online on November 3, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh330
© 2004 by Oxford University Press
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1 Department of Neurology, UCSF, San Francisco, California; Department of Human Genetics, University of Utah, Salt Lake City, Utah
* To whom correspondence should be addressed. Paroxysmal Nonkinesigenic 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 8 families. The mutations cause changes (Ala to Val) in the N-terminus 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.
Article
The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway
ek Drs.13*
2 Department of Neurology, UCSF, San Francisco, California
3 J.W. Goethe University Hospital, Frankfurt/M Germany
4 Erasme Hospital, Brussels, Belgium
5 Department of Neurology, Medical Academy of Warsaw, Warsaw, Poland
6 University of Ottawa, Ottawa Hospital, Division of Neurology, D715, Ottawa, Canada
7 University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
8 Institute of Medical Biochemistry & Genetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
9 Clinic of Nervous Diseases, Moscow Medical Academy, Moscow, Russia
10 Institute of Neurology, Catholic University, Rome, Italy
11 Department of Neurology, UCSF, San Francisco, California; National Institutes of Health/National Institute of Neurological Diseases and Stroke
12 Department of Human Genetics, University of Utah, Salt Lake City, Utah
13 Department of Neurology, University of California, Box 2922, 1550 4th Street, San Francisco, California 94143-2922; Howard Hughes Medical Institute
Louis J. Ptáek, E-mail: ptacek{at}itsa.ucsf.edu
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