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.
|
Authors | Hsien-Yang Lee, Ying Xu, Yong Huang, Andrew H Ahn, Georg W J Auburger, Massimo Pandolfo, Hubert Kwiecinski, David A Grimes, Anthony E Lang, Jorgen E Nielsen, Yuri Averyanov, Serenella Servidei, Andrzej Friedman, Patrick Van Bogaert, Marc J Abramowicz, Michiko K Bruno, Beatrice F Sorensen, Ling Tang, Ying-Hui Fu, Louis J Ptácek |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 13
Issue 24
Pg. 3161-70
(Dec 15 2004)
ISSN: 0964-6906 [Print] England |
PMID | 15496428
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
|
Chemical References |
- Muscle Proteins
- PNKD protein, human
- Protein Isoforms
|
Topics |
- Animals
- Central Nervous System
(metabolism)
- Chorea
(genetics, metabolism)
- Chromosome Mapping
- Female
- Humans
- In Situ Hybridization
- Male
- Mice
- Muscle Proteins
(genetics, metabolism)
- Mutation
- Pedigree
- Protein Isoforms
(genetics, metabolism)
- Sequence Analysis, DNA
- Stress, Physiological
(enzymology, genetics)
|