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-1L 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. © Oxford University Press 2004; all rights reserved.
Original language | English |
---|---|
Pages (from-to) | 3161-3170 |
Number of pages | 10 |
Journal | Human Molecular Genetics |
Volume | 13 |
DOIs | |
Publication status | Published - 2004 |
Keywords
- Animals
- Central Nervous System
- Chorea
- Chromosome Mapping
- Female
- Genetics
- Genetics (clinical)
- Humans
- In Situ Hybridization
- Male
- Mice
- Molecular Biology
- Muscle Proteins
- Mutation
- Pedigree
- Protein Isoforms
- Sequence Analysis, DNA
- Stress, Physiological