title: The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway.
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.affiliation: Department of Neurology, UCSF, San Francisco, CA, USA.
authors.forename: Hsien-Yang
authors.initials: HY
authors.lastname: Lee
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Ahn
authors.forename: Georg W J
authors.initials: GW
authors.lastname: Auburger
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: Hubert
authors.initials: H
authors.lastname: Kwiecinski
authors.forename: David A
authors.initials: DA
authors.lastname: Grimes
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.forename: Jorgen E
authors.initials: JE
authors.lastname: Nielsen
authors.forename: Yuri
authors.initials: Y
authors.lastname: Averyanov
authors.forename: Serenella
authors.initials: S
authors.lastname: Servidei
authors.forename: Andrzej
authors.initials: A
authors.lastname: Friedman
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Bogaert
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Abramowicz
authors.forename: Michiko K
authors.initials: MK
authors.lastname: Bruno
authors.forename: Beatrice F
authors.initials: BF
authors.lastname: Sorensen
authors.forename: Ling
authors.initials: L
authors.lastname: Tang
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Fu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptácek
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D002819:Chorea / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013312:Stress, Physiological / Q000201:enzymology* / Q000235:genetics
chemical_list: D009124:Muscle Proteins; C495444:PNKD protein, human; D020033:Protein Isoforms