The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway.
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.
Lee
Hsien-Yang
HY
Department of Neurology, UCSF, San Francisco, CA, USA.
Xu
Ying
Y
Huang
Yong
Y
Ahn
Andrew H
AH
Auburger
Georg W J
GW
Pandolfo
Massimo
M
Kwiecinski
Hubert
H
Grimes
David A
DA
Lang
Anthony E
AE
Nielsen
Jorgen E
JE
Averyanov
Yuri
Y
Servidei
Serenella
S
Friedman
Andrzej
A
Van Bogaert
Patrick
P
Abramowicz
Marc J
MJ
Bruno
Michiko K
MK
Sorensen
Beatrice F
BF
Tang
Ling
L
Fu
Ying-Hui
YH
Ptácek
Louis J
LJ
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
D009124:Muscle Proteins; C495444:PNKD protein, human; D020033:Protein Isoforms