Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.
Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.
de Carvalho Aguiar
Patricia
P
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Sweadner
Kathleen J
KJ
Penniston
John T
JT
Zaremba
Jacek
J
Liu
Liu
L
Caton
Marsha
M
Linazasoro
Gurutz
G
Borg
Michel
M
Tijssen
Marina A J
MA
Bressman
Susan B
SB
Dobyns
William B
WB
Brashear
Allison
A
Ozelius
Laurie J
LJ
D000595:Amino Acid Sequence; D002460:Cell Line; D004421:Dystonia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation; D020125:Mutation, Missense; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase