Mutations in the Na+/K+-ATPase α3 Gene ATP1A3 Are Associated with Rapid-Onset Dystonia Parkinsonism

Abstract

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.

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

“…In the central nervous system, mutations in Na,K-ATPase are known to cause neuronal dysfunction and neurodegeneration in Drosophila (8), familial hemiplegic migraine in humans (9), and rapidonset dystonia-Parkinsonism (10). In addition to maintaining the electrochemical gradient, the Na,K-ATPase has been shown to act as a receptor and signal transducer.…”

The genetics of the dystonias – a review based on the new classification of the dystonias

“…It has an autosomal dominant inheritance pattern and reduced penetrance. The gene responsible for the disease, DYT12/ATP1A3, has 23 exons and encodes the Na + /K + -ATPase α3 (ATP1A3), a catalytic subunit of the sodium pump 40,41 . Since the first mutations descripted by de Carvalho Aguiar et al 41 , several mutations across the gene have been associated with RPD.…”

“…The gene responsible for the disease, DYT12/ATP1A3, has 23 exons and encodes the Na + /K + -ATPase α3 (ATP1A3), a catalytic subunit of the sodium pump 40,41 . Since the first mutations descripted by de Carvalho Aguiar et al 41 , several mutations across the gene have been associated with RPD. However, the exact correlation between ATP1A3 and the pathological mechanism of RDP remains to be elucidated 40,41 .…”

“…Since the first mutations descripted by de Carvalho Aguiar et al 41 , several mutations across the gene have been associated with RPD. However, the exact correlation between ATP1A3 and the pathological mechanism of RDP remains to be elucidated 40,41 .…”

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…RDP is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the α3 subunit of the Na+/K+ ATPase gene [26,27]. It is inherited as an autosomal dominant trait with variable penetrance, and typically presents abruptly in the second or third decades with an abrupt onset of dystonic spasms, bradykinesia, postural instability, dysarthria, and dysphagia developing over hours to weeks followed by little progression [26,28].…”