Mutations in the Na+/K+-ATPase α3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism

Patricia De Carvalho Aguiar, Kathleen J. Sweadner, John T. Penniston, Jacek Zaremba, Liu Liu, Marsha Caton, Gurutz Linazasoro, Michel Borg, Marina A.J. Tijssen, Susan B. Bressman, William B. Dobyns, Allison Brashear, Laurie J. Ozelius

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439 Scopus citations


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 α3 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.

Original languageEnglish (US)
Pages (from-to)169-175
Number of pages7
Issue number2
StatePublished - Jul 22 2004
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank all patients and family members who participated in this study. We thank Wendy Zencheck, Audrey Holtzinger, Laura Boucai, and Soni Joseph for technical help with screening chromosome 19 candidate genes; Joël Lunardi for analysis of the RYR gene; and Herb Lachman for control DNA samples. The monoclonal antibody α6F developed by Dr. Douglas M. Fambrough was obtained from the Developmental Studies Hybridoma Bank, developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, Iowa 52242. This work was supported by research grants from the Dystonia Medical Research Foundation (L.J.O. and S.B.B.), the National Institute of Neurological Disorders and Stroke (NS26636, L.J.O. and S.B.B.), National Institutes of Aging (AG10133, A.B.), National Heart, Lung, and Blood Institute (HL36251, K.J.S.), the National Institute of General Medical Sciences (GM28835, J.T.P.), and the CAPES foundation (P.C.A.).


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