Human Molecular Genetics Advance Access published online on April 7, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp170
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A C-TERMINAL MUTATION OF ATP1A3 UNDERSCORES THE CRUCIAL ROLE OF SODIUM AFFINITY IN THE PATHOPHYSIOLOGY OF RAPID-ONSET DYSTONIA-PARKINSONISM
1 Grupo de Medicina Xenómica, Universidad de Santiago de Compostela, Spain. 2 Centro para Investigación en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain. 3 Centre for Membrane Pumps in Cells and Disease – PUMPKIN, Danish National, Research Foundation, Department of Physiology and Biophysics, Aarhus University, DK-8000 Aarhus C, Denmark. 4 Department of Neurology, UCLA School of Medicine, U.S.A. 5 Fundación Pública Galega de Medicina Xenómica- SERGAS, Santiago de Compostela, Spain. 6 Servicio de Neurología, Complexo Hospitalario Universitario de Vigo, Spain.
* Corresponding Author: Dr María-Jesús Sobrido, MD PhD, Fundación Pública Galega de Medicina Xenómica, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain. Phone: 34-981951491, Fax: 34-981951473, email: mariajesus.sobrido{at}usc.es
Received February 22, 2009; Revised April 5, 2009; Accepted April 5, 2009
The Na+/K+-ATPases are ion pumps of fundamental importance in maintaining the electrochemical gradient essential for neuronal survival and function. Mutations in ATP1A3 encoding the 
3 isoform cause rapid-onset dystonia-parkinsonism (RDP). We report a de novo ATP1A3 mutation in a patient with typical RDP, consisting of an in-frame insertion of a tyrosine residue at the very carboxy-terminus of the Na+/K+-ATPase 3-subunit – the first reported RDP mutation in the carboxy-terminus of the protein. Expression studies revealed that there is no defect in the biogenesis or plasma membrane targeting, although cells expressing the mutant protein showed decreased survival in response to ouabain challenge. Functional analysis demonstrated a drastic reduction in Na+ affinity in the mutant, which can be understood by structural modelling of the E1 and E2 conformations of the wild-type and mutant enzymes on the basis of the strategic location of the carboxy-terminus in relation to the third Na+ binding site. The dramatic clinical presentation, together with the biochemical findings, provides both in vivo and in vitro evidence for a crucial role of the carboxy terminus of the -subunit in the function of the Na+/K+-ATPase and a key impact of Na+ affinity in the pathophysiology of RDP.