Alternating Hemiplegia of Childhood mutations have a differential effect on Na(+),K(+)-ATPase activity and ouabain binding

Fulltext:
128411.pdf
Embargo:
until further notice
Size:
808.3Kb
Format:
PDF
Description:
publisher's version
Publication year
2014Source
Biochimica et Biophysica Acta. Molecular Basis of Disease, 1842, 7, (2014), pp. 1010-1016ISSN
Publication type
Article / Letter to editor

Display more detailsDisplay less details
Organization
Paediatrics - OUD tm 2017
Pharmacology-Toxicology
Human Genetics
Biochemistry (UMC)
Journal title
Biochimica et Biophysica Acta. Molecular Basis of Disease
Volume
vol. 1842
Issue
iss. 7
Page start
p. 1010
Page end
p. 1016
Subject
Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 12: Sensory disorders RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life SciencesAbstract
De novo mutations in ATP1A3, the gene encoding the alpha3-subunit of Na(+),K(+)-ATPase, are associated with the neurodevelopmental disorder Alternating Hemiplegia of Childhood (AHC). The aim of this study was to determine the functional consequences of six ATP1A3 mutations (S137Y, D220N, I274N, D801N, E815K, and G947R) associated with AHC. Wild type and mutant Na(+),K(+)-ATPases were expressed in Sf9 insect cells using the baculovirus expression system. Ouabain binding, ATPase activity, and phosphorylation were absent in mutants I274N, E815K and G947R. Mutants S137Y and D801N were able to bind ouabain, although these mutants lacked ATPase activity, phosphorylation, and the K(+)/ouabain antagonism indicative of modifications in the cation binding site. Mutant D220N showed similar ouabain binding, ATPase activity, and phosphorylation to wild type Na(+),K(+)-ATPase. Functional impairment of Na(+),K(+)-ATPase in mutants S137Y, I274N, D801N, E815K, and G947R might explain why patients having these mutations suffer from AHC. Moreover, mutant D801N is able to bind ouabain, whereas mutant E815K shows a complete loss of function, possibly explaining the different phenotypes for these mutations.
This item appears in the following Collection(s)
- Academic publications [204859]
- Electronic publications [103195]
- Faculty of Medical Sciences [81031]
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.