A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy.

Abstract

The ion pump Na+,K+-ATPase is a critical determinant of neuronal excitability; however, its role in the etiology of diseases of the central nervous system (CNS) is largely unknown. We describe here the molecular phenotype of a Trp931Arg mutation of the Na+,K+-ATPase catalytic α1 subunit in an infant diagnosed with therapy-resistant lethal epilepsy. In addition to the pathological CNS phenotype, we also detected renal wasting of Mg2+. We found that membrane expression of the mutant α1 protein was low, and ion pumping activity was lost. Arginine insertion into membrane proteins can generate water-filled pores in the plasma membrane, and our molecular dynamic (MD) simulations of the principle states of Na+,K+-ATPase transport demonstrated massive water inflow into mutant α1 and destabilization of the ion-binding sites. MD simulations also indicated that a water pathway was created between the mutant arginine residue and the cytoplasm, and analysis of oocytes expressing mutant α1 detected a nonspecific cation current. Finally, neurons expressing mutant α1 were observed to be depolarized compared with neurons expressing wild-type protein, compatible with a lowered threshold for epileptic seizures. The results imply that Na+,K+-ATPase should be considered a neuronal locus minoris resistentia in diseases associated with epilepsy and with loss of plasma membrane integrity.

• Authors: Sofia Ygberg, Evgeny E Akkuratov, Rebecca J Howard, Fulya Taylan, Daniel C Jans, Dhani R Mahato, Adriana Katz, Paula F Kinoshita, Benjamin Portal, Inger Nennesmo, Maria Lindskog, Steven J D Karlish, Magnus Andersson, Anna Lindstrand, Hjalmar Brismar, Anita Aperia
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 297 Issue 6 Pg. 101355 (12 2021) ISSN: 1083-351X [Electronic] United States
• PMID: 34717959 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anticonvulsants
• Protein Subunits
• Sodium-Potassium-Exchanging ATPase

Topics

• Animals
• Anticonvulsants (pharmacology)
• Brain (drug effects, metabolism, pathology)
• Cells, Cultured
• Drug Resistance
• Epilepsy (drug therapy, genetics, pathology)
• Humans
• Infant
• Molecular Dynamics Simulation
• Mutation, Missense (drug effects)
• Protein Subunits (analysis, genetics)
• Sodium-Potassium-Exchanging ATPase (analysis, genetics)
• Xenopus