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 Mg 2+ . 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.
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BibTeX
@article{ygberg2026missense,
title = {{A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy}},
author = {Sofia Ygberg and Evgeny Akkuratov and Rebecca Howard and Fulya Taylan and Daniel Jans and Dhani Mahato and Adriana Katz and Paula Kinoshita and Benjamin Portal and Inger Nennesmo and Maria Lindskog and Steven J.D. Karlish and Magnus Andersson and Anna Lindstrand and Hjalmar Brismar and Anita Aperia},
journal = {Journal of Biological Chemistry},
year = {2026},
month = oct,
doi = {10.1016/j.jbc.2021.101355},
url = {https://hal.science/hal-05788274v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy
AU - Sofia Ygberg
AU - Evgeny Akkuratov
AU - Rebecca Howard
AU - Fulya Taylan
AU - Daniel Jans
AU - Dhani Mahato
AU - Adriana Katz
AU - Paula Kinoshita
AU - Benjamin Portal
AU - Inger Nennesmo
AU - Maria Lindskog
AU - Steven J.D. Karlish
AU - Magnus Andersson
AU - Anna Lindstrand
AU - Hjalmar Brismar
AU - Anita Aperia
PY - 2026
DA - 2026/10/09
JO - Journal of Biological Chemistry
DO - 10.1016/j.jbc.2021.101355
UR - https://hal.science/hal-05788274v1
AB - 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 Mg 2+ . 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.
SN - 0021-9258
SN - 1083-351X
ER -