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

Ygberg, Sofia ; Akkuratov, Evgeny E. ; Howard, Rebecca J. ; Taylan, Fulya ; Jans, Daniel C. ; Mahato, Dhani R. ; Katz, Adriana ; Kinoshita, Paula F. ; Portal, Benjamin ; Nennesmo, Inger ; Lindskog, Maria ; Karlish, Steven J.D. ; Andersson, Magnus ; Lindstrand, Anna ; Brismar, Hjalmar ; Aperia, Anita

The Journal of biological chemistry, 2021-12, Vol.297 (6), p.101355-101355, Article 101355 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy
Autor: Ygberg, Sofia ; Akkuratov, Evgeny E. ; Howard, Rebecca J. ; Taylan, Fulya ; Jans, Daniel C. ; Mahato, Dhani R. ; Katz, Adriana ; Kinoshita, Paula F. ; Portal, Benjamin ; Nennesmo, Inger ; Lindskog, Maria ; Karlish, Steven J.D. ; Andersson, Magnus ; Lindstrand, Anna ; Brismar, Hjalmar ; Aperia, Anita
Assuntos: Animals ; Anticonvulsants - pharmacology ; arginine mutation ; Brain - drug effects ; Brain - metabolism ; Brain - pathology ; Cells, Cultured ; de novo mutation ; Drug Resistance ; epilepsy ; Epilepsy - drug therapy ; Epilepsy - genetics ; Epilepsy - pathology ; Humans ; Infant ; K-ATPase ; leak channel ; Medicin och hälsovetenskap ; Molecular Dynamics Simulation ; Mutation, Missense - drug effects ; Na,K-ATPase ; Protein Subunits - analysis ; Protein Subunits - genetics ; Sodium-Potassium-Exchanging ATPase - analysis ; Sodium-Potassium-Exchanging ATPase - genetics ; Xenopus
É parte de: The Journal of biological chemistry, 2021-12, Vol.297 (6), p.101355-101355, Article 101355
Notas: ObjectType-Case Study-2
SourceType-Scholarly Journals-1
ObjectType-Feature-4
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ObjectType-Report-1
ObjectType-Article-3
These authors contributed equally to this work as senior authors.
These authors contributed equally to this work.
Descrição: 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

United States: Elsevier Inc

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