Publications

From Leak to Disease

Published December 2021 in Journal of Biological Chemistry (doi 10.1016/j.jbc.2021.101355):

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

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 JD Karlish, Magnus Andersson*, Anna Lindstrand, Hjalmar Brismar*, Anita Aperia*

*Current and former members of the SciLifeLab biophysics community

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.

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