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.
Highlights
Epileptic encephalopathies are severe brain disorders that generally arise in infancy and cause developmental delay and sometimes early death
Clinical history The affected infant was the first child of healthy, non-consanguineous parents (Fig. 1A)
We describe here the case of an infant with severe therapy-resistant epilepsy and progressive encephalopathy who was diagnosed with a W931R mutation in the Na,K-ATPase catalytic α1 subunit
Summary
Epileptic encephalopathies are severe brain disorders that generally arise in infancy and cause developmental delay and sometimes early death. The etiology of epileptic encephalopathies is multifactorial, ranging from acquired structural deficits, such as stroke to congenital or genetic causes that may result in altered membrane potential, failure to propagate neuronal signals correctly, death of single neurons and/or loss of neuronal networks [1, 2]. The majority of mutated genes are directly involved in regulation of neuronal activity. Such genes include SCN1A and SCN8A, which encode voltage-gated sodium channels that initiate the action potential, and KCNQ2 and KCNT1, which encode voltage-gated potassium channels and contribute to restoration of the resting membrane potential after neuronal activity [3,4,5]. By transporting three Na+ ions out of the neuron and two K+ ions into the neuron at the expense of one ATP molecule, Na,K-ATPase build and maintain the Na+ and K+ electrochemical gradients that are central for the membrane potential
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