Emerging Concepts in Ion Channel Biophysics

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Emerging Concepts in Ion Channel Biophysics Poster Abstracts
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63-POS Board 63
Leak Current in a Mutant Sodium-potassium Pump Found in a Patient with Hypokalaemic
Periodic Paralysis
Marisol Sampedro Castañeda1, Edmar Zanoteli2, Renata Scalco1, Benjamin O’Callaghan1 ,
Richa Sud3, Samuel McCall3, Michael G. Hanna1, Hanne Poulsen 4, Emma Matthews1 , Roope
Männikkö1.
1MRC Center for Neuromuscular Diseases, UCL and National Hospital for Neurology and
Neurosurgery, London, United Kingdom, 2Department of Neurology, Medical School of the
University of São Paulo, São Paulo, Brazil, 3Neurogenetics Unit, Institute of Neurology, London,
United Kingdom, 4DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus
University, Aarhus, Denmark.
Hypokalaemic periodic paralysis (HypoPP) is a rare neuromuscular disease characterized by
disabling episodes of flaccid skeletal muscle paralysis, lasting hours to days, with accompanying
low serum K+ levels. The disease can progress to a permanent proximal myopathy. The general
consensus is that arginine-neutralizing mutations in the voltage sensor of NaV1.4 or CaV1.1
sarcolemmal ion channels lead to gating pore leak currents through their voltage sensing
domains. These currents depolarize the muscle and reduce excitability. We identified a young
boy who presented with recurrent episodes of quadriparesis and low serum K+ consistent with a
diagnosis of HypoPP who did not carry mutations in known HypoPP genes but instead a novel
mutation in the ATP1A2 gene, encoding the alpha 2 subunit of the Na +/K + ATPase. Creatine
kinase was elevated and a muscle biopsy myopathic, confirming a muscle pathology. The patient
also showed CNS symptoms (seizures and mild learning difficulties), consistent with alpha 2
expression in astrocytes. The missense mutation affects a serine residue (S779) in the K + binding
site of the pump, with predicted deleterious functional consequences. Electrophysiological
characterization of pump activity was perfomed using two electrode voltage clamp in Xenopus
laevis oocytes. The effects of the mutation were two-fold. 1. The mutant ATPase carries an
abnormal ouabain-sensitive leak current analogous to the omega currents known to cause
HypoPP. 2. The mutant ATPase presents reduced K+ affinity, resulting in a lower turnover rate at
physiological K+ concentrations. The leak current is carried by protons and potentially Na + ions.
This is the first report of a leak current through a membrane protein other than voltage-gated ion
channels as a patho-mechanism of HypoPP, and may warrant re-evaluation of the HypoPP
classification and genetic diagnosis practices.