Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

63-POS Board 63 Leak Current in a Mutant Sodium-potassium Pump Found in a Patient with Hypokalaemic Periodic Paralysis Marisol Sampedro Castañeda 1 , Edmar Zanoteli 2 , Renata Scalco 1 , Benjamin O’Callaghan 1 , Richa Sud 3 , Samuel McCall 3 , Michael G. Hanna 1 , Hanne Poulsen 4 , Emma Matthews 1 , Roope Männikkö 1 . 1 MRC Center for Neuromuscular Diseases, UCL and National Hospital for Neurology and Neurosurgery, London, United Kingdom, 2 Department of Neurology, Medical School of the University of São Paulo, São Paulo, Brazil, 3 Neurogenetics Unit, Institute of Neurology, London, United Kingdom, 4 DANDRITE, 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.

111