Résumé :
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Communication n° 473 Hypokalemic periodic paralysis (hypoPP) is a dominantly inherited skeletal muscle disease characterized by attacks of flaccid weakness accompanied by hypokalemia. This disease has been associated with missense mutations in the CACNA1S (hypoPP1) and SCN4A (hypoPP2) genes encoding the ? subunit of the voltage-gated Ca2+ and Na+ channels, respectively. All hypoPP-mutations described so far target an arginine in the S4 segment of different domains of the Na+ (DII-S4) or the Ca2+ (DII-S4 and DIV-S4) channel. We have identified a novel hypoPP2 mutation, which substitutes glutamine for arginine at an original site on DIII-S4 of the Na+ channel ? subunit (R1132Q). Previous studies on the functional consequences of hypoPP2 mutations have disclosed defects in both fast and slow inactivation, and a reduction in the Na+ current that may account for membrane hypo-excitability. We have stably expressed R1132Q channels in HEK293 cells, and recorded macroscopic Na+ currents using the whole-cell voltage clamp technique. A thorough analysis of the biophysical properties of R1132Q mutant channels and their comparison with those of the wild type revealed a slight hyperpolarization shift of the voltage-dependence of both fast and slow inactivation, and a loss of the voltage-dependence of channel deactivation from the inactivated state. We also demonstrated that the reduction of Na+ current reported in hypoPP2 was not caused by a decrease in channel unitary conductance. Indeed, single channel recordings of both R1132Q and another hypoPP mutant (R672S in DII-S4) yielded a unitary conductance that was comparable with that measured from the wild type (~17 pS). Overall, patch-clamp studies on hypoPP2-associated mutants have provided valuable data on channel dysfunction; but the links between the latter and the clinical phenotype remain to be clarified.
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