The A4078G mutation in the sodium channel alpha-subunit resulted in a two times slower decay of sodium currents and a -13 mV shift in steady-state inactivation compared to wild type channels.
Does the Met1360Val mutation alter the functional properties of the human muscle sodium channel alpha-subunit?
The Met1360Val mutation in the human muscle sodium channel alpha-subunit alters channel inactivation and causes a hyperkalemic paralytic and paramyotonic syndrome with incomplete penetrance.
A point mutation A4078G predicting the amino acid exchange Met1360Val in segment IV/S1 of the human muscle sodium channel alpha-subunit was identified in a family presenting features of hyperkalemic periodic paralysis and paramyotonia congenita with sex-related modification of expression. In this family, only one male member is clinically affected, presenting episodes of flaccid weakness as well as paradoxical myotonia and cold-induced weakness. Three female family members who have the same mutation show only myotonic bursts on EMG. We studied the functional defect caused by this mutation by investigating recombinant wild type (WT) and mutant sodium channels expressed in a mammalian cell line (HEK293) using the patch-clamp technique. With mutant channels, the decay of the sodium currents was two times slower than with WT, the steady-state inactivation curve was shifted by -13 mV, and recovery from inactivation was 1.5 times faster. High extracellular potassium (9 mM) did not affect channel gating. Single-channel measurements revealed prolonged mean open times and an increased number of channel reopenings. The results are remarkable with respect to the lack of complete penetrance usually seen with sodium channelopathies and the site of mutation that was formerly not thought to be involved in channel inactivation.
Wagner et al. (Wed,) conducted a other in Hyperkalemic periodic paralysis and paramyotonia congenita (n=4). A4078G mutation (Met1360Val) vs. Wild type (WT) sodium channels was evaluated on Functional defect of mutant sodium channels (decay of sodium currents, steady-state inactivation curve, recovery from inactivation). The A4078G mutation in the sodium channel alpha-subunit resulted in a two times slower decay of sodium currents and a -13 mV shift in steady-state inactivation compared to wild type channels.