A point mutation (D136G) predicting the substitution of glycine for aspartate in position 136 of the human muscle CI- channel (hCIC-1) causes recessive generalized myotonia. Heterologous expression of a recombinant D136G produces functional Cl- channels with profound alterations in voltage-dependent gating, without concomitant changes in pore properties. The mutant exhibits slowly activating current upon hyperpolarization, in contrast to wild-type channels, which display time-dependent current decay (deactivation) at negative membrane potentials. Steady-state activation of D136G depends upon the transmembrane Cl- gradient, reaching zero at voltages positive to the Cl- reversal potential in physiological Cl- distribution. This explains the reduced sarcolemmal Cl- conductance that causes myotonia. The functional disturbances exhibited by D136G may stem from a defect in the CIC-1 voltage sensor.
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