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. © 1995.
Fahlke, C., Riidel, R., Mitrovic, N., Zhou, M., & George, A. L. (1995). An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels. Neuron, 15(2), 463–472. https://doi.org/10.1016/0896-6273(95)90050-0