Autosomal dominant myotonia congenita (Thomsen’s disease) is caused by mutations in the muscle chloride channel CIC-1. Several point mutations found in affected families (1290M, R317Q P48OL, and Q552R) dramatically shift gating to positive voltages in mutant/WT heterooligomeric channels, and, when measurable, even more so in mutant homooligomers. These channels can no longer contribute to the repolarization of action potentials, fully explaining why they cause dominant myotonia. Most replacements of the isoleutine at position 290 shift gatlng toward positive voltages. MutantMlT heteroollgomers can be partially activated by repetitive depolarizations, suggesting a role in shortening myotonic runs. Remarkably, a human mutation affecting an adjacent residue (E291K) is fully recessive. Large shifts in the voltage dependence of gatlng may be common to many mutations in dominant myotonia congenita.