Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel.

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 (I29OM, R317Q, P480L, 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 isoleucine at position 290 shift gating toward positive voltages. Mutant/WT heterooligomers 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 gating may be common to many mutations in dominant myotonia congenita.