Characterization of the Kv1.1 I262T and S342I mutations associated with episodic ataxia 1 with distinct phenotypes

Episodic ataxia type 1 (EA-1) is an autosomal dominant neurological disorder caused by mutations in the potassium channel Kv1.1. Two EA-1 mutations, I262T and S342I, have been identified with unique clinical phenotypes, but their functional and biochemical properties have not been fully investigated. Here we characterized these two mutations in transfected mammalian cells both electrophysiologically and biochemically. We found that the I262T mutation resulted in a ∼7-fold reduction in the K+ current amplitude compared with wild type channels, whereas the S342I mutation produced an apparent nonfunctional channel when expressed alone. Co-expression of wild type and mutant channels showed that both I262T and S342I exerted dominant-negative effects on wild type function. The protein expression analysis showed that I262T resulted in ∼2-fold decrease in surface protein levels of Kv1.1, which partially contributed to the decreased surface conductance density, whereas the S342I mutation showed no effects on surface protein expression. Conservative amino acid substitution experiments suggest that the wild type amino acids at these two positions are required for normal channel function. Our results broaden the knowledge of EA-1 mutations and the underlying mechanisms of the associated disorder.

► The EA-1 I262T mutant displayed dysfunctional gating and low cell surface protein levels.
► The EA-1 S342I mutant was nonfunctional but its cell surface protein level was similar to wild type.
► Both EA-1 mutants showed a dominant-negative effect when co-expressed with wild type.
► Conservative amino acid substitutions at either site did not fully rescue gating function.