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Episodic ataxia type-1 mutations in the Kv1.1 potassium channel display distinct folding and intracellular trafficking properties.

L N Manganas, S Akhtar, D E Antonucci, C R Campomanes, J O Dolly, J S Trimmer

J. Biol. Chem., 2001 Dec 28 , 276, 49427-34

Episodic ataxia type 1 (EA-1) is a neurological disorder arising from mutations in the Kv1.1 potassium channel alpha-subunit. EA-1 patients exhibit substantial phenotypic variability resulting from at least 14 distinct EA-1 point mutations. We found that EA-1 missense mutations generate mutant Kv1.1 subunits with folding and intracellular trafficking properties indistinguishable from wild-type Kv1.1. However, the single identified EA-1 nonsense mutation exhibits intracellular aggregation and detergent insolubility. This phenotype can be transferred to co-assembled Kv1 alpha- and Kv beta-subunits associated with Kv1.1 in neurons. These results suggest that as in many neurodegenerative disorders, intracellular aggregation of misfolded Kv1.1-containing channels may contribute to the pathophysiology of EA-1.