Genetic modifiers of the Kvβ2-null phenotype in mice

Shaker-type potassium (K+) channels are composed of pore-forming alpha subunits associated with cytoplasmic beta subunits. Kv beta 2 is the predominant Kv beta subunit in the mammalian nervous system, but its functions in vivo are not clear. Kv beta 2-null mice have been previously characterized in our laboratory as having reduced lifespans, cold swim-induced tremors and occasional seizures, but no apparent defect in Kv alpha-subunit trafficking. To test whether strain differences might influence the severity of this phenotype, we analyzed Kv beta 2-null mice in different strain backgrounds: 129/SvEv (129), C57BL/ 6J (136) and two mixed B6/129 backgrounds. We found that strain differences significantly affected survival, body weight and thermoregulation in Kv beta 2-null mice. B6 nulls had a more severe phenotype than 129 nulls in these measures; this dramatic difference did not reflect alterations in seizure thresholds but may relate to strain differences we observed in cerebellar Kv1.2 expression. To specifically test whether Kv beta 1 is a genetic modifier of the Kv beta 2-null phenotype, we generated Kv beta 1.1-deficient mice by gene targeting and bred them to Kv beta 2-null mice. Kv beta 1.1/Kv beta 2 double knockouts had significantly increased mortality compared with either single knockout but still maintained surface expression of Kv1.2, indicating that trafficking of this alpha subunit does not require either Kv beta subunit. Our results suggest that genetic differences between 129/SvEv and C57BI/6J are key determinants of the severity of defects seen in Kv beta 2-null mice and that Kv beta 1.1 is a specific although not strain-dependent modifier.