Episodic ataxia 1 (EA1) is a rare autosomal dominant neurological disorder characterized
by brief attacks of cerebellar ataxia and continuous interictal myokymia. It results
from point mutations in the voltage-gated potassium channel gene KCNA1 on chromosome
12p. Here we investigated an EA1 mutation located in close vicinity of the pore region
of the channel.
We assessed whole-cell currents by two-electrode voltage clamp measurements in Xenopus
oocytes injected with mutant cRNA only, mutant and wild type (wt) cRNA at varying
ratios, and with cRNA coding for wt-mutant fusion proteins (concatemers). All oocytes
appeared to express functional delayed rectifier potassium channels.
The mutant subunit yielded a ˜10-fold reduced current amplitude as compared to wt.
When co-expressed with wt, mutant subunits however revealed current amplitudes indistinguishable
from wt. Moreover, the mutation affected the kinetics of activation and deactivation.
Oocytes expressing fusion proteins showed a ˜20 mV shift of the activation threshold
towards more positive potentials, and a significantly slowed time course of activation.
In contrast, the kinetics of deactivation were faster as compared to wt. The degree
of C-type inactivation did not differ from wt. Nevertheless, the wt-mutant concatemer
yielded a faster recovery from C-type inactivation.
Taken together, this study demonstrates that the altered channel function of the investigated
EA1 mutant leads to a reduction of the net delayed-rectifier potassium current in
Xenopus oocytes compared to the wt channel. In affected family members this reduction
of potassium ion outward flow may underlie the central and peripheral symptoms of
EA1.
Supported by Forschungsförderungsfonds Medizin.
