Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia

Abstract

Myokymia is characterized by spontaneous, involuntary muscle fiber group contraction visible as vermiform movement of the overlying skin. Myokymia with episodic ataxia is a rare, autosomal dominant trait caused by mutations in KCNA1, encoding a voltage-gated potassium channel. In the present study, we report a family with four members affected with myokymia. Additional clinical features included motor delay initially diagnosed as cerebral palsy, worsening with febrile illness, persistent extensor plantar reflex, and absence of epilepsy or episodic ataxia. Mutation analysis revealed a novel c.676C>A substitution in the potassium channel gene KCNA1, resulting in a T226K nonconservative missense mutation in the Kv1.1 subunit in all affected individuals. Electrophysiological studies of the mutant channel expressed in Xenopus oocytes indicated a loss of function. Co-expression of WT and mutant cRNAs significantly reduced whole-oocyte current compared to expression of WT Kv1.1 alone.

Fig. 1

Family pedigree. Squares indicate males, circles indicate females. Blackened symbols denote individuals with myokymia. Alleles at codon 226 are indicated (Thr = wild-type, Lys = mutation)

Fig. 2

Sequence chromatograms demonstrating c.676C>A resulting in T226K substitution in KCNA1. A DNA sequence from an affected patient (I-2) heterozygous for the mutation (top) and from a normal control (bottom) are presented

Fig. 3

Missense mutation T226K induces loss of function of human Kv1.1 channels expressed in Xenopus oocytes. a–c Representative family of whole-oocyte currents recorded from oocytes expressing human Kv1.1-WT (a), Kv1.1-T226K (b), and both Kv1.1 WT and T226K (c). Currents were evoked by a series of 350-ms test pulses from −80 to +60 mV in 10-mV increments from a hold potential of −90 mV. Tail currents were recoded at −40 mV. Scale bar, 100 ms and 1 μA. d I–V curves for three experimental conditions in a–c. Data were collected for 10–15 oocytes in each group. The peak currents in a and c are significantly different at test voltages between 0 and +60 mV (P < 0.05)