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.

Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release

“…TR exerts a dominant negative effect in Xenopus oocytes (Zuberi et al, 1999;Rea et al, 2002). Three other amino acid substitutions have been reported at this residue in EA1 (Comu et al, 1996;Scheffer et al, 1998), at least one of which also confers a dominant negative effect (Chen et al, 2007). However, no evidence for intracellular aggregation of TR (or of T226A or T226M) was found in COS cell expression (Manganas et al, 2001).…”

Neonatal hypertonia – a diagnostic challenge

“…The EMG shows continuous motor unit activity and persists during sleep . Some success has been reported with treatment using phenytoin and carbamazepine …”

Functional Analysis of the Kv1.1 N255D Mutation Associated with Autosomal Dominant Hypomagnesemia

“…Electrophysiological analyses of the episodic ataxia type 1/myokymiarelated mutant Kv1.1 channels showed either a significant reduction in current amplitude or altered kinetic properties when compared with wild-type Kv1.1 channels (14,19,20). The mutation identified in the Brazilian family caused substitution of the asparagine at amino acid position 255 into an aspartic acid (N255D).…”

“…Mutations in Kv1.1 in humans are the cause of periodic episodic ataxia type 1 and/or myokymia (13)(14)(15)(16)(17)(18). Electrophysiological analyses of these mutant Kv1.1 channels showed either a significant reduction in current amplitude or altered kinetic properties when compared with wild-type Kv1.1 channels (14,19,20).…”