Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K ⁺ channel

Abstract

KCNQ2 and KCNQ3 are two homologous K ؉ channel subunits that can combine to form heterotetrameric channels with properties of neuronal M channels. Loss-of-function mutations in either subunit can lead to benign familial neonatal convulsions (BFNC), a generalized, idiopathic epilepsy of the newborn. We now describe a syndrome in which BFNC is followed later in life by myokymia, involuntary contractions of skeletal muscles. All affected members of the myokymia͞BFNC family carried a mutation (R207W) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia is thought to result from hyperexcitability of the lower motoneuron, and indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC.

Genotype–phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K v 7.2 potassium channel subunits

“…The R6 mutations described here seem to be within this latter group. However, the R6W mutation caused gating changes qualitatively and quantitatively similar to those of previously described BFNS mutations (14,15,31,32). By contrast, the 16-mV positive shift in V 1/2 observed upon incorporation of a single K V 7.2 R6Q subunit in heteromeric configuration with K V 7.2 and K V 7.3 subunits to recapitulate the genotype of the individual affected with K V 7.2 encephalopathy (8), is the most dramatic among the functional changes described in K V 7.2 channelopathies (33).…”

Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains

“…Consistent with reports of the ability of KCNQ channels to modulate motor axon excitability (9,22) and transmitter release (23), KCNQ2 and KCNQ3 proteins have been detected in axons (5,6,24,25), the axonal initial segment (AIS) and nodes of Ranvier (26,27). It remains possible, however, that the neuronal soma and dendrites express functional KCNQ channels, given the transmitter modulation of KCNQ channels (2) and strong somatodendritic KCNQ2 and KCNQ3 immunoreactivity (3,5,6).…”

“…The overlapping expression patterns of KCNQ2 and KCNQ3 include brain areas implicated in seizure development, such as hippocampus, neocortex, and thalamus (3,5,6). The critical involvement of KCNQ channels in controlling neuronal excitability is underscored further by the fact that benign familial neonatal convulsions (BFNC) mutations in KCNQ2 and KCNQ3 cause epilepsy (7,8) and myokymia (9). Consistently, retigabine, a potent KCNQ channel opener (10) can suppress seizures in a number of animal models (11)(12)(13) and attenuate neuropathic pain (14,15), whereas linopirdine and XE991, developed as ''cognitive enhancer'' drugs for treatment of Alzheimer disease and other memory disorders, are potent blockers of KCNQ channels (10).…”

Atypical Gating Of M-Type Potassium Channels Conferred by Mutations in Uncharged Residues in the S4Region of KCNQ2 Causing Benign Familial Neonatal Convulsions

“…Changes in voltage-dependent gating have been described previously in heterologously expressed channels carrying BFNCcausing mutations affecting charged residues in the S 4 segment of KCNQ2, namely the R207W (Dedek et al, 2001) and the R214W (Castaldo et al, 2002) substitutions. In contrast, the only other known BFNC mutation in KCNQ2 affecting an uncharged residue in S 4 , the M208V substitution, has been shown not to affect the midpoint potential for current activation but rather to slightly increase the slope of the conductance to voltage curve and to lower the amount of expressed current (Singh et al, 2003), suggesting that the M208V mutation reduced I KM function by mechanisms additional to gating alterations.…”

“…Mutation-induced I KM impairment may occur by several mechanisms: some mutations preferentially alter the intracellular stability and trafficking of subunits (Soldovieri et al, 2006), whereas others interfere with their polarized neuronal targeting (Chung et al, 2006) or with their function once normally inserted into the plasma membrane (Dedek et al, 2001;Castaldo et al, 2002). Both the A196V and the A196V/L197P mutations appear to belong to the latter group, although the present results, obtained in non-neuronal context, cannot rule out a possible effect of the mutation on channel trafficking or localization.…”