Benign Familial Neonatal Convulsions Caused by Altered Gating of KCNQ2/KCNQ3 Potassium Channels

Abstract

The muscarinic-regulated potassium current (M-current), formed by the heteromeric assembly of subunits encoded by the KCNQ2 and KCNQ3 genes, is a primary regulator of neuronal excitability; this regulation is accomplished by impeding repetitive firing and causing spike-frequency adaptation. Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal convulsions (BFNC), a rare autosomal-dominant generalized epilepsy of newborns, by reducing the maximal current carried by the M-channels without affecting ion selectivity or gating properties. Here we show that KCNQ2/KCNQ3 channels carrying a novel BFNC-causing mutation leading to an arginine to tryptophan substitution in the voltage-sensing S4 domain of KCNQ2 subunits (R214W) displayed slower opening and faster closing kinetics and a decreased voltage sensitivity with no concomitant changes in maximal current or plasma membrane expression. These results suggest that mutation-induced gating alterations of the M-current may cause epilepsy in neonates.

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

“…This variant did not alter channel expression and had the mildest effect of the four variants studied. Consistent with previous findings on KCNQ2 mutations, 22 reduced function of Kv7.5 channels resulting from these variants is predicted to cause a lowered seizure threshold as a result of decreased neuronal repolarization reserve mediated by the M-current.…”

“…Mutations in other KCNQ homologs, KCNQ2 and less commonly KCNQ3, can also result in epilepsy either by loss-of-function or by gainof-function effects. 7,[22][23][24] In neurons, Kv7.5 is important for regulation of the M-type current, and hence firing rates. The M-current is a slowly activating and deactivating neuronal potassium current that plays a crucial role in regulating neuronal excitability by impeding repetitive (E) Relative functional channel expression.…”

“…These effects are characteristic of a loss-of-function effect. [22][23][24] The severity of the loss-offunction phenotype in these mutant channels is possibly lessened by the slowed deactivation kinetics caused by the mutations, which would be predicted to increase repolarizing currents and reduce action-potential firing; however, the reduced channel expression would be expected to dominate. Channels with p.Ser448Ile also slowed the kinetics of early activation and are therefore likely to produce a loss of function.…”

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).…”

“…K + currents carried by homomeric K V 7.2 channels displayed double-exponential activation kinetics (1,14), with a voltagedependent fast time constant (τ f ) and a slow time constant (τ s ) showing little voltage sensitivity between −20 and +60 mV (15). τ f relative amplitude accounted for approximately 90% of the total activation process.…”