KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum

Abstract

Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant generalized epilepsy of the newborn infant. Seizures occur repeatedly in the first days of life and remit by approximately 4 months of age. Previously our laboratory cloned two novel potassium channel genes, KCNQ2 and KCNQ3, and showed that they are mutated in patients with BFNC. In this report, we characterize the breakpoints of a previously reported interstitial deletion in the KCNQ2 gene and show that only KCNQ2 is deleted. We identify 11 novel mutations in KCNQ2 and one novel mutation in the KCNQ3 potassium channel genes. In one family, the phenotype extends beyond neonatal seizures and includes rolandic seizures, and a subset of families has onset of seizures in infancy. In the Xenopus oocyte expression system, we characterize five KCNQ2 and one KCNQ3 disease-causing mutations. These mutations cause a variable loss of function, and selective effects on the biophysical properties of KCNQ2/KCNQ3 heteromultimeric channels. We report here the first dominant negative mutation in KCNQ2 that has a phenotype of neonatal seizures without permanent clinical CNS impairment.

Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants

“…Therefore, we compared the consequences of the charge neutralization R333Q mutant. No significant changes on voltage dependence were observed for the heteromeric channels carrying Kv7.2 K526N (Figure 2(c)) or R333Q subunits (data no shown), whereas R333Q caused a large reduction in current (~80%), in accordance with previous reports [20]; (Figure 2(a,b)).…”

“…Two other members also presented epileptic encephalopathy and mental retardation. The electrophysiological properties of both mutants have been previously analyzed [20,27], but the impact on CaM binding and the effect on channel trafficking and function remains unexplored. We have examined the consequences on CaM binding, exploring the effect on channel trafficking and function.…”

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

“…Of the C-terminal truncation mutations of KCNQ2, the Q323X missense mutation deletes the entire KCNQ2 C-terminal domain (33), whereas the Y534X mutation caused by a 5-bp insertion at wild-type (n ϭ 19; *** , P Ͻ 0.001) or a KCNQ2 C-tail with the E810A͞D812A mutation (n ϭ 10; *** , P Ͻ 0.001), but not KCNQ3 C-tail (n ϭ 30; P Ͼ 0.05) or a KCNQ3 C-tail with E837A͞D839A mutation (n ϭ 12; P Ͼ 0.05). The AIS͞distal axon ratio revealing AIS enrichment of CD4 fused to KCNQ2 C-tail ( * , P Ͻ 0.05) or KCNQ3 C-tail ( *** , P Ͻ 0.001) but not either C-tail with mutated ankyrin-G binding motif (P Ͼ 0.05).…”

Novel Animal Models of Pediatric Epilepsy

“…KCNQ2/3 Channels and Effects of Retigabine KCNQ2/3 (also known as KV7.2/7.3) are potassium channels that mediate M-type K + currents and play important roles in the regulation of neuronal excitability [125,126]. Mutations in the genes encoding KNCQ2/3 have been associated with the benign familial neonatal seizures, which rescind during the first month of life [127]. Qiu et al [128] established that K + M-current plays critical role in regulating the transition from interictal to ictal bursts in the 0 Mg 2+ seizure model in vitro and that this mechanism is particularly important in immature neurons.…”