A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family

Abstract

Epileptic disorders affect about 20-40 million people worldwide, and 40% of these are idiopathic generalized epilepsies (IGEs; ref. 1). Most of the IGEs that are inherited are complex, multigenic diseases. To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-dominant mode of inheritance: the benign familial neonatal convulsions (BFNC; refs 2,3). Genetic heterogeneity of BFNC has been observed. Two loci, EBN1 and EBN2, have been mapped by linkage analysis to chromosome 20q13 (refs 5,6) and chromosome 8q24 (refs 7,8), respectively. By positional cloning, we recently identified the gene for EBN1 as KCNQ2 (ref. 9). This gene, a voltage-gated potassium channel, based on homology, is a member of the KQT-like family. Here we describe an additional member, KCNQ3. We mapped this new gene to chromosome 8, between markers D8S256 and D8S284 on a radiation hybrid map. We screened KCNQ3 for mutations in the large BFNC family previously linked to chromosome 8q24 in the same marker interval. We found a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype. The same conserved amino acid is also mutated in KVLQT1 (KCNQ1) in an LQT patient. KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs.

Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K+Channels That Underlie the Neuronal M Current

“…KCNQ2 and KCNQ3 are not expressed in the heart but rather in numerous brain regions and sympathetic ganglia (Biervert et al, 1998;Wang et al, 1998;Yang et al, 1998). Several mutations in either of these neuronal channel genes cause a form of neonatal epilepsy in humans (Biervert et al, 1998;Charlier et al, 1998;Singh et al, 1998). If neuronal M current indeed does result from KCNQ2 and KCNQ3 channel expression, then the dysfunction seen in individuals with non-or weakly functional mutant forms of these channels demonstrates that the M current plays an important stabilizing role in the nervous system.…”

Benign familial infantile convulsions: a clinical study of seven Dutch families

“…[19][20][21] Other epilepsy syndromes have been shown to be caused by mutations in genes encoding ion channels as well. [22][23][24][25][26][27][28][29] Our families showed autosomal dominant inheritance with high penetrance.…”

Generalized Epileptic Disorders: An Update

“…This has allowed the genetic basis of this idiopathic generalized epilepsy syndrome to be identified with a positional cloning strategy. BFNC occurs in two genetic forms: (a) EBN1, whose gene has been localized to chromosome 20q13.3; and (b) EBN2, a rarer form to date conclusively identified in only one pedigree, in which the gene is on chromosome 8q24 (25,26). The genes affected in EBN1 and EBN2 have recently been identified and shown to encode the two novel homologous voltage-gated K + channels KCNQ2 and KCNQ3.…”