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

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.

Charlier C ，Singh NA ，Ryan SG ，Lewis TB ，Reus BE ，Leach RJ ，Leppert M ... -  《NATURE GENETICS》

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Singh NA ，Charlier C ，Stauffer D ，DuPont BR ，Leach RJ ，Melis R ，Ronen GM ，Bjerre I ，Quattlebaum T ，Murphy JV ，McHarg ML ，Gagnon D ，Rosales TO ，Peiffer A ，Anderson VE ，Leppert M ... -  《NATURE GENETICS》

Complete loss of the cytoplasmic carboxyl terminus of the KCNQ2 potassium channel: a novel mutation in a large Czech pedigree with benign neonatal convulsions or other epileptic phenotypes.

Benign neonatal familial convulsions (BNFCs) represent a rare epileptic disorder with autosomal dominant mode of inheritance. To date, two voltage-gated potassium (K+) channel genes, KCNQ2 and KCNQ3, have been identified in typical BNFC families. The study of new pedigrees may help detect new mutations and define genotype-phenotype correlations. A large Czech family was detected in which BNFC was inherited together with a broad range of various nonneonatal epileptic phenotypes. Genetic linkage study and direct mutation analysis were performed to find the disease-causing mutation. In seven patients with BNFCs and no recurrence of seizures, a novel two-base-pair deletion (1369del2) was identified within the coding sequence of the KCNQ2 gene. The mutation led to a putative protein that lacked nearly all its carboxyl terminus part, which plays a critical role for the accurate expression of the functional K+ channels. Three patients with generalized tonic-clonic seizures (GTCSs), all without any history of BNFCs, also displayed 1369del2. Three other patients with other idiopathic epileptic phenotypes did not have the mutation. A novel 2-bp deletion within the coding sequence of the potassium channel KCNQ2 gene was detected in patients from a large and heterogeneous family with BNFCs or non-BNFC seizures.

Pereira S ，Roll P ，Krizova J ，Genton P ，Brazdil M ，Kuba R ，Cau P ，Rektor I ，Szepetowski P ... -  《EPILEPSIA》

Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor.

:Benign familial neonatal convulsions (BFNC) is a rare autosomal inherited epilepsy. We studied the KCNQ2 coding region in a large, four-generation, Italian family with BFNC. A missense mutation C686T predicting the change of one of the innermost arginine (R214W) of the key functional voltage sensor (S4 helix), has been found in all affected members. This substitution probably reduces the movement of the voltage sensor that precedes channel opening during voltage-dependent activation. Several mutations affecting the trans-membrane domain and the pore region of the K+ channels belonging to the KQT-like family have been described in some human diseases associated with altered regulation of cellular excitability (ie BFNC, some LQT syndromes and DFNA2). R214W represents the first mutation involving the region of the voltage sensor.

Miraglia del Giudice E ，Coppola G ，Scuccimarra G ，Cirillo G ，Bellini G ，Pascotto A ... -  《EUROPEAN JOURNAL OF HUMAN GENETICS》

A KCNQ2 splice site mutation causing benign neonatal convulsions in a Scottish family.

Lee WL ，Biervert C ，Hallmann K ，Tay A ，Dean JC ，Steinlein OK ... -  《NEUROPEDIATRICS》