Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions

Abstract

Mutations in the voltage-gated potassium channel gene KCNQ2 on chromosome 20q13.3 are responsible for benign familial neonatal convulsions (BFNC), a rare monogenic idiopathic epilepsy. Here we report the determination of the detailed genomic structure of KCNQ2, and use of this information in mutational analysis. There are at least 18 exons, occupying more than 50 kb of genomic DNA. Several formerly unknown polymorphisms and splice variants as well as a new single base pair deletion mutation of unusual localization are described. In addition to facilitating more effective mutation detection among BFNC patients, the results presented here provide the basis for analysing the role of KCNQ2 in other types of epilepsy.

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

“…An alignment of the longest clone 3H2 with the genomic sequence of KCNQ2, showed that it corresponds to fulllength exons 12-14, and to the unspliced intron 14 according to the nomenclature of Biervert and Steinlein. 20 Despite the lack of intron 14 splicing-out, this latter remains in frame with exon 14, over 55 amino-acid residues. The new encoded intracytoplasmic domain, although shorter than that of the canonical KCNQ2 isoform 1 (KCNQ2 wild type (wt)), 19 presents a complete A-domain and a large part of the B-domain described as essential for channel functionality 21 ( Figure 1a and Supplementary information, Figure 1a).…”

Generalized Epileptic Disorders: An Update

“…A characteristic feature of BFNC is that seizures are expressed mainly during the first several weeks or months of life. In the majority of affected individuals, long-term development is normal, and only ∼16% of patients have epileptic seizures later in life (28,29). It may be postulated that the expression of KCNQ2/KCNQ3 channels is at a critical level in infancy but that there is redundancy in these or related K + channels later in life, accounting for the disappearance of symptoms in most affected individuals.…”

“…A recent analysis of the gene structure of the KCNQ2 gene revealed that the gene consists of at least 18 exons that can occur in alternatively spliced forms (29). In addition, a single nucleotide polymorphism resulting in an amino acid substitution T752N was identified.…”

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

“…The KCNQ2 coding region including the exon-intron boundaries of patients I-1, II-5-7-9, III-1-4, IV-1-2 and of the unaffected members of the kindred, I-2, II-2-4-6-8, III-2-3-5, were amplified using the primers and the conditions described by Biervert and Steinlein 11 and directly sequenced using an ABI PRISM 310 sequencer and the Big Dye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystem, Foster City, CA, USA).…”

“…10 Four BFNC-causing mutations lie in the conserved, carboxyl-terminal portion of the KCNQ2 protein. 11,12 In the remaining three BFNC cases identified mutations involve the pore region (two cases) or the transmembrane domain S6. 2 The functional expression of some of these mutants in Xenopus oocytes resulted in a 20% drop in repolarising potassium currents compared with the wild type.…”