Length variation of a polyglutamine array in the gene encoding a small-conductance, calcium-activated potassium channel (hKCa3) and susceptibility to idiopathic generalized epilepsy

Abstract

The present association study tested whether length variations of two adjacent polymorphic CAG repeats in the coding sequence of a small-conductance, calcium-activated potassium channel (hKCa3) confer susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). We found no significant difference in the allelic length distribution of the CAG repeats between 290 healthy German controls and the entire sample of 126 German IGE patients (Wilcoxon rank-sum test, P=0.44) or two subgroups, comprising either 78 patients with juvenile myoclonic epilepsy (Wilcoxon rank-sum test, P=0.74) or 59 patients with idiopathic absence epilepsies (Wilcoxon rank-sum test, P=0.44). Moreover, the allelic distribution in parents-child trios of 46 IGE offspring did not differ significantly between the transmitted and non-transmitted parental alleles (Wilcoxon rank-sum test, P=0.48). Therefore, our association study provides no evidence that length variations of polyglutamine arrays in the N-terminus of the hKCa3 channel exert a frequent and relevant effect in the epileptogenesis of common subtypes of IGE.

Introduction

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsy (IGE), which accounts for 40% of all epilepsies (Sander, 1996, Janz, 1997). Accordingly, molecular genetic studies are aiming to identify susceptibility alleles of IGE and, subsequently, to elucidate the molecular pathways of epileptogenesis (Noebels, 1996, Szepetowski and Monaco, 1998). Childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME) represent common subtypes of IGE with age-related onset (Commission on Classification and Terminology of the International League Against Epilepsy, 1989, Janz, 1997). Their familial clustering and their subsequent occurrence in patients suggest that this IGE spectrum shares predisposing genetic factors (Janz, 1997, Berkovic et al., 1987). However, it is likely that several genetic factors, influencing neuronal excitability, synaptic plasticity and brain development, are involved in the pathogenesis of this IGE spectrum (Noebels, 1996, Szepetowski and Monaco, 1998). So far, genetic causes of the common IGE syndromes have not been identified due to complex inheritance and genetic heterogeneity (Lander and Schork, 1994, Sander, 1996, Szepetowski and Monaco, 1998).

Mutations in two novel and related genes encoding voltage-gated potassium channels (KCNQ2, KCNQ3) have recently been identified to cause a rare autosomal dominantly inherited subtype of IGE, the benign familial neonatal convulsions (BFNC) (Biervert et al., 1998, Charlier et al., 1998, Singh et al., 1998). In addition, mutant mice lacking either the gene encoding the G protein-gated inwardly rectifying potassium channel Grik2 or the gene encoding the voltage-gated potassium channel Kcna1 display frequent spontaneous seizures without cerebellar abnormalities (Signorini et al., 1997, Smart et al., 1998). Together, these findings emphasize the important role of potassium channels in controlling neuronal excitability. Thus, potassium channel genes represent high-ranking candidate genes for IGE (Stoffel and Jan, 1998).

Small conductance calcium-activated potassium channels play a critical role in determining the firing pattern of neurons via the generation of slow after-hyperpolarization and the regulation of intracellular calcium channels (Köhler et al., 1996). Recently, a novel human gene encoding a neuronal, small conductance calcium-activated potassium channel (hKCa3) has been isolated (Chandy et al., 1998). The hKCa3 gene encodes a protein of 731 amino acids containing two adjacent polyglutamine arrays in its N-terminal domain separated by 25 amino acids. The C-terminal polyglutamine array is highly polymorphic in length. SKCa channels hyperpolarize the membrane potential (Moghaddam et al., 1997), and thereby, amongst other effects, inactivate NMDA receptors, which contribute to excitatory neurotransmission and play an important role in seizure generation. Accordingly, hypoactive hKCa3 channels would be expected to enhance NMDA receptor function. Therefore, variations in the lengths of the polyglutamine stretches may modulate hKCa3 function and might thereby increase neuronal excitability and seizure liability. The present association study was designed to test the hypothesis that length variation of the exonic CAG arrays in the hKCa3 gene confers susceptibility to common IGE syndromes.