Search

Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.

Abstract —The aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac remodeling in rats with 2-kidney, 1 clip (2K1C) renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro and induces cardiac collagen synthesis. The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy, media/lumen ratio of intracardiac arteries, and left ventricular fibrosis were also analyzed. This study demonstrated that the overall left ventricular cardiac endothelin system has a similar activity in the early, middle, and late stages of 2K1C renovascular hypertension compared with sham-operated controls. Fibrosis of the left ventricle and hypertrophy of intracardiac arteries, however, were markedly altered after long-term treatment with endothelin receptor antagonists in a blood pressure–independent manner. These 2 effects are mediated by different subtypes of endothelin receptors. ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries ( P P

Context Missense mutations in the GABRG2 gene, which encodes the γ2 subunit of central nervous γ-aminobutyric acid (GABA) A receptors, have recently been described in 2 families with idiopathic epilepsy. In one of these families, the affected individuals predominantly exhibited childhood absence epilepsy and febrile convulsions. Objective To assess the role of GABRG2 in the genetic predisposition to idiopathic absence epilepsies. Design The GABRG2 gene was screened by single-strand conformation analysis for mutations. Furthermore, a population-based association study assessing a common exon 5 polymorphism (C588T) was carried out. Patients The sample was composed of 135 patients with idiopathic absence epilepsy and 154 unrelated and ethnically matched controls. Results A point mutation (IVS6 + 2T→G) leading to a splice–donor site mutation in intron 6 was found. The mutation, which is predicted to lead to a nonfunctional protein, cosegregates with the disease status in a family with childhood absence epilepsy and febrile convulsions. The association study did not find any significant differences in the allele and genotype frequencies of the common exon 5 polymorphism (C588T) between patients with idiopathic absence epilepsy and controls ( P >.35). Conclusions Our study identified a splice–donor-site mutation that was probably causing a nonfunctional GABRG2 subunit. This mutation occurred in heterozygosity in the affected members of a single nuclear family, exhibiting a phenotypic spectrum of childhood absence epilepsy and febrile convulsions. The GABRG2 gene seems to confer a rare rather than a frequent major susceptibility effect to common idiopathic absence epilepsy syndromes.

We tested the hypothesis that genetic variation in the human sodium channel gene SCN2A confers liability to idiopathic generalized epilepsy (IGE). We performed a systematic search for mutations in 46 familial IGE cases and detected three novel polymorphisms, however, allele frequencies did not differ significantly between patients and controls. A rare mutation (R1918H) was identified in one patient but was absent in one further affected family member. Thus, our results do not suggest a major role of SCN2A in the etiology of IGE.

Background In two kidney-one clip renovascular hypertension (2K1C), blood flow is reduced in the clipped kidney leading to ischaemia. The non-clipped kidney is characterized by increased shear stress. Circulating Ang II is elevated. All these factors are stimuli of the paracrine renal endothelin system. Indeed, we demonstrated an activation of the renal endothelin system in the 2K1C rat model. Methods We analysed the effects of chronic treatment with the ETA receptor antagonist BQ-123 on blood pressure, heart rate, plasma renin activity, and on the progression of glomerulosclerosis, interstitial fibrosis and vascular remodeling in the clipped and non-clipped kidney. Results Long-term treatment with BQ-123 led to a fibrotic atrophy of the clipped kidney characterized by a significantly reduced weight of the clipped kidney compared to the clipped kidney of the placebo-treated group. Computer-aided image analysis revealed a markedly enhanced interstitial fibrosis of these clipped kidneys after long-term ETA blockade. The effects of ETA receptor antagonists on the non-clipped kidney were less pronounced. Neither blood pressure nor plasma renin activity were significantly altered by BQ-123 treatment. Conclusions The present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.