Mutations and polymorphisms of the
            <i>CLCN2</i>
            gene in idiopathic epilepsy

D’Agostino, Daniela; Bertelli, Matteo; Gallo, Silvia; Cecchin, Stefano; Albiero, Elena; Garofalo, P; Gambardella, Antonio; Hilaire, J.-M. St.; Kwieciński, Hubert; Andermann, Eva; Pandolfo, Massimo

doi:10.1212/01.wnl.0000142093.94998.1a

Cited by 64 publications

(45 citation statements)

References 12 publications

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“…This difference in result may reflect an underlying population stratification which might affect the case-control analysis but not the PDT. This polymorphism was also detected in a previous study in one Polish family in which the proband and his father had familial frontal lobe Everett 15 epilepsy (FFLE) (D'Agostino et al, 2004). The minor allele was found to segregate with the disease and was not found in any control samples.…”

Section: Discussionsupporting

confidence: 66%

“…The second variant which demonstrated statistical disease association was IVS4+12G>A, which has also been detected in families with idiopathic epilepsy (D'Agostino et al, 2004). We found no evidence for preferential transmission of This study has provided further support for a potential role for CLCN2 in IGE, specifically CAE.…”

Section: Discussionsupporting

confidence: 64%

“…Two different mutations (Arg688Gly and Glu718Asp) and an intronic variant (IVS17-3C>T) have been shown to cosegregate with epilepsy in two families with idiopathic epilepsy (D'Agostino et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Linkage and mutational analysis of CLCN2 in childhood absence epilepsy

et al. 2007

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In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score = 2.3, p<0.009; HLOD = 1.5, α = 0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT  2(1) = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele:  2(1) = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11, and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 64%

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Linkage and mutational analysis of CLCN2 in childhood absence epilepsy

et al. 2007

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“…No human disease has been unequivocally related to mutations in CLCN2, the gene encoding ClC-2. Heterozygous mutations in CLCN2 were described as a cause of idiopathic generalised epilepsies, [11][12][13][14][15][16][17] but this fi nding was later refuted 1,18 and the original paper was retracted. 17 Because mutant mice without functional ClC-2 have a leukoencephalopathy with intramyelinic oedema, 5,6,19 ClC-2 was proposed to have a role in brain ion and water homoeostasis; 5,6 however, this hypothesis has not been confi rmed in human beings.…”

Section: Introductionmentioning

confidence: 99%

Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

Depienne¹,

Bugiani²,

Dupuits³

et al. 2013

The Lancet Neurology

158

204

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SummaryBackground Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confi rmed in human beings. We aimed to defi ne novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifi cally interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis.

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“…In rare families, pathogenic mutations in single genes have been reported. Mutations in the GABRG2 gene were identified in families with febrile seizures and childhood absence epilepsy [35,36], a mutation in the GABRA1 gene was identified in a family with dominantly inherited juvenile myoclonic epilepsy [159], and mutations in CLCN2 in families with heterogeneous IGE phenotypes, including childhood absences epilepsy [160]. Rare variants in CACNA1H have been identified in childhood absence epilepsy and other generalized epilepsy phenotypes (Table 1) [161,162].…”

Section: Iges With Complex Inheritancementioning

confidence: 99%

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

2014

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Research in genetics of epilepsy represents an area of great interest both for clinical purposes and for understanding the basic mechanisms of epilepsy. Most mutations in epilepsies without structural brain abnormalities have been identified in ion channel genes, but an increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing. Targeted molecular diagnosis is now available for different forms of epilepsy. The identification of epileptogenic mutations in patients before epilepsy onset and the possibility of developing therapeutic strategies tested in experimental models may facilitate experimental approaches that prevent epilepsy or decrease its severity. Functional analysis is essential for better understanding pathogenic mechanisms and gene interactions. In vitro experimental systems are either cells that usually do not express the protein of interest or neurons in primary cultures. In vivo/ex vivo systems are organisms or preparations obtained from them (e.g., brain slices), which should better model the complexity of brain circuits and actual pathophysiological conditions. Neurons differentiated from induced pluripotent stem cells generated from the skin fibroblasts of patients have recently allowed the study of mutations in human neurons having the genetic background of a given patient. However, there is remarkable complexity underlying epileptogenesis in the clinical dimension, as reflected by the fact that experimental models have not provided yet results having clinical translation and that, with a few exceptions concerning rare conditions, no new curative treatment has emerged from any genetic finding in epilepsy.

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Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy

Cited by 64 publications

References 12 publications

Linkage and mutational analysis of CLCN2 in childhood absence epilepsy

Linkage and mutational analysis of CLCN2 in childhood absence epilepsy

Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

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