Association Analysis of (gamma) 2 Subunit of (gama)-Aminobutyric Acid Type A Receptor Polymorphisms with Febrile Seizures

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题名:	Association Analysis of (gamma) 2 Subunit of (gama)-Aminobutyric Acid Type A Receptor Polymorphisms with Febrile Seizures
作者:	周宜卿(I-Ching Chou);彭慶添(Ching-Tien Peng);黃朝慶(CC Huang);蔡進發(JJ Tsai);蔡輔仁(Fuu-Jen Tsai)*;蔡長海(Chang-Hai Tsai)
贡献者:	中醫學院針灸研究所;中國附醫兒童醫學中心小兒神經科
日期:	2003-07
上传时间:	2009-08-20 17:59:25 (UTC+8)
摘要:	An alternation of γ-aminobutyric acid (GABA)-ergic neurotransmission has been implicated as an etiologic factor in epileptogenesis. Missense mutations in the GABRG2 gene, which encodes the γ2 subunit of central nervous GABAA receptors, have recently been described in one family with childhood absence epilepsy and febrile seizures (FSs). FSs represent the majority of childhood seizures and have a genetic predisposition. It is not known, however, whether polymorphisms in those genes involved in familial epilepsies also contribute to the pathogenesis of FSs. By performing an association study, we used single-nucleotide polymorphisms to investigate the distribution of genotypes of GABRG2 in patients with FSs. A total of 104 children with FSs and 83 normal control subjects were included in the study. PCR was used to identify the C/T and A/G polymorphisms of the GABRG2 gene on chromosome 5q33. Genotypes and allelic frequencies for the GABRG2 gene polymorphisms in both groups were compared. The GABRG2 (nucleotide position 3145 in intron G→A) gene in both groups was not significantly different. In contrast, the number of individuals with the GABRG2 (SNP211037)-C/C genotype in patients with FSs was significantly greater compared with that in healthy control subjects (p = 0.017), and the GABRG2 (SNP211037)-C allele frequency in patients with FSs was significantly higher than that in healthy control subjects (p = 0.009). The odds ratio for developing FSs in individuals with the GABRG2 (SNP211037)-C/C genotype was 2.56 compared with individuals with the GABRG2 (SNP211037)-T/T genotype. These data suggest that the GABRG2 gene might be one of the susceptibility factors for FSs. Abbreviations: FSs, febrile seizures, GABA, γ-aminobutyric acid, GABR, GABA type A receptor, GABRG2, γ2 subunit of GABR FSs are the most common seizure subtypes, affecting about 2% to 5% of children before the age of 5 y (1). FSs are characterized by a short duration of seizures during rapidly rising fever. Children with FSs are not predisposed to epilepsy, and the condition is not associated with neurologic abnormalities (2). The pathogenesis of FSs remains obscure. Possible causes include viral infection of the CNS and lowered threshold for seizures in the presence of fever (3). In fact, FSs of children may involve a complex interaction between the immunoinflammatory process, cytokine activation, and genetic factors. It has long been known that approximately 30% of children with FSs have a family history of FSs (2). The genetic susceptibility to FSs seems to involve multiple genes in most instances (4). Some forms of family epilepsy may initially present as FSs and several of these disorders are caused by channelopathies such as neuronal sodium channels (5, 6) or GABA receptors (7). Thus, because of sharing important clinical features, FSs and these family epilepsies may share a common genetic etiology. It is not known, however, whether polymorphisms in those genes involved in familial epilepsies also contribute to the pathogenesis of FSs, because less than 3% of children with FSs progress to persistent epilepsy (1). An alternation of GABAergic neurotransmission has been implicated as an etiologic factor in epileptogenesis (8-11). Neuronal inhibition in the mammalian brain is largely mediated by the binding of GABA to heteromeric GABRs (10, 11). GABR, a ligand-gated Cl- channel, functions as a tetramer consisting of α, β, γ, and π subunits. Each subunit has several subtypes, and the main GABR in the CNS is composed of α1, β2, and γ2 subunits. The genes encoding GABR subunits represent high-ranking candidates for idiopathic generalized epilepsy susceptibility genes because of the widespread distribution of GABRs in the CNS, their ability to produce postsynaptic inhibition, and their modulation by clinically important anticonvulsant drug, including benzodiazepines and barbiturates (10). Genetic evidence for a potential role of the GABAergic system in epileptogenesis (9-11), however, has been obtained only recently by the discovery of different GABRG2 mutations identified in two families. The phenotype in one of these families was described to be compatible with generalized epilepsy with FS plus, but no further details regarding the seizure types observed in the affected pedigree members were given (12). In the second affected family, individuals predominantly had childhood absence epilepsy and FSs (7). Accordingly, these findings raise the question of whether genetic variation of the GABRG2 gene confers susceptibility to the epileptogenesis of FSs. Genetic studies of complex diseases such as FSs are difficult to approach because of the uncertainty of polygenic traits. We previously used single-nucleotide polymorphisms as a tool to search for genetic makers of FSs (13, 14). Single-nucleotide polymorphisms are the most abundant types of DNA sequence variation in the human genome (15, 16). It is a single base pair on the DNA that varies from person to person. Single-nucleotide polymorphisms are markers that may provide a new way to identify complex gene-associated diseases such as FSs. In this study, we tested the hypothesis that genetic variation in the GABRG2 gene confers susceptibility to FSs in children. Two synonymous polymorphic repeat markers have been identified in single-nucleotide polymorphism (17): the G→A nucleotide exchange at nucleotide position 3145 in the intronic sequence, and SNP211037 (Asn196Asn), at nucleotide position 588, allowing researchers to detect disease-causing gene association.
關聯:	PEDIATRIC RESEARCH54(1):26~29
显示于类别:	[針灸研究所] 期刊論文

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