Izzi Claudia, Barbon Alessandro, Kretz Rebekka, Sander Thomas, Barlati Sergio
Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnologies, Brescia University Medical School, Brescia, Italy.
Am J Med Genet. 2002 Apr 8;114(3):354-9. doi: 10.1002/ajmg.10254.
Hereditary factors play a major role in the etiology of juvenile absence epilepsy (JAE) that is a common subtype of idiopathic generalized epilepsy (IGE). Sander et al. [1997: Am J Med Genet 74:416-421] reported an allelic association of JAE with the nine-copy allele of a tetranucleotide repeat polymorphism in the third intron of the kainate-selective GluR5 receptor gene (GRIK1) and supportive evidence for linkage of IGE to GRIK1 in families of JAE probands. These findings suggest that a major genetic determinant of GRIK1 confers susceptibility to JAE. Assuming that the GRIK1 tetranucleotide repeat polymorphism is unlikely to have functional relevance itself, we have sequenced the coding regions and regulatory sequences of the GRIK1 gene in eight JAE patients who carry the nine-repeat allele of the GRIK1 tetranucleotide repeat polymorphism to detect a putative functional GRIK1 mutation that is in linkage disequilibrium with the nine-repeat allele. Seven of them were derived from families showing positive evidence for linkage to GRIK1. Our mutation analysis of coding regions and splice junctions revealed only two silent polymorphisms (A522C and C1173T) out of the five SNPs present in public databases and no mutations affecting protein structure. No significant differences were found in the allele frequencies of the detected polymorphisms between the JAE patients and controls. High levels of sequence conservation were also found in the promoter, in the 5' and both the 3' untranslated regions and in the RNA secondary structure involved in the editing reaction. The results presented indicate that mutations in the coding sequences, in the intron-exon boundaries and in the main regulatory regions of the GRIK1 are not commonly involved in the etiology of JAE.
遗传因素在青少年失神癫痫（JAE）的病因中起主要作用，青少年失神癫痫是特发性全身性癫痫（IGE）的一种常见亚型。桑德等人[1997年：《美国医学遗传学杂志》74卷：416 - 421页]报告了青少年失神癫痫与红藻氨酸选择性谷氨酸受体5基因（GRIK1）第三内含子中四核苷酸重复多态性的九拷贝等位基因存在等位基因关联，并为IGE与青少年失神癫痫先证者家族中的GRIK1存在连锁提供了支持性证据。这些发现表明，GRIK1的一个主要遗传决定因素赋予了对青少年失神癫痫的易感性。假设GRIK1四核苷酸重复多态性本身不太可能具有功能相关性，我们对8名携带GRIK1四核苷酸重复多态性九重复等位基因的青少年失神癫痫患者的GRIK1基因编码区和调控序列进行了测序，以检测与九重复等位基因处于连锁不平衡状态的假定功能性GRIK1突变。其中7名患者来自显示与GRIK1存在连锁阳性证据的家族。我们对编码区和剪接连接的突变分析仅发现了公共数据库中存在的5个单核苷酸多态性中的两个沉默多态性（A522C和C1173T），没有发现影响蛋白质结构的突变。在青少年失神癫痫患者和对照组之间，所检测到的多态性等位基因频率没有显著差异。在启动子、5'非翻译区、3'非翻译区以及参与编辑反应的RNA二级结构中也发现了高度的序列保守性。所呈现的结果表明，GRIK1的编码序列、内含子 - 外显子边界和主要调控区域的突变通常不参与青少年失神癫痫的病因。
