Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis
Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis
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DOI：
10.1002/ana.410430514
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发表时间：
1998-05-01
影响因子：
11.2
通讯作者：
Brown, RH
中科院分区：
文献类型：
--
作者：
Aoki, M;Lin, CLG;Brown, RH
最近，在60%的散发性肌萎缩侧索硬化症(SALS)患者的脑组织中检测到星形胶质细胞谷氨酸转运体EAAT2的不同mRNA转录。我们已经验证了EAAT2基因在某些ALS病例中可能存在缺陷的假设。在16个SOD1无突变的家族性ALS(FALS)家系中，我们未能检测到与EAAT2基因座的遗传连锁。接下来，我们确定了EAAT2基因的基因组结构，并使用基因组DNA的单链构象多态分析来鉴定单个SALS患者中的一个新突变和两个受影响的FALS兄弟姐妹中的两个新突变。在SALS患者中，突变用丝氨酸取代了天冬酰胺，天冬酰胺可能参与EAAT2蛋白的N-连接糖基化。在FALS家系中的2例受累个体中，我们同时检测到内含子7的5‘端突变和外显子5的234密码子的沉默G->；A转换。目前尚不清楚该内含子7突变是否与有缺陷的mRNA剪接有关。这些研究表明，EAAT2基因的胚系突变是罕见的，并不能解释超过一半的ALS病例中存在EAAT2的不同mRNA转录本。
Recently, variant mRNA transcripts for the astroglial glutamate transporter EAAT2 have been detected in brain tissues of 60% of patients with sporadic amyotrophic lateral sclerosis (SALS). We have tested the hypothesis that the gene for EAAT2 may be defective in some ALS cases. In 16 familial ALS (FALS) pedigrees without mutations in SOD1, we failed to detect genetic linkage to the EAAT2 locus. We next characterized the genomic organization of the EAAT2 gene and used single-strand conformation polymorphism analysis of genomic DNA to identify one novel mutation in a single SALS patient and two novel mutations in 2 affected FALS siblings. In the SALS patient, the mutation substitutes serine for an asparagine that might be involved in N-linked glycosylation of the EAAT2 protein. In the 2 affected individuals in the FALS family, we detected both a mutation in the 5' end of intron 7 and a silent G --> A transition at codon 234 in exon 5. It remains unclear whether this intron 7 mutation is related to the defective mRNA splicing. These studies indicate that germline mutations in the EAAT2 gene are infrequent and do not explain the presence of variant mRNA transcripts of EAAT2 in more than one-half of ALS cases.