MUTATIONS IN THE GLUTAMATE TRANSPORTER EAAT2 GENE DO NOT CAUSE ABNORMAL EAAT2 TRANSCRIPTS IN AMYOTROPHIC-LATERAL-SCLEROSIS

Recently, variant mRNA transcripts for the astroglial glutamate transp orter EAAT2 have been detected in brain tissues of 60% of patients wit h sporadic amyotrophic lateral sclerosis (SALS). We have tested the hy pothesis that the gene for EAAT2 may be defective in some ALS cases. I n 16 familial ALS (FALS) pedigrees without mutations in SOD1, we faile d to detect genetic linkage to the EAAT2 locus. We next characterized the genomic organization of the EAAT2 gene and used single-strand conf ormation polymorphism analysis of genomic DNA to identify one novel mu tation in a single SALS patient and two novel mutations in 2 affected FALS siblings. In the SALS patient, the mutation substitutes serine fo r an asparagine that might be involved in N-linked glycosylation of th e 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 i ntron 7 mutation is related to the defective mRNA splicing. These stud ies indicate that germline mutations in the EAAT2 gene are infrequent and do not explain the presence of variant mRNA transcripts of EAAT2 i n more than one-half of ALS cases.