title: Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Cecil B. Day Laboratory for Neuromuscular Research, Massachusetts General Hospital, Charlestown 02129, USA.
authors.forename: M
authors.initials: M
authors.lastname: Aoki
authors.forename: C L
authors.initials: CL
authors.lastname: Lin
authors.forename: J D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: B A
authors.initials: BA
authors.lastname: Geller
authors.forename: B A
authors.initials: BA
authors.lastname: Hosler
authors.forename: T L
authors.initials: TL
authors.lastname: Munsat
authors.forename: H R
authors.initials: HR
authors.lastname: Horvitz
authors.forename: R H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D027342:Excitatory Amino Acid Transporter 2; D005091:Exons / Q000235:genetics; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D012326:RNA Splicing / Q000235:genetics; D017981:Receptors, Neurotransmitter / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D017981:Receptors, Neurotransmitter