Polymorphisms in the glutamate transporter gene EAAT2 in European ALS patients

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder characterised by degeneration of upper and lower motor neurons. Whilst the primary pathogenic trigger is unknown in most cases, evidence is mounting t o implicate a role for glutamate-mediated neurotoxicity in the disorder. Re cent studies have shown reduced levels of the mainly astroglial glutamate t ransporter EAAT2 in ALS motor cortex and spinal cord and multiple abnormal EAAT2 mRNA species in ALS brain tissue. One cause of the low EAAT2 levels m ay be that point mutations in the EAAT2 gene, EAAT2, result in an abnormal unstable protein. To test this hypothesis we analysed EAAT2 in 128 sporadic and 23 familial European ALS cases. No variants within the coding sequence of EAAT2 to affect the protein sequence nor in the consensus splice sites of the flanking intronic sequences were found in any cases, similar to find ings in other reports. Frequent polymorphisms within the flanking intronic sequences of both exons 2 and 4 were seen but at similar frequencies in con trols. Mechanisms other than mutations within the coding region of EAAT2 mu st therefore be responsible for the low levels of EAAT2. seen in most cases of ALS.