IDENTIFICATION OF NEW MUTATIONS IN THE CU ZN SUPEROXIDE-DISMUTASE GENE OF PATIENTS WITH FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS/

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disor der affecting motor neurons. Although most cases of ALS are sporadic, similar to 10% are inherited as an autosomal dominant trait. Mutations in the Cu/Zn superoxide dismutase gene (SOD 1) are responsible for a fraction of familial ALS (FALS). Screening our FALS kindreds by SSCP, we have identified mutations in 15 families, of which 9 have not been previously reported. Two of the new mutations alter amino acids that h ave never been implicated in FALS. One of them affects a highly conser ved amino acid involved in dimer contact, and the other one affects th e active-site loop of the enzyme. These two mutations reduce significa ntly SOD 1 enzyme activity in lymphoblasts. Our results suggest that S OD 1 mutations are responsible for greater than or equal to 13% of FAL S cases.