title: A novel ALS SOD1 C6S mutation with implications for aggregation related toxicity and genetic counseling.
abstract: In this report we describe an ALS family with a novel missense SOD1 mutation with substitution of serine for cysteine at the sixth amino acid (C6S). This mutation has interesting implications for the role of disulfides in causing disease. After identification of the ALS proband, we examined 17 members of an extended family and performed DNA mutation analysis on 21 family members. The level and activity of SOD1 in C6S carriers and wild-type family members was analyzed in erythrocytes. We found that the C6S mutation results in disease with an autosomal dominant mode of inheritance and markedly reduced penetrance. The S6 mutated protein demonstrates high stability relative to the C6 wild-type protein. The specific dismutation activity of S6 SOD1 is normal. In conclusion, C6S is a novel FALS associated mutation with reduced disease penetrance, long survival time and a phenotype very different from the other SOD1 mutations reported in codon C6. This mutation may provide insight into the role of SOD1 structural changes in disease.
authors.affiliation: Department of Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Terrell
authors.initials: T
authors.lastname: Brotherton
authors.forename: Meraida
authors.initials: M
authors.lastname: Polak
authors.forename: Crystal
authors.initials: C
authors.lastname: Kelly
authors.forename: Anna
authors.initials: A
authors.lastname: Birve
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004220:Disulfides / Q000737:chemistry; D005260:Female; D005817:Genetic Counseling; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012694:Serine / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D004220:Disulfides; C000606290:SOD1 protein, human; D012694:Serine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003545:Cysteine