title: 50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis.
abstract: The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion. Reporter gene expression analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation studies were utilized to examine the functional effects of the deletion. The genetic association for homozygosity for the promoter deletion with an increased age of symptom onset was confirmed overall in this further study (p=0.032), although it was only statistically significant in the Irish subset, and remained highly significant in the combined set of all cohorts (p=0.001). Functional studies demonstrated that this polymorphism reduces the activity of the SOD1 promoter by approximately 50%. In addition we revealed that the transcription factor SP1 binds within the 50bp deletion region in vitro and in vivo. Our findings suggest the hypothesis that this deletion reduces expression of the SOD1 gene and that levels of the SOD1 protein may modify the phenotype of SALS within selected populations.
authors.affiliation: Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. wendy.broom@gmail.com
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Broom
authors.forename: Matthew
authors.initials: M
authors.lastname: Greenway
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.forename: Carsten
authors.initials: C
authors.lastname: Russ
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Auwarter
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Glajch
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupre
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Swingler
authors.forename: Shaun
authors.initials: S
authors.lastname: Purcell
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sapp
authors.forename: Diane
authors.initials: D
authors.lastname: McKenna-Yasek
authors.forename: Paul N
authors.initials: PN
authors.lastname: Valdmanis
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bouchard
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: Betsy A
authors.initials: BA
authors.lastname: Hosler
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.forename: Meraida
authors.initials: M
authors.lastname: Polack
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Jang-Ho J
authors.initials: JH
authors.lastname: Cha
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011792:Quebec / Q000453:epidemiology; D012307:Risk Factors; D012606:Scotland / Q000453:epidemiology; D017384:Sequence Deletion; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014481:United States / Q000453:epidemiology
chemical_list: C000606290:SOD1 protein, human; D016329:Sp1 Transcription Factor; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1