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

• Published in: Amyotrophic lateral sclerosis 2008-01, Vol.9 (4), p.229-237
• Main Authors: Broom, Wendy J., Greenway, Matthew, Sadri-Vakili, Ghazaleh, Russ, Carsten, Auwarter, Kristen E., Glajch, Kelly E., Dupre, Nicolas, Swingler, Robert J., Purcell, Shaun, Hayward, Caroline, Sapp, Peter C., McKenna-Yasek, Diane, Valdmanis, Paul N., Bouchard, Jean-Pierre, Meininger, Vincent, Hosler, Betsy A., Glass, Jonathan D., Polack, Meraida, Rouleau, Guy A., Cha, Jang-Ho J., Hardiman, Orla, Brown, Robert H.
• Format: Article
• Language: English
• Subjects: Age of Onset; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - epidemiology; Amyotrophic Lateral Sclerosis - genetics; Base Sequence; DNA Mutational Analysis; Female; Gene Expression; genetic; Genetic Predisposition to Disease; Genotype; heredity; Homozygote; Humans; Ireland - epidemiology; Male; Middle Aged; nucleic acid; Phenotype; polymorphism; Polymorphism, Genetic; Promoter Regions, Genetic; Quebec - epidemiology; regulatory sequences; Risk Factors; Scotland - epidemiology; Sequence Deletion; Sp1 Transcription Factor - metabolism; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; United States - epidemiology
• ISSN: 1748-2968; 1471-180X
• DOI: 10.1080/17482960802103107

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.