Laura M Fiori1, Naguib Mechawar, Gustavo Turecki. 1. McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
Abstract
BACKGROUND: We have previously shown that the expression of spermidine/spermine N1-acetyltransferase (SAT1) is decreased in the brain Brodmann areas (BA)4, BA8/9, and BA11 of suicide completers and found an association between rs6526342, a SAT1 promoter single nucleotide polymorphism (SNP), with suicide completion (1). METHODS: We genotyped 18 promoter polymorphisms in SAT1 in a French-Canadian population. The relationship between haplotypes and gene expression was assessed with microarray analysis of three brain regions as well as reporter gene assays in three cell lines. Site-directed mutagenesis was used to examine the role of individual polymorphisms in reporter gene expression. RESULTS: We identified two major and several minor haplotypes in the promoter region of SAT1. Subjects who possessed the haplotype containing the risk allele for rs6526342 demonstrated decreased SAT1 expression in BA4, BA8/9, and BA11. This haplotype was also associated with decreased expression in reporter gene assays. Site-directed mutagenesis identified three polymorphisms-an insertion/deletion (rs6151267), and two SNPs (rs6526342 and rs928931)-that were involved in determining reporter gene expression. These polymorphisms do not seem to exert their effects through the polyamine responsive element, because all constructs were induced to a similar extent in the presence of spermine. CONCLUSIONS: Our results indicate that genetic variations in the promoter region of SAT1 are involved in determining levels of gene expression and might provide a mechanism for the decreased SAT1 expression observed in suicide completers.
BACKGROUND: We have previously shown that the expression of spermidine/spermine N1-acetyltransferase (SAT1) is decreased in the brain Brodmann areas (BA)4, BA8/9, and BA11 of suicide completers and found an association between rs6526342, a SAT1 promoter single nucleotide polymorphism (SNP), with suicide completion (1). METHODS: We genotyped 18 promoter polymorphisms in SAT1 in a French-Canadian population. The relationship between haplotypes and gene expression was assessed with microarray analysis of three brain regions as well as reporter gene assays in three cell lines. Site-directed mutagenesis was used to examine the role of individual polymorphisms in reporter gene expression. RESULTS: We identified two major and several minor haplotypes in the promoter region of SAT1. Subjects who possessed the haplotype containing the risk allele for rs6526342 demonstrated decreased SAT1 expression in BA4, BA8/9, and BA11. This haplotype was also associated with decreased expression in reporter gene assays. Site-directed mutagenesis identified three polymorphisms-an insertion/deletion (rs6151267), and two SNPs (rs6526342 and rs928931)-that were involved in determining reporter gene expression. These polymorphisms do not seem to exert their effects through the polyamine responsive element, because all constructs were induced to a similar extent in the presence of spermine. CONCLUSIONS: Our results indicate that genetic variations in the promoter region of SAT1 are involved in determining levels of gene expression and might provide a mechanism for the decreased SAT1 expression observed in suicide completers.
Authors: Spiro P Pantazatos; Stuart J Andrews; Jane Dunning-Broadbent; Jiuhong Pang; Yung-Yu Huang; Victoria Arango; Peter L Nagy; J John Mann Journal: Neurobiol Dis Date: 2015-05-08 Impact factor: 5.996
Authors: Laura M Fiori; Brigitte Wanner; Valérie Jomphe; Jordie Croteau; Frank Vitaro; Richard E Tremblay; Alexandre Bureau; Gustavo Turecki Journal: PLoS One Date: 2010-11-30 Impact factor: 3.240
Authors: Jeffrey A Gross; Laura M Fiori; Benoit Labonté; Juan Pablo Lopez; Gustavo Turecki Journal: J Psychiatr Res Date: 2012-12-20 Impact factor: 4.791
Authors: Eric T Monson; Kelly de Klerk; Sophia C Gaynor; Alex H Wagner; Marie E Breen; Meredith Parsons; Thomas L Casavant; Peter P Zandi; James B Potash; Virginia L Willour Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2016-05-27 Impact factor: 3.568
Authors: H Le-Niculescu; D F Levey; M Ayalew; L Palmer; L M Gavrin; N Jain; E Winiger; S Bhosrekar; G Shankar; M Radel; E Bellanger; H Duckworth; K Olesek; J Vergo; R Schweitzer; M Yard; A Ballew; A Shekhar; G E Sandusky; N J Schork; S M Kurian; D R Salomon; A B Niculescu Journal: Mol Psychiatry Date: 2013-08-20 Impact factor: 15.992