title: Single nucleotide polymorphism creating a variable upstream open reading frame regulates glucocorticoid receptor expression.
abstract: The glucocorticoid and mineralocorticoid receptors are known to play a crucial role in cellular responses to acute and chronic stress conditions. However, the influence of genetic variants and regulatory mechanisms within the glucocorticoid and mineralocorticoid receptor genes NR3C1 and NR3C2 is still incompletely understood. We therefore investigated putative upstream open reading frames, a motif regulating gene expression, from the 5' untranslated regions of the predominant human glucocorticoid receptor gene NR3C1 isoform alpha variant 1 and from the human mineralocorticoid receptor NR3C2 variants 1 and 2. The in silico analysis displayed one SNP (rs10482612), being present heterozygously in about 1.2% of the world population and 1.8% of the European population (according to the NCBI database), whose minor allele 'A' creates an upstream start codon. Our functional analysis performed by reporter gene assay and quantitative real-time PCR confirmed that the minor allele 'A' of the SNP rs10482612 can indeed alter protein activity of the subsequent gene during baseline conditions and cellular stress by creating a functional uORF in the 5'UTR of the NR3C1 transcript variant 1.
authors.affiliation: Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University Munich, Goethestraße 29, 80336 Munich, Germany; Department of Physiology and Pharmacology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Marceca
authors.affiliation: Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University Munich, Goethestraße 29, 80336 Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Pfob
authors.affiliation: Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany; Department of Physiology and Pharmacology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Gustav
authors.initials: G
authors.lastname: Schelling
authors.affiliation: Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University Munich, Goethestraße 29, 80336 Munich, Germany.
authors.forename: Ortrud K
authors.initials: OK
authors.lastname: Steinlein
authors.affiliation: Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University Munich, Goethestraße 29, 80336 Munich, Germany. Electronic address: Marlene.Eggert@med.uni-muenchen.de.
authors.forename: Marlene
authors.initials: M
authors.lastname: Eggert
mesh_terms: D020121:5' Untranslated Regions; D018387:Codon, Initiator; D003198:Computer Simulation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D018387:Codon, Initiator; C497713:NR3C1 protein, human; C561839:NR3C2 protein, human; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid
keywords: Cellular stress; Glucocorticoid receptor; Mineralocorticoid receptor; NR3C1; NR3C2; SNP; Upstream open reading frame