title: IMPDH2 genetic polymorphism: a promoter single-nucleotide polymorphism disrupts a cyclic adenosine monophosphate responsive element.
abstract: Inosine 5'-monophosphate dehydrogenase (IMPDH), which catalyzes a key step in the de novo biosynthesis of guanine nucleotide, is mediated by two highly conserved isoforms, IMPDH1 and IMPDH2. In this study, IMPDH2 genetic polymorphism was investigated in 96 individuals of Caucasian origin. Four single-nucleotide polymorphisms were identified, comprising one previously described single base-pair substitution in the close vicinity of the consensus donor splice site of intron 7 (IVS7+10T>C), and three novel polymorphisms, one silent substitution in exon 9 (c.915C>G), one single base-pair insertion (g.6971_6972insT) within the 3'-untranslated region of the gene, and one substitution located in the promoter region (c.-95T>G) in a transcription factor binding site CRE(A) (cyclic adenosine monophosphate [cAMP] response element). Considering the nature and location of this latter polymorphism, its functional relevance was examined by transfecting HEK293 and Jurkat cell lines with constructs of the related region of IMPDH2/luciferase reporter gene. The c.-95T>G mutation leads to a significant decrease of luciferase activity (HEK293: 55% decrease, p < 0.05; Jurkat: 65% decrease, p < 0.05) compared with the wild-type promoter sequence and, therefore, is likely to determine interindividual differences in IMPDH2 transcriptional regulation. These results might contribute to a better understanding of the variability in clinical outcome and dose adjustments of certain immunosuppressors that are metabolized through the IMPDH pathway or that are IMPDH inhibitors.
authors.affiliation: EA267, Faculty of Medicine, University Lille Nord de France, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Garat
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
authors.forename: Rima
authors.initials: R
authors.lastname: Hamdan-Khalil
authors.forename: François
authors.initials: F
authors.lastname: Glowacki
authors.forename: Aurore
authors.initials: A
authors.lastname: Devos
authors.forename: Julie
authors.initials: J
authors.lastname: Leclerc
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lionet
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lo-Guidice
authors.forename: Franck
authors.initials: F
authors.lastname: Broly
mesh_terms: D001665:Binding Sites / Q000235:genetics; D051699:Cyclic AMP Response Element-Binding Protein A / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D019169:Jurkat Cells; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements / Q000235:genetics*
chemical_list: D051699:Cyclic AMP Response Element-Binding Protein A; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human