title: MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.
abstract: Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery but little is known regarding the role of each Mediator subunits. Mutations in MED12 are linked with a broad spectrum of genetic disorders with X-linked intellectual disability that are difficult to range as Lujan, Opitz-Kaveggia or Ohdo syndromes. Here, we investigated several MED12 patients mutations (p.R206Q, p.N898D, p.R961W, p.N1007S, p.R1148H, p.S1165P and p.R1295H) and show that each MED12 mutations cause specific expression patterns of JUN, FOS and EGR1 immediate early genes (IEGs), reflected by the presence or absence of MED12 containing complex at their respective promoters. Moreover, the effect of MED12 mutations has cell-type specificity on IEG expression. As a consequence, the expression of late responsive genes such as the matrix metalloproteinase-3 and the RE1 silencing transcription factor implicated respectively in neural plasticity and the specific expression of neuronal genes is disturbed as documented for MED12/p.R1295H mutation. In such case, JUN and FOS failed to be properly recruited at their AP1-binding site. Our results suggest that the differences between MED12-related phenotypes are essentially the result of distinct IEGs expression patterns, the later ones depending on the accurate formation of the transcription initiation complex. This might challenge clinicians to rethink the traditional syndromes boundaries and to include genetic criterion in patients' diagnostic.
authors.affiliation: Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden, France.
authors.forename: Lise-Marie
authors.initials: LM
authors.lastname: Donnio
authors.affiliation: Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Bidon
authors.affiliation: Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden, France.|Department of Clinical Pharmacology and Therapeutics Oita University Faculty of Medicine, Yufu city, Oita 879-5593, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29649, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: May
authors.affiliation: Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden, France.
authors.forename: Alexey
authors.initials: A
authors.lastname: Epanchintsev
authors.affiliation: Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden, France.
authors.forename: Colm
authors.initials: C
authors.lastname: Ryan
authors.affiliation: Fullerton Genetics Center, Asheville, NC 28803, USA.
authors.forename: William
authors.initials: W
authors.lastname: Allen
authors.affiliation: Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.affiliation: School of Medicine, and the Robinson Research Institute, The University of Adelaide, and South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29649, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Skinner
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29649, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525?HP, The Netherlands.
authors.forename: Arjan P M
authors.initials: APM
authors.lastname: de Brouwer
authors.affiliation: Département de Génétique et Procréation, Centre Hospitalier-Universitaire, Institut Albert Bonniot, CNRS/INSERM/Université Grenoble Alpes, 38000 Grenoble, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Coutton
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier-Universitaire, 63003 Clermont-Ferrand, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Francannet
authors.affiliation: Département de Génétique et Procréation, Centre Hospitalier-Universitaire, Institut Albert Bonniot, CNRS/INSERM/Université Grenoble Alpes, 38000 Grenoble, France.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Jouk
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29649, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.affiliation: Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D016569:Blepharophimosis / Q000235:genetics; D001763:Blepharoptosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D017781:Genes, Immediate-Early / Q000235:genetics*; D050172:Genes, X-Linked / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D038901:X-Linked Intellectual Disability / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
chemical_list: D056892:Mediator Complex; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C460107:MED12 protein, human