title: MED23 mutation links intellectual disability to dysregulation of immediate early gene expression.
abstract: MED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, BP 163, 67404 Illkirch Cedex, C. U. Strasbourg, France.
authors.forename: Satoru
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Sarah
authors.initials: S
authors.lastname: Boissel
authors.forename: Mohammed
authors.initials: M
authors.lastname: Zarhrate
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D016762:Genes, fos; D016758:Genes, jun; D006657:Histones / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D011401:Promoter Regions, Genetic; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497325:EGR1 protein, human; C494112:ELK1 protein, human; D051766:Early Growth Response Protein 1; D006657:Histones; C492159:MED23 protein, human; D056892:Mediator Complex; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1