title: MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling.
abstract: Recurrent missense mutations in the RNA polymerase II Mediator subunit MED12 are associated with X-linked intellectual disability (XLID) and multiple congenital anomalies, including craniofacial, musculoskeletal, and behavioral defects in humans with FG (or Opitz-Kaveggia) and Lujan syndromes. However, the molecular mechanism(s) underlying these phenotypes is poorly understood. Here we report that MED12 mutations R961W and N1007S causing FG and Lujan syndromes, respectively, disrupt a Mediator-imposed constraint on GLI3-dependent Sonic Hedgehog (SHH) signaling. We show that the FG/R961W and Lujan/N1007S mutations disrupt the gene-specific association of MED12 with a second Mediator subunit, CDK8, identified herein to be a suppressor of GLI3 transactivation activity. In FG/R961W and Lujan/N1007S patient-derived cells, we document enhanced SHH pathway activation and GLI3-target gene induction coincident with impaired recruitment of CDK8 onto promoters of GLI3-target genes, but not non-GLI3-target genes. Together, these findings suggest that dysregulated GLI3-dependent SHH signaling contributes to phenotypes of individuals with FG and Lujan syndromes and further reveal a basis for the gene-specific manifestation of pathogenic mutations in a global transcriptional coregulator.
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, CA 94270, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhou
authors.forename: Jason M
authors.initials: JM
authors.lastname: Spaeth
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Kim
authors.forename: Xuan
authors.initials: X
authors.lastname: Xu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friez
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Boyer
mesh_terms: D002460:Cell Line; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D056892:Mediator Complex / Q000502:physiology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology*; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C460107:MED12 protein, human; D056892:Mediator Complex; D009419:Nerve Tissue Proteins; C509239:SHH protein, human; D000074290:Zinc Finger Protein Gli3