ArticleProceedings of the National Academy of Sciences of the United States of America2012
MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 64 citations in OpenAlex.
- Pathogenicity of Mediator Complex Subunit 27 (MED27) in a Neurodevelopmental Disorder with Cerebellar Atrophy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- MED12 dysregulation: insights into cancer and therapeutic resistance.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Epigenetic regulation of MED12: a key contributor to the leukemic chromatin landscape and transcriptional dysregulation.Epigenetics & chromatin · 2025Article
- Subunits Med12 and Med13 of Mediator Cooperate with Subunits SAYP and Bap170 of SWI/SNF in Active Transcription inInternational journal of molecular sciences · 2024Article
- Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Article
- Natural compounds solasonine and alisol B23-acetate target GLI3 signaling to block oncogenesis in MED12-altered breast cancer.Molecular biology research communications · 2024Article
- Genetic alterations in MED12 promote castration-resistant prostate cancer through modulation of GLI3 signaling.Molecular biology research communications · 2023Article
- Multiprotein GLI Transcriptional Complexes as Therapeutic Targets in Cancer.Life (Basel, Switzerland) · 2022Review
- The role of mediator subunit 12 in tumorigenesis and cancer therapeutics.Oncology letters · 2022Review
- Transcription Pause and Escape in Neurodevelopmental Disorders.Frontiers in neuroscience · 2022Review
- GLI3 Is Stabilized by SPOP Mutations and Promotes Castration Resistance via Functional Cooperation with Androgen Receptor in Prostate Cancer.Molecular cancer research : MCR · 2022Article
- Identification and characterization of the mediator kinase-dependent myometrial stem cell phosphoproteome.F&S science · 2021Article
- Review
- The Mediator CDK8-Cyclin C complex modulates Dpp signaling in Drosophila by stimulating Mad-dependent transcription.PLoS genetics · 2020Article
- Article
- Mutations in Mediator Complex GenesMolecular syndromology · 2020Article
- De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.American journal of human genetics · 2019Article
- Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders.Molecular genetics & genomic medicine · 2019Article
- Review
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7 authors at 3 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.