MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling

Haiying Zhou, Jason M. Spaeth, Nam Hee Kim, An Xu, Michael J. Friez, Charles E. Schwartz, Thomas G. Boyer

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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 ofGLI3-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.

Original languageEnglish (US)
Pages (from-to)19763-19768
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number48
StatePublished - Nov 27 2012

ASJC Scopus subject areas

  • General


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