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

• DOI: 10.1073/pnas.1121120109
• Publication Date: 2012-10-23T05:55:32Z
• Authors: Haiying Zhou; Jason M. Spaeth; Nam Hee Kim; Xuan Xu; Michael J. Friez; Charles E. Schwartz; Thomas G. Boyer
• Keywords: GLI3; GLI2; Mediator; RNA polymerase II

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, behavioral defects humans FG (or Opitz-Kaveggia) Lujan syndromes. However, molecular mechanism(s) underlying these phenotypes is poorly understood. Here we report that R961W N1007S causing syndromes, respectively, disrupt a Mediator-imposed constraint on GLI3-dependent Sonic Hedgehog (SHH) signaling. We show FG/R961W Lujan/N1007S gene-specific association of second subunit, CDK8, identified herein to be suppressor GLI3 transactivation activity. In patient-derived cells, document enhanced SHH pathway activation GLI3-target gene induction coincident impaired recruitment CDK8 onto promoters genes, but not non–GLI3-target genes. Together, findings suggest dysregulated signaling contributes individuals syndromes further reveal basis for manifestation pathogenic global transcriptional coregulator.