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

Content Provider	PubMed Central
Author	Zhou, Haiying Spaeth, Jason M. Kim, Nam Hee Xu, Xuan Friez, Michael J. Schwartz, Charles E. Boyer, Thomas G.
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.
Related Links	http://dx.doi.org/10.1073/pnas.1121120109
Ending Page	19768
Page Count	6
Starting Page	19763
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	48
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-11-27
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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