Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders

Mol Genet Genomic Med. 2019 Apr;7(4):e00569. doi: 10.1002/mgg3.569. Epub 2019 Feb 6.


Background: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood.

Methods: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations.

Results: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain.

Conclusions: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.

Keywords: MED12; Mutation; SHH Signaling; XLID; qRT-PCR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism
  • Cells, Cultured
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / pathology
  • Cyclic AMP Response Element-Binding Protein A / genetics
  • Cyclic AMP Response Element-Binding Protein A / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Male
  • Mediator Complex / chemistry
  • Mediator Complex / genetics*
  • Mediator Complex / metabolism
  • Mental Retardation, X-Linked / genetics*
  • Mental Retardation, X-Linked / pathology
  • Middle Aged
  • Mutation, Missense*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pedigree
  • Protein Domains
  • Signal Transduction


  • BMP4 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Protein 4
  • CREB5 protein, human
  • Cyclic AMP Response Element-Binding Protein A
  • Hedgehog Proteins
  • MED12 protein, human
  • Mediator Complex
  • NEUROG2 protein, human
  • Nerve Tissue Proteins
  • SHH protein, human