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Gene Review

MED12  -  mediator complex subunit 12

Homo sapiens

Synonyms: ARC240, Activator-recruited cofactor 240 kDa component, CAG repeat protein 45, CAGH45, FGS1, ...
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Disease relevance of MED12

  • These findings thus link MED12 to the modulation of Gli3-dependent Shh signaling and further implicate Mediator in a broad range of developmental and pathological processes driven by Shh signal transduction [1].
  • A recent study suggested that a dodecamer duplication in exon 42 of the HOPA gene in Xq13 may be a significant factor in the etiology of X-linked mental retardation [2].
  • We therefore examined the HOPA gene in a group of 111 probands from a larger cohort of multiplex families with schizophrenia, several of whom (n = 53) also had a family history of hypothyroidism [3].
  • We found that that HOPA polymorphisms were associated with increased risk for obesity (P <.001) [4].
  • Urinary organic acids in elderly Japanese patients with ketosis and encephalopathy who have taken panto-yl-gamma-aminobutyrate, calcium salt (calcium hopantenate, HOPA) [5].

Psychiatry related information on MED12

  • The gene encoding HOPA, which contains a rare polymorphism tightly associated with non-specific mental retardation, is 25 kb in length and consists of 44 exons [6].
  • HOPA variant subjects continued to show significant differences in depressive symptoms when controlling for gene-environment interaction [4].
  • The association of a HOPA polymorphism with major depression and phobia [4].

High impact information on MED12

  • We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex [7].
  • We propose that activated Gli3 physically targets the MED12 interface within Mediator in order to functionally reverse Mediator-dependent suppression of Shh target gene transcription [1].
  • Here, we identify and characterize a physical and functional interaction between Gli3 and the MED12 subunit within the RNA polymerase II transcriptional Mediator [1].
  • The Brg1 subunit of SWI/SNF and the TRAP230 subunit of TRAP/Mediator were shown to interact directly with RTA [8].
  • DPY-22 is a glutamine-rich protein that is most similar to human TRAP230, a component of a transcriptional mediator complex [9].

Biological context of MED12

  • These novel and specific phenotypes suggest that TRAP240 and TRAP230 act in concert to mediate an unknown developmental signal or a combination of signals [10].
  • Four males and two females were found with an alteration in exon 42 of the HOPA gene compared with 8/492 males and 18/471 females (942 X chromosomes) compared with consecutively screened newborns (chi(2) = 3.92, P < 0.05) [3].
  • HOPA is an Xq13 chromosome gene that codes for a RXR nuclear receptor co-activator [11].
  • There was suggestive evidence that the increased psychiatric morbidity in these subjects could represent epistasis, e.g., an interaction between the HOPA variant and a genetic diathesis for another psychiatric condition such as biologic parent antisocial behavior [4].

Anatomical context of MED12

  • The HOPA gene in Xq13 is coding for a protein involved in a nuclear thyroid receptor complex [12].
  • We have identified mutations in two genes, blind spot and kohtalo, that encode Drosophila homologues of human TRAP240 and TRAP230, components of a large transcriptional coactivation complex homologous to the yeast Mediator complex [10].

Physical interactions of MED12

  • Using co-transfection experiments, we have also shown that the TRAP230 interacting domain can act in a dominant-negative manner regarding SOX9 activity [13].

Other interactions of MED12


  1. Mediator modulates gli3-dependent sonic hedgehog signaling. Zhou, H., Kim, S., Ishii, S., Boyer, T.G. Mol. Cell. Biol. (2006) [Pubmed]
  2. Evidence that a dodecamer duplication in the gene HOPA in Xq13 is not associated with mental retardation. Friez, M.J., Essop, F.B., Krause, A., Castiglia, L., Ragusa, A., Sossey-Alaoui, K., Nelson, R.L., May, M.M., Michaelis, R.C., Srivastava, A.K., Schwartz, C.E., Stevenson, R.E., Goldman, A., Villard, L., Longshore, J.W. Hum. Genet. (2000) [Pubmed]
  3. Investigation of a candidate gene for schizophrenia on Xq13 previously associated with mental retardation and hypothyroidism. DeLisi, L.E., Smith, A.B., Razi, K., Stewart, J., Wang, Z., Sandhu, H.K., Philibert, R.A. Am. J. Med. Genet. (2000) [Pubmed]
  4. The association of a HOPA polymorphism with major depression and phobia. Philibert, R., Caspers, K., Langbehn, D., Troughton, E.P., Yucuis, R., Sandhu, H.K., Cadoret, R.J. Comprehensive psychiatry. (2002) [Pubmed]
  5. Urinary organic acids in elderly Japanese patients with ketosis and encephalopathy who have taken panto-yl-gamma-aminobutyrate, calcium salt (calcium hopantenate, HOPA). Nakanishi, T., Funahashi, S., Shimizu, A., Hayashi, A. Clin. Chim. Acta (1990) [Pubmed]
  6. The genomic structure and developmental expression patterns of the human OPA-containing gene (HOPA). Philibert, R.A., Winfield, S.L., Damschroder-Williams, P., Tengstrom, C., Martin, B.M., Ginns, E.I. Hum. Genet. (1999) [Pubmed]
  7. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Risheg, H., Graham, J.M., Clark, R.D., Rogers, R.C., Opitz, J.M., Moeschler, J.B., Peiffer, A.P., May, M., Joseph, S.M., Jones, J.R., Stevenson, R.E., Schwartz, C.E., Friez, M.J. Nat. Genet. (2007) [Pubmed]
  8. Principal role of TRAP/mediator and SWI/SNF complexes in Kaposi's sarcoma-associated herpesvirus RTA-mediated lytic reactivation. Gwack, Y., Baek, H.J., Nakamura, H., Lee, S.H., Meisterernst, M., Roeder, R.G., Jung, J.U. Mol. Cell. Biol. (2003) [Pubmed]
  9. A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in C. elegans. Moghal, N., Sternberg, P.W. Development (2003) [Pubmed]
  10. Drosophila homologues of the transcriptional coactivation complex subunits TRAP240 and TRAP230 are required for identical processes in eye-antennal disc development. Treisman, J. Development (2001) [Pubmed]
  11. Population-based association analyses of the HOPA12bp polymorphism for schizophrenia and hypothyroidism. Philibert, R.A., Sandhu, H.K., Hutton, A.M., Wang, Z., Arndt, S., Andreasen, N.C., Crowe, R., Wassink, T.H. Am. J. Med. Genet. (2001) [Pubmed]
  12. Association studies of the HOPA dodecamer duplication variant in different subtypes of autism. Beyer, K.S., Klauck, S.M., Benner, A., Poustka, F., Poustka, A. Am. J. Med. Genet. (2002) [Pubmed]
  13. SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex. Zhou, R., Bonneaud, N., Yuan, C.X., de Santa Barbara, P., Boizet, B., Schomber, T., Scherer, G., Roeder, R.G., Poulat, F., Berta, P., Tibor, S. Nucleic Acids Res. (2002) [Pubmed]
  14. Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. Nagase, T., Seki, N., Ishikawa, K., Tanaka, A., Nomura, N. DNA Res. (1996) [Pubmed]
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