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

• Stretches of typical CAG (Gln) repeats, which were often correlated with genetic disorders, were found in KIAA0181 and KIAA0192 [14].
• We report the ability of SOX9 to interact with TRAP230, a component of the thyroid hormone receptor-associated protein (TRAP) complex [13].

References