SUMMARY Mediator occupies a central role in RNA polymerase II transcription as a sensor, integrator, and processor of regulatory signals that converge on protein-coding gene promoters. Compared to its role in gene activation, little is known regarding the molecular mechanisms and biological implications of Mediator as a transducer of repressive signals. Here, we describe a protein interaction network required for extra-neuronal gene silencing comprising Mediator, G9a histone methyltransferase, and the RE1 silencing transcription factor (REST; also known as neuron restrictive silencing factor, NRSF). We show that the MED12 interface in Mediator links REST with G9a-dependent histone H3K9 di-methylation to suppress neuronal genes in non-neuronal cells. Notably, missense mutations in MED12 causing the X-linked mental retardation (XLMR) disorders FG syndrome and Lujan syndrome disrupt its REST corepressor function. These findings implicate Mediator in epigenetic restriction of neuronal gene expression to the nervous system and suggest a pathologic basis for MED12-associated XLMR involving impaired REST-dependent neuronal gene regulation.

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. 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.

A novel missense mutation in the mediator of RNA polymerase II transcription subunit 12 (MED12) gene has been found in the original family with Lujan syndrome and in a second family (K9359) that was initially considered to have Opitz-Kaveggia (FG) syndrome. A different missense mutation in the MED12 gene has been reported previously in the original family with FG syndrome and in five other families with compatible clinical findings. Neither sequence alteration has been found in over 1400 control X chromosomes. Lujan (Lujan-Fryns) syndrome is characterised by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild-to-moderate mental retardation, behavioural aberrations and dysgenesis of the corpus callosum. Although Lujan syndrome has not been previously considered to be in the differential diagnosis of FG syndrome, there are some overlapping clinical manifestations. Specifically, these are dysgenesis of the corpus callosum, macrocephaly/relative macrocephaly, a tall forehead, hypotonia, mental retardation and behavioural disturbances. Thus, it seems that these two X-linked mental retardation syndromes are allelic, with mutations in the MED12 gene.

A Cambridge Structural Database (CSD) analysis on halogen···halogen contacts (X···X) in organic crystals has been carried out to review the classification criteria for type I, type II, and quasi type I/II halogen interactions. Trends observed in previous CSD analyses of the phenomenon are reinforced in the present study. The manner in which these interactions are manifested in cocrystals of 4-bromobenzamide and dicarboxylic acid is examined. The design strategy for these cocrystals uses synthon theory and follows from an understanding of the crystal structures of γ-hydroquinone and a previously studied set of 4-hydroxybenzamide dicarboxylic acid cocrystals, making use of Br/OH isostructurality. All cocrystals are obtained by clean insertion of dicarboxylic acids between 4-bromobenzamide molecules. The strategy is deliberate and the prediction of synthons done well in advance, as evidenced from the robustness of the acid–amide heterosynthons in all nine crystal structures, with no aberrant structures in the crystallization experiments. Formation of the acid–amide synthon in these cocrystals is identified with IR spectroscopy. The packing in these cocrystals can be distinguished in terms of whether the Br···Br interactions are type I or II. Eight sets of dimorphs were retrieved from the CSD, wherein the basis of the polymorphism is that one crystal has a type I Br···Br interaction, while the other has a type II interaction.

Structural information on the solid forms of efavirenz, a non-nucleoside reverse transcriptase inhibitor, is limited, although various polymorphic forms of this drug have been patented. We report here structural studies of four new crystal formsa pure form, a cyclohexane solvate, and cocrystals with 1,4-cyclohexanedione and 4,4′-bipyridine. Temperature dependent single-crystal to single-crystal phase transitions are observed for the pure form and for the cyclohexane solvate with an increase in the number of symmetry independent molecules, Z′, upon a lowering of temperature. Other issues related to these solid forms, such as thermal stability, conformational flexibility, and high Z′ occurrences, are addressed by using a combined experimental and computational approach.