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Discovery of a Molecular Signature of Intellectual Disability

Figure 1: Role of the Mediator complex in gene transcription
Figure 2: For the JUN gene, MED23 protein does not allow any more the assembly necessary for trasncription

Aug. 26, 2011

Intellectual disability of ID is defined as 'significantly impaired intellectual functions with substantial deficits in adaptive behavior'. Nearly 3% of the general population is afflicted by ID. While 20% of ID may be attributed to environmental factors and 40% to known genetic factors, the causes for the disease in nearly half the cases are still unknown. This why research conducted by Laurence Colleaux (Research Unit Genetics and Epigenetics of Metabolic, Neurosensory and Developmental Diseases, INSERM- Paris Descartes University- Necker Children's Hospital-Imagine Foundation) and Jean-Marc Egly (Joint Research Unit 'Institute of Genetics and Molecular and Cellular Biology, INSERM-CNRS-Strasbourg University) is so important. Their research findings have just been published in the August 26, 2011 issue of Science.

Nonsyndromic intellectual disabilities are characterized by an isolated, non progressive decrease of intellectual performance. So, the scientists took a closer look at these types of disabilities, as the genes to blame participate directly in the processes linked to cognitive functions (i.e. memorization, learning, behavior). They identified a mutation of gene MED23 linked to an isolated intellectual disability. MED23 codes for one of the subunits of a large multi-protein complex called Mediator (MED). The complex is known for the part it plays during a key stage of gene expression regulation called transcription. It enables special transcription factors of a gene to assemble and interact with RNA polymerase, a key enzyme during this stage.
The two research teams have proven that the cells of patients afflicted with an intellectual disability present a lack of expression of some genes, among which the 'early' JUN and FOS genes, which are involved in the expression of a cascade of genes linked to various cellular functions, specifically in the central nervous system. The rapid, temporary activation of the genes is a major stage in brain development and plasticity. The mutation identified by the scientists leads to the synthesis of a modified MED23 protein, which has become unable to interact properly with the specific factors of the two relevant genes. For instance, in the case of the JUN gene, the assembly enabling transcription is defective due to a poor contact between the mutated protein MED23 and the TCF4 factor.
According to Laurence Colleaux, the study of intellectually disabled patients with mutations that alter other proteins involved in transcription suggests that the anomaly of early gene expression may be a molecular signature of the disorder. The results published in Science provide another argument in favor of the major role of genetic expression anomalies in the search for the causes of intellectual disabilities.

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