Molecular signature of intellectual disability

August 26 2011

Although intellectual disability (ID) is not uncommon, affecting almost 3% of the general population, little is known about its causes. Teams led by Laurence Colleaux at Inserm’s Joint Research Unit for "Genetics and Epigenetics of Metabolical, Neurosensory and Development-related Diseases” (1) and Jean Marc Egly at the "Institute of Genetics and Molecular & Cellular Biology" (2) have now discovered a mutation in a gene involved in the transcription of DNA to messenger RNA (the first stage of a complex process resulting in protein synthesis). This mutation disrupts the expression of genes that are essential in terms of neuroplasticity: i.e. all the mechanisms the brain uses to modify the organisation of its neural networks in accordance with life experience. The study suggests that the anomaly of these “immediate early” genes is one of the “molecular signatures” of intellectual disability.

The results are published in Science on 26 August 2011.

Intellectual disability is defined as "lower than average general intellectual functioning, combined with significant limitations in adaptive behaviour”. "Non-syndromic” forms of intellectual disability are characterised by an isolated and non-progressive reduction in intellectual performance. The researchers focused on these forms of disability since the genes involved participate directly in the processes related to cognitive functions: memory, learning, behaviour, etc.

Figure 1: Role of Mediator complex in gene transcription

Figure 1: Role of Mediator complex in gene transcription

The research teams led by Laurence Colleaux and Jean Marc Egly have identified a mutation in the MED23 gene that is linked to isolated intellectual disability. MED23 encodes one of the subunits in a large multiprotein complex: the Mediator (MED, see Figure 1). This complex is known to play a role in a key stage of regulating gene expression: transcription. It enables gene-specific transcription factors to bind for interaction with RNA polymerase (the key enzyme in this stage.

During the study, the researchers demonstrated that the cells in patients suffering from intellectual disability showed an expression defect for some genes, including “immediate early” genes JUN and FOS. The latter are involved in the expression of a gene cascade related to various cellular functions, including those in the central nervous system. Their rapid and transient activation is a key stage in development and neuroplasticity.

Figure 2: In the case of the JUN gene, mutated MED23 protein no longer enables the binding required for transcription

Figure 2: In the case of the JUN gene, mutated MED23 protein no longer enables the binding required for transcription

The identified mutation leads to the synthesis of a modified MED23 protein, which is no longer able to interact correctly with the specific factors of the two genes in question. For example, in the case of the JUN gene, the binding required for transcription is defective further to a poor connection between mutated MED23 protein and TCF4 factor (in blue, see Figure 2).

"Studying patients with intellectual disabilities, who are carriers of mutations that modify other proteins involved in transcription, suggests that the expression anomaly in "immediate early" genes may be the "molecular signature" of this disorder," explained Laurence Colleaux. As such, these results provide a new argument substantiating the major role that gene expression anomalies play in research into the causes of intellectual disabilities.


Intellectual disability in figures
3% of the general public are affected.
Each year there are between 6,000 and 8,500 newborns with a mental disability.
Although 20% of intellectual disabilities can be attributed to environmental factors and 40% to known genetic causes, the causes remain unknown in almost fifty percent of cases.

(1) Unité 781 Inserm - Université Paris Descartes - Hôpital Necker-Enfants Malades - Fondation Imagine
(2) Unité 964 Inserm - CNRS - Université de Strasbourg

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"MED23 Mediator subunit links intellectual disability to dysregulation of immediate early gene expression"

Satoru Hashimoto,1* Sarah Boissel,2* Mohammed Zarhrate,2 Marlène Rio,2 Arnold Munnich,2 Jean-Marc Egly,1 Laurence Colleaux2

1) Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/Inserm-Université de Strasbourg, BP 163, 67404 Illkirch Cedex, C. U. Strasbourg, France.
2) Unité Inserm 781 and Département de Génétique, Fondation IMAGINE, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris 75015, France.
*These authors contributed equally to this work.

Science, 26 August 2011

Research contacts

Laurence Colleaux PhD
U781 "Génétique et épigénetique des maladies métaboliques, neurosensorielles et du développement" (Inserm-Université Paris Descartes-Hôpital Necker-Enfants Malades-Fondation Imagine)
+33 (0)1 44 49 51 52 / +33 (0)1 44 49 49 56

Jean-Marc Egly
Unité mixte "Institut de génétique et de biologie moléculaire et cellulaire" (Inserm - CNRS - Université de Strasbourg)
+33 (0)6 73 98 19 38

Press contact

Juliette Hardy
+33 (0)1 44 23 60 98

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