Journal
SCIENCE
Volume 333, Issue 6046, Pages 1161-1163Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1206638
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Funding
- European Research Council [2009]
- French National Research Agency [ANR-08-GENOPAT-042, ANR-08-MNP-010]
- Association pour la Recherche sur le Cancer [SL220100601335]
- Centre National de la Recherche Scientifique
- INSERM
- Region Ile-de France
- Fondation pour la Recherche Medicale
- Fondation Jerome Lejeune
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MED23 is a subunit of the Mediator complex, a key regulator of protein-coding gene expression. Here, we report a missense mutation (p. R617Q) in MED23 that cosegregates with nonsyndromic autosomal recessive intellectual disability. This mutation specifically impaired the response of JUN and FOS immediate early genes (IEGs) to serum mitogens by altering the interaction between enhancer-bound transcription factors (TCF4 and ELK1, respectively) and Mediator. Transcriptional dysregulation of these genes was also observed in cells derived from patients presenting with other neurological disorders linked to mutations in other Mediator subunits or proteins interacting with MED. These findings highlight the crucial role of Mediator in brain development and functioning and suggest that altered IEG expression might be a common molecular hallmark of cognitive deficit.
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