MED23 Mutation Links Intellectual Disability to Dysregulation of Immediate Early Gene Expression
MED23 Mutation Links Intellectual Disability to Dysregulation of Immediate Early Gene Expression
复制标题
DOI：
10.1126/science.1206638
复制
发表时间：
2011-08-26
期刊：
影响因子：
56.9
通讯作者：
Colleaux, Laurence
中科院分区：
文献类型：
--
作者：
Hashimoto, Satoru;Boissel, Sarah;Colleaux, Laurence
MED23是介体复合物的亚基，介体复合物是蛋白质编码基因表达的关键调节因子。在这里，我们报告一个错义突变（p.R617Q）在MED23共分离与非综合征性常染色体隐性智力残疾。该突变通过改变增强子结合的转录因子（分别为TCF 4和ELK 1）和介体之间的相互作用，特异性地损害了JUN和FOS立即早期基因（IEG）对血清有丝分裂原的反应。这些基因的转录失调也观察到来自其他神经系统疾病的患者与其他中介子亚基或蛋白质突变与MED相互作用的细胞。这些研究结果突出了中介在大脑发育和功能的关键作用，并建议改变IEG的表达可能是一个共同的分子标志认知缺陷。
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.