Increased unfolded protein responses caused by MED17 mutations
Increased unfolded protein responses caused by MED17 mutations
复制标题
MED17 突变引起的未折叠蛋白反应增加
DOI：
10.1007/s10048-021-00661-6
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发表时间：
2021
期刊：
影响因子：
2.2
通讯作者：
Hashimoto Satoru
中科院分区：
文献类型：
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作者：
Terabayashi Takeshi;Hashimoto Satoru
介体（MED）是蛋白质编码基因表达的关键调节因子，MED亚基的突变与多种疾病相关。由于MED 17突变导致常染色体隐性遗传疾病，包括小头畸形、智力残疾、癫痫和共济失调，这些疾病几乎没有报道，迄今为止只有3例病例报道，因此应阐明基因型-表型相关性。在这里，我们研究了MED 17突变对细胞反应的影响，发现来自MED 17突变日本患者的成纤维细胞的未折叠蛋白反应（UPR）增加。UPR基因CHOP和ATF 4的表达上调，eIF 2a的磷酸化水平在患者细胞中基础增加。基于我们的研究结果，我们认为MED 17突变引起的UPR增加可能有助于临床表型。
Mediator (MED) is a key regulator of protein-coding gene expression, and mutations in MED subunits are associated with a broad spectrum of diseases. Because mutations inMED17result in autosomal recessive disorders, including microcephaly, intellectual disability, epilepsy, and ataxia, which are barely reported, with only three case reports to date, genotype–phenotype association should be elucidated. Here, we investigated the impact ofMED17mutations on cellular responses and found increased unfolded protein responses (UPRs) in fibroblasts derived from Japanese patients withMED17mutations. The expression of the UPR genesCHOPandATF4was upregulated, and the phosphorylation of eIF2a was basally increased in patients’ cells. Based on our findings, we propose that increased UPRs caused byMED17mutations might contribute to the clinical phenotype.