Nat Commun:线粒体蛋白RNA聚合酶突变导致神经系统疾病

2021-02-19 haibai MedSci原创

最近,研究人员对来自7个无关家庭的8个个体的POLRMT变异的临床和分子性质进行了表征。患者在儿童期表现为整体发育迟缓、肌张力低下、身材矮小和语言/智力障碍。

线粒体疾病包括广泛的遗传性疾病,具有不同的临床特征和患者预后。这些疾病可以是散发性的,或者是由线粒体DNA(mtDNA)或线粒体功能和维护所需的约1200个核编码基因的遗传性致病变异导致的。

mtDNA的转录是由线粒体RNA聚合酶(POLRMT)和线粒体转录因子A(TFAM)和B2(TFB2M),介导的。虽然在线粒体DNA(mtDNA)聚合酶γ中已经发现了超过300个致病变异,但目前,没有线粒体表型与POLRMT(负责线粒体基因组转录的RNA聚合酶)相关。

最近,研究人员对来自7个无关家庭的8个个体的POLRMT变异的临床和分子性质进行了表征。患者在儿童期表现为整体发育迟缓、肌张力低下、身材矮小和语言/智力障碍;其中一名受试者表现出不稳定的进行性外眼角膜炎表型。

研究人员对所有受试者进行大规模平行测序,确定了POLRMT基因的隐性和显性变异。患者成纤维细胞有线粒体mRNA合成缺陷,但无mtDNA缺失或拷贝数异常

重组POLRMT突变体的体外特征揭示了对线粒体转录的可变但有害的影响。该研究对POLRMT变体的体内和体外功能研究共同确立了线粒体转录缺陷是一种重要的疾病机制。

 

 

原始出处:

Monika Oláhová et al. POLRMT mutations impair mitochondrial transcription causing neurological disease. Nature Communications (2021). 

 

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