Roos Dirk, de Boer Martin
Sanquin Blood Supply Organization, Dept. of Blood Cell Research, Landsteiner Laboratory, Amsterdam University Medical Centre, location AMC, University of Amsterdam, Amsterdam, the Netherlands.
Sanquin Blood Supply Organization, Dept. of Blood Cell Research, Landsteiner Laboratory, Amsterdam University Medical Centre, location AMC, University of Amsterdam, Amsterdam, the Netherlands.
Biochim Biophys Acta Mol Basis Dis. 2021 Sep 1;1867(9):166166. doi: 10.1016/j.bbadis.2021.166166. Epub 2021 May 8.
Genetic mutations that cause hereditary diseases usually affect the composition of the transcribed mRNA and its encoded protein, leading to instability of the mRNA and/or the protein. Sometimes, however, such mutations affect the synthesis, the processing or the translation of the mRNA, with similar disastrous effects. We here present an overview of mRNA synthesis, its posttranscriptional modification and its translation into protein. We then indicate which elements in these processes are known to be affected by pathogenic mutations, but we restrict our review to mutations in cis, in the DNA of the gene that encodes the affected protein. These mutations can be in enhancer or promoter regions of the gene, which act as binding sites for transcription factors involved in pre-mRNA synthesis. We also describe mutations in polyadenylation sequences and in splice site regions, exonic and intronic, involved in intron removal. Finally, we include mutations in the Kozak sequence in mRNA, which is involved in protein synthesis. We provide examples of genetic diseases caused by mutations in these DNA regions and refer to databases to help identify these regions. The over-all knowledge of mRNA synthesis, processing and translation is essential for improvement of the diagnosis of patients with genetic diseases.
导致遗传性疾病的基因突变通常会影响转录的mRNA及其编码蛋白的组成，导致mRNA和/或蛋白的不稳定。然而，有时此类突变会影响mRNA的合成、加工或翻译，产生类似的灾难性后果。我们在此概述mRNA的合成、转录后修饰及其翻译成蛋白质的过程。然后指出已知这些过程中的哪些元件会受到致病突变的影响，但我们将综述限制在顺式突变，即在编码受影响蛋白质的基因的DNA中。这些突变可能存在于基因的增强子或启动子区域，它们作为参与前体mRNA合成的转录因子的结合位点。我们还描述了聚腺苷酸化序列以及外显子和内含子剪接位点区域的突变，这些区域参与内含子的去除。最后，我们纳入了mRNA中与蛋白质合成有关的科扎克序列中的突变。我们提供了由这些DNA区域突变引起的遗传疾病的实例，并参考数据库以帮助识别这些区域。对mRNA合成、加工和翻译的全面了解对于改善遗传病患者的诊断至关重要。
