Shelby Myeshia V
Department of Genetics and Human Genetics, Howard University Graduate School, Howard University, USA.
J Rare Dis Res Treat. 2017;2(6):31-40. Epub 2017 Dec 10.
Through a combination of in silico research and reviews of previous work, mechanisms by which nonsense-mediated mRNA decay (NMD) affects the inheritance and expressivity of Waardenburg syndrome is realized. While expressivity and inheritance both relate to biochemical processes underlying a gene's function, this research explores how alternative splicing and premature termination codons (PTC's) within mRNAs mutated in the disease are either translated into deleterious proteins or decayed to minimize expression of altered proteins. Elucidation of splice variants coupled with NMD perpetuating the various symptoms and inheritance patterns of this disease represent novel findings. By investigating nonsense mutations that lie within and outside the NMD boundary of these transcripts we can evaluate the effects of protein truncation versus minimized protein expression on the variable expressivity found between Type I and Type III Waardenburg syndrome, while comparatively evaluating and role in inheritance of Type IV subtypes of the disease. This review will demonstrate how alternative splicing perpetuates or limits NMD activity by way of PTC positioning, thereby affecting the presentation of Waardenburg syndrome.
通过计算机模拟研究与对先前工作的综述相结合，实现了无义介导的mRNA衰变（NMD）影响瓦登伯格综合征遗传和表达性的机制。虽然表达性和遗传性都与基因功能背后的生化过程相关，但本研究探索了疾病中发生突变的mRNA内的可变剪接和提前终止密码子（PTC）如何要么被翻译成有害蛋白质，要么衰变以尽量减少改变蛋白质的表达。阐明与NMD相关的剪接变体，这些变体使该疾病的各种症状和遗传模式持续存在，代表了新的发现。通过研究这些转录本NMD边界内外的无义突变，我们可以评估蛋白质截短与蛋白质表达最小化对I型和III型瓦登伯格综合征之间可变表达性的影响，同时比较评估该疾病IV型亚型在遗传中的作用。本综述将展示可变剪接如何通过PTC定位使NMD活性持续存在或受到限制，从而影响瓦登伯格综合征的表现。
