Wood Katherine A, Eadsforth Megan A, Newman William G, O'Keefe Raymond T
Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom.
Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
Front Genet. 2021 Jan 28;12:636620. doi: 10.3389/fgene.2021.636620. eCollection 2021.
Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes - variants in , , and are associated with retinitis pigmentosa (RP), while variants in and cause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (, , , , and ) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes - RP, craniofacial defects or cancer - is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders.
前体mRNA剪接由剪接体执行，剪接体是一种动态的大分子复合物，由五种富含尿苷的小核糖核蛋白复合物（U1、U2、U4、U5和U6 snRNP）和众多辅助剪接因子组成。大量人类疾病是由影响剪接因子功能和/或表达的基因变异引起的，包括核心snRNP蛋白。编码U5 snRNP蛋白的基因变异会导致两种不同的、组织特异性的人类疾病表型—— 、 和 基因的变异与色素性视网膜炎（RP）相关，而 和 基因的变异分别导致颅面疾病Guion-Almeida型下颌面骨发育不全（MFDGA）和Burn-McKeown综合征（BMKS）。此外，一些U5 snRNP蛋白（ 、 、 、 和 ）的复发性体细胞突变或表达水平变化与人类癌症有关。目前尚不清楚，在所有人类细胞中前体mRNA剪接所需的普遍表达的剪接体蛋白变异如何以及为何会导致组织限制性疾病表型。此外，构成同一核心剪接体snRNP的不同但相互作用的蛋白质变异为何会导致完全不同的疾病结果——RP、颅面缺陷或癌症，也尚不清楚。在这篇综述中，我们定义了不同U5 snRNP蛋白在RP、颅面疾病和癌症中的作用，包括疾病相关基因变异如何影响前体mRNA剪接以及提出的疾病机制。然后，我们提出了关于U5 snRNP变异如何导致组织特异性从而导致有限且独特的人类疾病的潜在假设。
