Davenport Mackenzie L, Swanson Maurice S
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, Gainesville, Florida 32610, USA.
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, Gainesville, Florida 32610, USA
RNA. 2025 Feb 19;31(3):349-358. doi: 10.1261/rna.080277.124.
As adaptors, catalysts, guides, messengers, scaffolds, and structural components, RNAs perform an impressive array of cellular regulatory functions often by recruiting RNA-binding proteins (RBPs) to form ribonucleoprotein complexes (RNPs). While this RNA-RBP interaction network allows precise RNP assembly and the subsequent structural dynamics required for normal functions, RNA motif mutations may trigger the formation of aberrant RNP structures that lead to cell dysfunction and disease. Here, we provide our perspective on one type of RNA motif mutation, RNA gain-of-function mutations associated with the abnormal expansion of short tandem repeats (STRs) that underlie multiple developmental and degenerative diseases. We first discuss our current understanding of normal polymorphic STR functions in RNA processing and localization followed by an assessment of the pathogenic roles of STR expansions in the neuromuscular disease myotonic dystrophy. We also highlight ongoing questions and controversies focused on STR-based insights into the regulation of nuclear RNA processing and export as well as the relevance of the RNA gain-of-function pathomechanism for other STR expansion disorders in both coding and noncoding genes.
作为衔接子、催化剂、引导物、信使、支架和结构成分，RNA常常通过招募RNA结合蛋白（RBP）形成核糖核蛋白复合物（RNP）来执行一系列令人印象深刻的细胞调节功能。虽然这种RNA-RBP相互作用网络允许精确的RNP组装以及正常功能所需的后续结构动态变化，但RNA基序突变可能会触发异常RNP结构的形成，从而导致细胞功能障碍和疾病。在此，我们就一种RNA基序突变发表观点，即与短串联重复序列（STR）异常扩增相关的RNA功能获得性突变，这些突变是多种发育性和退行性疾病的基础。我们首先讨论目前对RNA加工和定位中正常多态性STR功能的理解，随后评估STR扩增在神经肌肉疾病强直性肌营养不良中的致病作用。我们还强调了一些持续存在的问题和争议，这些问题聚焦于基于STR对核RNA加工和输出调控的见解，以及RNA功能获得性发病机制与编码和非编码基因中其他STR扩增疾病的相关性。
