RNA Gain-of-Function Mechanisms in Short Tandem Repeat Diseases

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 non-coding genes.