RNA gain-of-function mechanisms in short tandem repeat diseases

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• RNAs act as adaptors, catalysts, and scaffolds, regulating cellular functions by forming ribonucleoprotein complexes (RNPs) with RNA-binding proteins (RBPs).
• Mutations in RNA motifs can disrupt RNP assembly, leading to aberrant structures, cell dysfunction, and disease.
• Short tandem repeat (STR) expansions are a class of RNA motif mutations implicated in various developmental and degenerative diseases.

Purpose of the Study:

• To provide a perspective on RNA gain-of-function mutations driven by STR expansions.
• To discuss the normal functions of polymorphic STRs in RNA processing and localization.
• To assess the pathogenic roles of STR expansions in diseases like myotonic dystrophy and explore their relevance in other disorders.

Main Methods:

• Review and synthesis of current literature on RNA-RBP interactions, STRs, and associated diseases.
• Analysis of the RNA gain-of-function pathomechanism in the context of STR expansion disorders.
• Discussion of ongoing questions and controversies in the field.

Main Results:

• Normal polymorphic STRs play roles in RNA processing and localization.
• STR expansions can lead to pathogenic RNP structures and cellular dysfunction, as exemplified by myotonic dystrophy.
• The RNA gain-of-function mechanism is relevant for a broader range of STR expansion disorders.

Conclusions:

• STR expansions represent a significant class of mutations causing disease through altered RNP formation and function.
• Understanding STRs in RNA regulation offers insights into nuclear RNA processing, export, and the pathomechanisms of various genetic disorders.
• Further research is needed to fully elucidate the role of STRs in both normal physiology and disease pathogenesis.