Identification of Key Long Non-Coding RNAs (LncRNAs) Affecting Alternative Splicing and Gene Expression in the Frontal Cortex of Myotonic Dystrophy Type 1 Patients

Myotonic dystrophy type 1 (DM1) is a rare and complex genetic disorder characterized by the expansion of CTG repeats within the 3' untranslated region of the dystrophia myotonic protein kinase (DMPK) gene. With a prevalence of approximately 10 per 100,000 people worldwide, DM1 presents with severe neuromuscular symptoms, including early-onset ataxia, dysarthria, muscle weakness, and exercise intolerance. The multisystemic nature of DM1 underscores the importance of exploring its molecular underpinnings to develop targeted therapeutic strategies.

In this study, I investigated the role of long non-coding RNAs (lncRNAs) in DM1 pathophysiology. Once dismissed as "genomic junk," lncRNAs are now recognized as pivotal regulators of gene expression and alternative splicing, making them key candidates for understanding the mechanisms underlying DM1. My research identified NUTM2A-AS1 as a critical lncRNA influencing splicing patterns in DM1-affected brains. Notably, NUTM2A-AS1 exhibited non-coding repeat expansions, implicating it in DM1's development and progression. Other lncRNAs were also found to be prevalent in splicing mechanisms in DM1.

Further, I identified additional lncRNAs, such as those associated with KHDRBS3 and HDAC2, that significantly impact alternative splicing. These findings provide unique insights into the regulatory networks involved in DM1. My analysis of differential gene expression highlighted several lncRNAs and their corresponding genes or proteins, including MAP6, FOSL2, and HLA-DQB1, all of which contribute to the disorder's multifaceted pathology.

These discoveries advance our understanding of the molecular mechanisms underlying DM1, emphasizing the intricate interplay of lncRNAs, genes, and proteins. This research lays the groundwork for future studies aimed at developing targeted therapies to address the diverse manifestations of this debilitating disorder.