Dystrophin pre-messenger RNA (DMD pre-mRNA) (DMD pre-mRNA)

Dystrophin pre-messenger RNA (DMD pre-mRNA) is the primary transcript of the DMD gene, which is the largest known gene in the human genome (National Institutes of Health). It serves as the essential precursor for mature mRNA, which encodes the dystrophin protein, a vital structural component that links the internal cytoskeleton of muscle fibers to the surrounding extracellular matrix (UniProt). Mutations in the DMD gene, most commonly large deletions that disrupt the open reading frame, lead to the absence of functional dystrophin and the subsequent development of Duchenne muscular dystrophy (DMD), a progressive and fatal muscle-wasting disease (PubMed). Therapeutic intervention targeting the DMD pre-mRNA involves the use of antisense oligonucleotides (ASOs) designed to induce 'exon skipping.' By binding to specific splice motifs, these drugs cause the cellular machinery to bypass mutated exons during splicing, thereby restoring the reading frame and allowing for the production of a truncated but partially functional dystrophin protein (Nature Reviews Drug Discovery). This approach effectively converts a severe Duchenne phenotype into a milder Becker-like phenotype (FDA).

Other names

DMD pre-mRNADystrophin precursor mRNADMD transcriptDystrophin RNA

Antisense oligonucleotides (ASOs) bind to specific exonic splicing enhancer (ESE) sequences within the dystrophin pre-mRNA via Watson-Crick base pairing. This binding sterically hinders the spliceosome machinery, resulting in the exclusion (skipping) of a specific exon from the mature mRNA transcript, which restores the translational reading frame in patients with specific deletions (PubMed, FDA).