Dystrophin gene splice-site cytosines (DMD splice-site C)

The Dystrophin (DMD) gene splice-site cytosines are specific nucleotide targets within the human genome utilized for therapeutic base editing (Yuan et al., 2018, PubMed: 30050077). These cytosines are located within or adjacent to the conserved splice donor (GT) or acceptor (AG) sequences of the DMD gene, which is the largest known human gene (NCBI Gene ID: 1756). Mutations in this gene often lead to Duchenne Muscular Dystrophy (DMD) by disrupting the reading frame and preventing the production of functional dystrophin protein (StatPearls, 2023). By targeting these specific cytosines with Cytosine Base Editors (CBEs), the C-to-T conversion can permanently disrupt the splicing signals of specific exons (Zhang et al., 2022, PubMed: 35110434). This disruption induces exon skipping, a process that bypasses mutated exons to restore the translational reading frame of the mRNA transcript (Nature Communications, 2018). The resulting truncated but partially functional dystrophin protein can significantly ameliorate the muscle-wasting phenotype seen in patients. Unlike antisense oligonucleotides, which require lifelong administration, targeting these genomic cytosines offers the potential for a durable, one-time treatment (Beam Therapeutics, 2024). Current research focuses on optimizing the delivery of these editors via viral vectors or lipid nanoparticles to muscle tissues. Safety monitoring for this target involves assessing off-target editing events across the genome and the long-term stability of the edited locus (UniProt: P11532). This approach represents a precision medicine strategy tailored to the specific genetic architecture of a patient's DMD mutation.

Other names

DMD splice donor cytosinesDMD splice acceptor cytosinesDystrophin gene splicing targetsDMD exon skipping base editing sites

Targeted deamination of cytosine to uracil (which becomes thymine after repair/replication) at splice donor or acceptor sites to disrupt canonical splicing and induce exon skipping, thereby restoring the open reading frame of the dystrophin gene (Yuan et al., 2018, PubMed: 30050077).