Cystic fibrosis transmembrane conductance regulator pre-mRNA (3849+10kb C>T mutation) (CFTR pre-mRNA (3849+10kb C>T))

The Cystic fibrosis transmembrane conductance regulator (CFTR) pre-mRNA containing the 3849+10kb C>T mutation is a specific genetic target for antisense therapy in cystic fibrosis (Highsmith et al., 1994, PMID: 7514567). This mutation is located deep within intron 22 and creates a cryptic 5' splice site that the cellular splicing machinery mistakenly recognizes. Consequently, an 84-nucleotide pseudo-exon is included in the mature mRNA, which contains a premature stop codon (Kim et al., 2022, PMID: 36104124). This leads to the degradation of the mRNA via nonsense-mediated decay or the production of a truncated, non-functional protein, resulting in deficient chloride transport. Therapeutic agents like SPL84 are antisense oligonucleotides designed to bind specifically to this mutated sequence in the pre-mRNA (SpliSense, 2024). By sterically hindering the spliceosome's access to the cryptic site, these drugs promote correct splicing and the production of full-length, functional CFTR protein. This approach is highly specific to patients carrying this particular mutation, offering a precision medicine alternative to general CFTR modulators. Clinical evaluation of drugs targeting this pre-mRNA focuses on restoring lung function and normalizing sweat chloride levels.

Other names

c.3718-2477C>T3849+10kb C->TCFTR pseudo-exon mutationCFTR intron 22 cryptic splice site mutation

Antisense oligonucleotide-mediated splice modulation to block cryptic splice site recognition and prevent pseudo-exon inclusion.