The dystrophin transcript is read by the ribosome in non-overlapping 3-base codons. A genomic deletion removes whole exons; if the total number of bases removed is not a multiple of 3, every codon downstream of the splice junction is shifted into the wrong frame, producing nonsense amino acids until a premature stop codon (PTC) is hit — the transcript is then degraded by nonsense-mediated decay and no dystrophin is made (Duchenne phenotype).
frame shift Δ = ( Σ bases removed ) mod 3
Δ = 0 → in frame → translation runs to the end
Δ = 1,2 → frameshift → premature stop, no protein
A splice-switching ASO (the eteplirsen/golodirsen class of phosphorodiamidate morpholino oligomers) hybridizes over exon 51's splicing signals, hiding it from the spliceosome so exon 51 is additionally excluded from the mature mRNA — without touching the DNA. If exon 51's own length brings the total removed length back to a multiple of 3, the reading frame downstream is restored: the ribosome now reads through the whole transcript and produces an internally shortened but largely functional dystrophin (the milder Becker-type phenotype), instead of none at all.
This only works for genotypes whose arithmetic actually resolves to Δ=0 after adding exon 51 — it is genotype-specific, which is why real ASO drugs are prescribed against a patient's exact deletion breakpoints (eteplirsen → exon 51, golodirsen/viltolarsen → exon 53, casimersen → exon 45). Try Δ49–50 here: adding exon 51 does not zero the shift, so this simulator correctly shows the skip failing to rescue that genotype.
ASO skipping efficiency(dose) = 1 / ( 1 + e^-((dose − EC50)/k) )
EC50 = 45% of max dose, k = 12 (illustrative dose–response sigmoid)
- Genotype buttons — set which dystrophin exons are genomically deleted in this patient.
- ASO dose — raises the fraction of transcripts in which exon 51 is successfully skipped.
- Translation speed — how fast the ribosome moves along the focus transcript.
- Resample population — redraws a fresh stochastic outcome for each transcript in the population strip below, using the current dose's skipping probability.
Exon lengths used here are representative values for the human dystrophin exon 43–55 hotspot region, chosen to reproduce the correct real reading-frame outcome for each genotype shown; the underlying frame-arithmetic and dose–response model are the same ones used to design and prescribe real splice-switching ASO drugs.