Integrated hypotheses
Integrated Mechanistic Hypotheses
Last scientific review: 2026-10-12.
The dominant pathogenic mechanism is unknown. The following possibilities organize experimental questions; they are not mutually exclusive established causes. Supporting claims: C032unresolved
RNA-processing route. Enhanced cryptic-site use could generate abnormal transcripts. The proposed long-form product carrying the 50-nt deletion is a precise conditional reconstruction, with potential NMD-compatible geometry. Its existence, amount and decay have not been measured. Supporting claims: C010predictionC016conditionalC018conditionalC019unresolved
Protein route. Normally spliced RNA could encode full-length G1526R with an intrinsic folding, maturation or cellular effect. Local energy predictions provide limited leads, while structure and MD do not establish native dysfunction. Supporting claims: C026predictionC029unresolvedC031conditional
Combined route. Altered splicing and an independent missense effect could coexist. Their relative contributions cannot be inferred from the current model scores. Supporting claims: C032unresolved
Isoform-dependent route. Different terminal architectures could produce different consequences. The classical short transcript cannot be assigned the long-form exon-22 junction, and isoform-specific functional contributions remain unresolved. Supporting claims: C006annotationC020unresolved
Downstream protein fate. A translated product of the deletion-containing transcript would lack the long protein’s membrane and cytoplasmic regions. Whether that RNA survives, whether protein is made and how it is processed or localized are unanswered questions. No G1526-specific partner-binding defect is established. Supporting claims: C018conditionalC019unresolvedC030unresolvedC031conditional
Evidence Limitations
The predicted deletion-containing splice product has not been experimentally observed in this project. Actual abnormal RNA abundance is unknown. NMD has not been experimentally demonstrated. Supporting claims: C018conditionalC019unresolved
AlphaFold, Rosetta and MD do not establish native protein function. Model confidence, energy scores and short trajectories cannot be converted into a functional percentage, cellular protein amount or an individual clinical outcome. Supporting claims: C023predictionC025predictionC026predictionC029unresolvedC003annotation
The dominant pathogenic mechanism is unknown, and isoform-specific functional contributions remain unresolved. General published usherin experiments are not variant-specific validation. Supporting claims: C009published experimentC020unresolvedC032unresolved
No therapeutic efficacy has been established by this project. A proposed splicing-restoration approach is a research hypothesis, not an available treatment. Supporting claims: C033unresolved