USH2A Molecular Research InitiativeProject 01 · USH2A G1526R Molecular Mechanism

Patient-initiated · computationally characterized · experimentally unresolved

Research overview

Research Overview

Last scientific review: 2026-10-12.

This patient-initiated project investigates how the public USH2A variant c.4576G>A, p.Gly1526Arg (G1526R), might affect RNA processing and protein behavior. Its purpose is to turn reproducible computational observations into clearly defined laboratory questions. Supporting claims: C001sequence factC034scope

The work currently comprises reference-sequence verification, splice prediction, conditional RNA reconstruction and local protein modeling. This handoff adds no new molecular predictions or laboratory results. Supporting claims: C044scope

What the current evidence supports

Known from sequence and annotation: the nucleotide and amino-acid changes are verified, and the classical long and short isoforms have different terminal architectures. 1 2 Supporting claims: C001sequence factC002sequence factC004sequence factC006annotation

Computationally predicted: three models identify a concordant splice-site effect. AlphaGenome additionally predicts a cryptic donor–exon22 pair that can be used to reconstruct a 50-nt deletion in the long transcript. The RNA-splicing route is therefore a priority for testing, not an established predominant mechanism. 6 7 8 Supporting claims: C010predictionC011predictionC016conditionalC032unresolvedC036proposed

Not demonstrated: 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. Protein calculations do not establish native function. Supporting claims: C018conditionalC019unresolvedC029unresolved

The dominant pathogenic mechanism is unknown. RNA and protein effects could coexist, and isoform-specific functional contributions remain unresolved. Supporting claims: C020unresolvedC032unresolved

A verified variant branches into a predicted cryptic-splicing route and a conditional missense-protein route. Both lead to unresolved RNA amount, protein fate and mechanism, with RNA assays and an intron-free protein comparison proposed.
FIG-01 · Variant-to-mechanism overview. Verified G1526R sequence identity is separated from the predicted RNA route and the conditional normally spliced missense route. The proposed deletion-containing RNA, potential NMD and downstream protein effects remain conditional or unresolved. Arrows organize research questions; they do not establish a causal sequence or dominant mechanism.

Limitations: No experimentally observed deletion-containing RNA, demonstrated NMD or native functional result is shown.

Claims shown in this figure: C001C010C011C016C018C019C029C032C036C039 Evidence: USH2A-E001, USH2A-E005, USH2A-E006, USH2A-E007, USH2A-E012, USH2A-E013 References: REF-001, REF-008
Text description of the figure

Verified variant identity branches into predicted RNA processing and conditional missense-protein routes. A 50-nt deletion, frameshift and possible NMD are conditional; abundance, function and predominant mechanism are unresolved.

A verified variant branches into a predicted cryptic-splicing route and a conditional missense-protein route. Both lead to unresolved RNA amount, protein fate and mechanism, with RNA assays and an intron-free protein comparison proposed.

The diagram is wider than the screen: scroll it horizontally (drag, swipe, or arrow keys once focused) to read every panel.

FIG-01 · Variant-to-mechanism overview. Verified G1526R sequence identity is separated from the predicted RNA route and the conditional normally spliced missense route. The proposed deletion-containing RNA, potential NMD and downstream protein effects remain conditional or unresolved. Arrows organize research questions; they do not establish a causal sequence or dominant mechanism.

Limitations: No experimentally observed deletion-containing RNA, demonstrated NMD or native functional result is shown.

Why collaboration matters

Sequence-confirmed RNA measurements, followed by quantitative and isoform-aware analysis, can test whether the predicted junction is used. A matched intron-free protein comparison can separately test the amino-acid substitution. These complementary measurements address gaps that the present models cannot resolve. Supporting claims: C036proposedC037proposedC038proposedC039proposed

The project seeks laboratory expertise rather than presenting an established treatment program. No therapeutic efficacy has been established by this project. A proposed splicing-restoration approach is a research hypothesis, not an available treatment. Supporting claims: C033unresolvedC042scope

Explore the molecular evidence · Review the proposed experiments · Collaboration areas