Retained intronic sequences contain cryptic nuclear retention elements that recruit export inhibitory complexes (PHAX, AlyREF, UAP56), sequestering the TREX complex on intron-retained transcripts. This depletes the available TREX pool for properly spliced GBA mRNA, causing nuclear accumulation and reduced cytoplasmic export. The model requires the aberrant transcripts to outcompete the far more abundant mature mRNA pool for limited export factors.
Curated pathway from expert analysis
flowchart TD
A["NXF1 TAP<br/>Nuclear Export"]
B["THOC4 AlyREF<br/>Adaptor"]
C["DDX39B UAP56<br/>Helicase"]
D["PHAX<br/>Regulatory Protein"]
E["mRNA Export<br/>Sequestration"]
F["Cytoplasmic<br/>Depletion"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#004d40,stroke:#80cbc4,color:#80cbc4
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NXF1 yet. Search RCSB →
Median TPM across 13 brain regions for NXF1 (TAP), THOC4 (AlyREF), DDX39B (UAP56); PHAX from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for NXF1 (TAP), THOC4 (AlyREF), DDX39B (UAP56); PHAX.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF siRNA-mediated knockdown of PHAX reduces the pool of nuclear export inhibitory complexes in fibroblasts derived from Gaucher disease patients with GBA intron retention, THEN cytoplasmic GBA mRNA le | Cytoplasmic GBA mRNA will increase >50% following PHAX depletion | — no observation — | pending | 0.65 |
| IF overexpression of THOC4 (AlyREF) increases the available TREX complex pool in fibroblasts showing high GBA intron retention, THEN nuclear accumulation of GBA mRNA will decrease by >40% and cytoplas | Nuclear GBA mRNA will decrease >40%; cytoplasmic/nuclear ratio will increase | — no observation — | pending | 0.58 |