🧪
hypothesis

C9orf72 Nucleocytoplasmic Transport Rescue for ALS/FTD

Hypothesis

C9orf72 Nucleocytoplasmic Transport Rescue for ALS/FTD

C9orf72 intronic GGGGCC repeats produce dipeptide repeat proteins and RNA foci that sequester nuclear import factors (TNPO1, RanGAP1), causing cytoplasmic TDP-43 accumulation and nuclear Ran-GTP depletion.
🧬 C9orf72🩺 neurodegeneration🎯 Composite 60%💱 $0.56▼6.4%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 4 support✗ 4 oppose
✓ All Quality Gates Passed
Mechanistic 0.52 (15%) Evidence 0.60 (15%) Novelty 0.70 (12%) Feasibility 0.45 (12%) Impact 0.62 (12%) Druggability 0.55 (10%) Safety 0.60 (8%) Competition 0.65 (6%) Data Avail. 0.70 (5%) Reproducible 0.58 (5%) KG Connect 0.50 (8%) 0.597 composite
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🧪 Overview

C9orf72 intronic GGGGCC repeats produce dipeptide repeat proteins and RNA foci that sequester nuclear import factors (TNPO1, RanGAP1), causing cytoplasmic TDP-43 accumulation and nuclear Ran-GTP depletion. Restoring nucleocytoplasmic transport may prevent neurodegeneration, though incomplete penetrance suggests additional modifiers required.

🧬 Mechanism

No curated mechanism pathway recorded for this hypothesis.

⚖️ Evidence

⚖️ Evidence Matrix4 supports4 contradicts
Supports
C9orf72 expansions cause ALS/FTD with TDP-43 pathology
PMID:21944778
Supports
DPR proteins localize to nuclear pores and disrupt nuclear import
PMID:26146186
Supports
RanGAP1 mislocalization demonstrated in C9-BAC transgenic mice
PMID:26699408
Supports
C9-BAC mice develop motor deficits and TDP-43 pathology
PMID:23393093
Contradicts
~50% of C9orf72 expansion carriers remain asymptomatic by age 80 (incomplete penetrance)
PMID:review
Contradicts
C9orf72 knockout mice develop splenomegaly and immune dysfunction, not neurodegeneration
PMID:27103069
Contradicts
RanGAP1 mislocalization occurs in sporadic ALS without C9orf72 mutation
PMID:28757421
Contradicts
TDP-43 pathology is common endpoint of ALS/FTD regardless of genetic cause
PMID:review
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — C9ORF72

No curated PDB or AlphaFold mapping for C9ORF72 yet. Search RCSB →

💉 Clinical Trials

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.

🔍 Search ClinVar for C9orf72 →

No DepMap CRISPR Chronos data found for C9orf72.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

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💾 Resource Usage

No resource usage or linked notebooks recorded for this hypothesis yet.

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