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ID: h-fc7311c6be
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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Composite60%

🧪 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
Supports
DPR proteins localize to nuclear pores and disrupt nuclear import
Supports
RanGAP1 mislocalization demonstrated in C9-BAC transgenic mice
Supports
C9-BAC mice develop motor deficits and TDP-43 pathology
Contradicts
~50% of C9orf72 expansion carriers remain asymptomatic by age 80 (incomplete penetrance)
Contradicts
C9orf72 knockout mice develop splenomegaly and immune dysfunction, not neurodegeneration
Contradicts
RanGAP1 mislocalization occurs in sporadic ALS without C9orf72 mutation
Contradicts
TDP-43 pathology is common endpoint of ALS/FTD regardless of genetic cause
📖 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.

🏆 Tournament

🏆 Arenas / Elo

No arena matches recorded yet. Browse Arenas →

📊 Market Indicators

7d Trend
↔
Stable
7d Momentum
▼ 0.8%
Volatility
Low
0.0014
Events (7d)
3
Price History
▼6.4%

💾 Resource Usage

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

▸Metadataorigin_type: debate_synthesizer
origin_typedebate_synthesizer
target_geneC9orf72
_schema_version1
composite_score0.597
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting 0 contradicting 0 neutral
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