C. elegans Ciliopathy/IFT Pathway Project
Overview
Cilia are microtubule-based organelles essential for sensory perception and signaling. In C. elegans, 60 of 302 neurons are ciliated, making it an excellent model for studying ciliogenesis and ciliopathy mechanisms. The worm lacks motile cilia but has sensory cilia that are structurally and functionally conserved with vertebrate primary cilia.
Ciliopathies are human genetic disorders caused by defects in ciliary structure or function, including Bardet-Biedl syndrome (BBS), nephronophthisis (NPHP), Meckel syndrome (MKS), and polycystic kidney disease (PKD).
Model Species
Primary: Caenorhabditis elegans (worm)
- UniProt species code: CAEEL
- 60 ciliated sensory neurons
- Well-characterized IFT machinery
- Excellent genetic tractability for ciliopathy gene function
Core Pathway Architecture
1. Transcriptional Regulation
Master regulator of ciliary gene expression:
- daf-19 - RFX transcription factor (controls X-box containing ciliary genes)
2. Intraflagellar Transport (IFT) - Anterograde
Kinesin-2 motors and IFT-B complex:
- osm-3 - Kinesin-2 motor (homodimeric)
- klp-11 - Kinesin-2 motor (heterotrimeric with klp-20/kap-1)
- osm-5 - IFT88 ortholog (IFT-B complex)
- osm-6 - IFT52 ortholog
- che-2 - IFT80 ortholog
- che-13 - IFT57 ortholog
- dyf-1 - Required for osm-3 function
- dyf-3 - IFT54 ortholog
- dyf-6 - IFT46 ortholog
- dyf-11 - IFT54 ortholog
- dyf-13 - TTC26 ortholog
3. Intraflagellar Transport (IFT) - Retrograde
Dynein motor and IFT-A complex:
- che-3 - Cytoplasmic dynein heavy chain
- xbx-1 - Dynein light intermediate chain
- dyf-2 - IFT144/WDR19 ortholog (IFT-A)
- daf-10 - IFT122 ortholog (IFT-A)
- che-11 - IFT140 ortholog (IFT-A)
4. Transition Zone (MKS/NPHP Complexes)
Gatekeepers of ciliary compartment:
- mks-1 - MKS1 ortholog (B9 domain)
- mks-2 - TMEM216 ortholog
- mks-3 - TMEM67 ortholog
- mks-5 - RPGRIP1L ortholog
- mks-6 - CC2D2A ortholog
- mksr-1 - B9D1 ortholog
- mksr-2 - B9D2 ortholog
- nphp-1 - NPHP1 ortholog
- nphp-2 - Inversin ortholog
- nphp-4 - NPHP4 ortholog
5. BBSome Complex
Bardet-Biedl syndrome proteins:
- bbs-1 - BBS1 ortholog
- bbs-2 - BBS2 ortholog
- bbs-4 - BBS4 ortholog
- bbs-5 - BBS5 ortholog
- bbs-7 - BBS7 ortholog
- bbs-8 - BBS8/TTC8 ortholog
- bbs-9 - BBS9/PTHB1 ortholog
6. Polycystic Kidney Disease Genes
7. Ciliary Signaling/Function
- tax-2 - Cyclic nucleotide-gated channel alpha
- tax-4 - Cyclic nucleotide-gated channel beta
- odr-1 - Guanylyl cyclase
- pef-1 - PPEF phosphatase (2024 discovery)
Genes for Review (Priority Order)
Priority 1: Core IFT Machinery (~8 genes)
| Gene | UniProt | Human Ortholog | Disease |
|---|---|---|---|
| daf-19 | O16371 | RFX3 | Ciliopathy TF |
| osm-3 | P46873 | KIF17 | IFT motor |
| osm-5 | Q9XWS4 | IFT88 | NPHP/OFD |
| che-2 | Q20719 | IFT80 | Jeune/SRPS |
| che-3 | G5EGD7 | DYNC2H1 | SRPS |
| bbs-1 | Q9N5H8 | BBS1 | BBS |
| bbs-8 | Q9N3X5 | TTC8 | BBS |
| mks-3 | Q9XTR1 | TMEM67 | MKS/JBTS |
Priority 2: Transition Zone (~6 genes)
| Gene | UniProt | Human Ortholog | Disease |
|---|---|---|---|
| nphp-1 | Q18409 | NPHP1 | NPHP |
| nphp-4 | Q9XWG9 | NPHP4 | NPHP |
| mks-1 | Q9XTR3 | MKS1 | MKS |
| mks-5 | G5EBV8 | RPGRIP1L | MKS/JBTS |
| mks-6 | Q9U2F5 | CC2D2A | MKS/JBTS |
| mksr-2 | Q09620 | B9D2 | MKS |
Priority 3: Additional BBSome and PKD (~6 genes)
| Gene | UniProt | Human Ortholog | Disease |
|---|---|---|---|
| bbs-2 | Q86DC7 | BBS2 | BBS |
| bbs-5 | Q20259 | BBS5 | BBS |
| bbs-7 | Q9TZI0 | BBS7 | BBS |
| lov-1 | Q9GZL9 | PKD1 | ADPKD |
| pkd-2 | Q9BL14 | PKD2 | ADPKD |
| pef-1 | TBD | PPEF1/2 | Novel (2024) |
Key C. elegans Ciliopathy Phenotypes
- Dye-filling defects (Dyf) - Failure to uptake lipophilic dyes
- Osmotic avoidance defects (Osm) - Cannot avoid high osmolarity
- Chemotaxis defects (Che) - Impaired chemosensation
- Dauer formation defects (Daf) - Altered dauer entry/exit
- Male mating defects (Lov) - Location of vulva defects
Key References
- Inglis PN et al. (2007) Curr Biol - X-box ciliary gene identification
- Williams CL et al. (2011) Nat Genet - MKS/NPHP transition zone
- Blacque OE et al. (2004) Curr Biol - BBS genes in IFT
- Wei Q et al. (2012) J Cell Biol - NPHP-2 genetic interactions
- Scheidel N & Bharat T (2024) Sci Rep - PEF-1 ciliary localization
Project Status
- [x] Create gene folders and fetch UniProt/GOA data
- [x] Priority 1 genes review (8/8 COMPLETE)
- [x] Priority 2 genes review (6/6 COMPLETE)
- [x] Priority 3 genes review (6/6 COMPLETE)
- [x] Pathway summary and integration (COMPLETE)
Status Update - 2025-12-29
CILIOPATHY PROJECT COMPLETE ✅
All 20 C. elegans ciliopathy genes have been comprehensively reviewed and documented.
Deep Research Status: All 20 genes completed (100%)
- Priority 1 (daf-19, osm-3, osm-5, che-2, che-3, bbs-1, bbs-8, mks-3): ✅ COMPLETE
- Priority 2 (nphp-1, nphp-4, mks-1, mks-5, mks-6, mksr-2): ✅ COMPLETE
- Priority 3 (bbs-2, bbs-5, bbs-7, lov-1, pkd-2, pef-1): ✅ COMPLETE
Gene Review Summary
All 20 genes reviewed:
- Total annotations: 477
- Publication-ready (ACCEPT): 368 (77%)
- Changes recommended: 109 (23%)
Priority 1 (Core IFT Machinery - 8 genes):
- daf-19 ✅ (17 ann, 13 ACCEPT)
- osm-3 🟡 (47 ann, 38 ACCEPT, 9 changes)
- osm-5 🟡 (23 ann, 18 ACCEPT, 5 changes)
- che-2 🟡 (21 ann, 11 ACCEPT, 10 changes)
- che-3 🟡 (33 ann, 25 ACCEPT, 8 changes)
- bbs-1 🟡 (22 ann, 17 ACCEPT, 5 changes)
- bbs-8 🟡 (28 ann, 22 ACCEPT, 6 changes)
- mks-3 🔴 (10 ann, 6 ACCEPT, 4 changes)
Priority 2 (Transition Zone - 6 genes):
- nphp-1 🟡 (17 ann, 12 ACCEPT, 5 changes)
- nphp-4 🔴 (30 ann, 20 ACCEPT, 10 changes)
- mks-1 🔴 (6 ann, 2 ACCEPT, 4 changes)
- mks-5 🟡 (24 ann, 20 ACCEPT, 4 changes)
- mks-6 ✅ (11 ann, 11 ACCEPT)
- mksr-2 🔴 (17 ann, 9 ACCEPT, 8 changes)
Priority 3 (BBSome and PKD - 6 genes):
- bbs-2 🟡 (20 ann, 14 ACCEPT, 6 changes)
- bbs-5 🟡 (17 ann, 14 ACCEPT, 3 changes)
- bbs-7 🟡 (24 ann, 20 ACCEPT, 4 changes)
- lov-1 🟡 (30 ann, 25 ACCEPT, 5 changes)
- pkd-2 ✅ (60 ann, 60 ACCEPT)
- pef-1 🔴 (20 ann, 11 ACCEPT, 9 changes)
Deliverables
- CAEEL_CILIOPATHY_CURATION_RECOMMENDATIONS.md (NEW)
- Comprehensive curation recommendations for all 20 genes
- Summary table with annotation counts and change requirements
- Detailed sections for genes requiring modifications
- Overall statistics by priority level
-
Status: COMPLETE
-
CAEEL_CILIOPATHY-pathway.md (NEW)
- Comprehensive pathway integration document
- Functional organization of 20 genes into 7 pathway components
- Human disease relevance and ortholog information
- Conservation analysis and validation
- Open questions and suggested experiments
-
Status: COMPLETE
-
Gene Review YAML Files (20 COMPLETE)
- All existing_annotations reviewed with action recommendations
- Each gene includes core_functions and suggested_questions
- References and evidence code validation
- Status: All files in
/Users/cjm/repos/ai-gene-review/genes/worm/[GENE]/[GENE]-ai-review.yaml
Key Findings
Strengths:
- 77% of annotations are publication-ready
- Core IFT machinery (OSM-3, CHE-3) well-annotated
- PKD-2 has exceptionally thorough curation (60 ann, 100% ACCEPT)
- MKS-6 also publication-ready (100% ACCEPT)
- Strong phylogenetic evidence for most annotations
Areas for Improvement:
- Some transition zone genes need consolidation (NPHP-4, MKS-1, MKSR-2)
- A few genes need modifier specificity (OSM-3, CHE-2)
- PEF-1 annotations require more detailed functional evidence
- Minor inconsistencies in annotation granularity between genes
Next Steps
For Publication:
1. Implement recommended modifications for Priority 1 genes (9 changes)
2. Consolidate Priority 2 transition zone annotations (36 changes)
3. Review Priority 3 modifications (27 changes)
4. Run just validate-all and verify schema compliance
5. Create pull request with all ciliopathy gene reviews
For Curation Enhancement:
1. Add new annotations for genes with minimal coverage (MKSR-2: 17 ann, MKS-1: 6 ann)
2. Validate PEF-1 annotations against recent publications
3. Consider literature-based improvements to CHE-2 and NPHP-4 specificity
4. Add cross-references between related pathway components
Files Generated
Project Documentation:
- /Users/cjm/repos/ai-gene-review/projects/CAEEL_CILIOPATHY-pathway.md
- /Users/cjm/repos/ai-gene-review/CAEEL_CILIOPATHY_CURATION_RECOMMENDATIONS.md
Gene Review Files (20 total):
- Location: /Users/cjm/repos/ai-gene-review/genes/worm/[GENE]/[GENE]-ai-review.yaml
- All files in COMPLETE status with full annotation reviews
Timeline and Effort
- Data Acquisition: 20 genes × UniProt/GOA fetch
- Deep Research: Falcon provider for all 20 genes (in background)
- Review and Curation: All 20 genes systematically reviewed
- Documentation: Pathway summary and recommendations created
- Total: Comprehensive ciliopathy pathway analysis
Related Projects
Completed:
- CAEEL_SURVEILLANCE_IMMUNITY (18 genes, ✅ COMPLETE)
- CAEEL_MITOPHAGY (12 genes, ✅ COMPLETE)
- CAEEL_P_GRANULES (8 genes, ✅ COMPLETE)
- CAEEL_UPR_STRESS (11 genes, ✅ COMPLETE)
In Progress:
- CAEEL_CILIOPATHY (20 genes, ✅ REVIEW COMPLETE)
Pending:
- CAEEL_PROTEOSTASIS (18 genes, not started)