{"gene":"NPHP1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2019,"finding":"The N-terminal coiled-coil domain (NPHP1CC) of nephrocystin-1 folds into a monomeric left-handed antiparallel three-stranded coiled coil in solution, structurally similar to the BAG domain family, and is required for resistance to apoptotic stimuli in the context of the full-length protein.","method":"NMR structural determination, solution biophysics (monomeric state), functional anti-apoptosis assay with full-length protein","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure determination plus functional validation (anti-apoptotic assay) in a single study with orthogonal methods","pmids":["31345020"],"is_preprint":false},{"year":2023,"finding":"TMEM237 interacts with NPHP1 and strengthens the interaction between NPHP1 and Pyk2, triggering phosphorylation of Pyk2 and ERK1/2, thereby promoting hepatocellular carcinoma progression.","method":"Co-immunoprecipitation, IP-MS, luciferase reporter, ChIP, gain- and loss-of-function experiments in vitro and in vivo","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and IP-MS with functional readout, single lab, multiple orthogonal methods","pmids":["37041420"],"is_preprint":false},{"year":2025,"finding":"NPHP1 physically binds LATS1/2 (core Hippo pathway kinases), as demonstrated by co-immunoprecipitation in kidney organoids, and loss of NPHP1 activates the canonical Hippo pathway (elevated Kibra, p-MST1/2, p-LATS, p-YAP), leading to fibrosis.","method":"Co-immunoprecipitation in NPHP1-deficient iPSC-derived kidney organoids; siRNA knockdown epistasis; Hippo pathway inhibitor rescue","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, Co-IP plus epistasis rescue, single study","pmids":["40968381"],"is_preprint":false},{"year":2025,"finding":"In nphp1 knockout MDCK cells and mice, Kibra and canonical Hippo pathway components (p-MST1/2, p-LATS, p-YAP) are aberrantly upregulated, and Kibra knockdown suppresses Hippo activation, inhibiting renal cyst formation and fibrosis; Nphp1 re-expression reverses Hippo pathway activation in cells.","method":"CRISPR knockout cells and mice, siRNA knockdown epistasis, AAV9-mediated Kibra knockdown in vivo, pathway component phosphorylation assays, histology","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with KO and rescue in vitro and in vivo, single lab, multiple orthogonal methods","pmids":["39995111"],"is_preprint":false},{"year":2021,"finding":"NPHP1 is required at the ciliary transition zone to prevent infiltration of inner segment plasma membrane proteins (STX3, SNAP25, IMPG2) into the outer segment during photoreceptor outer segment development; this requirement diminishes after outer segment elongation is complete. Genetic interaction with Cep290 was demonstrated: reduced Cep290 gene dose in Nphp1 mutant mice causes continued retinal degeneration into adulthood.","method":"Gene-trap mouse model (Nphp1 hypomorph), immunofluorescence for protein localization, genetic epistasis (Nphp1 × Cep290 double mutant), RT-PCR for splicing analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence, genetic epistasis, single lab with multiple orthogonal methods","pmids":["33961633"],"is_preprint":false},{"year":2021,"finding":"Loss of NPHP1 in MDCK cells activates the TGF-β/Smad signaling pathway (increased Smad2, Smad3, p-Smad3, Smad4; nuclear translocation of Smad3; decreased Smad7) and induces epithelial-mesenchymal transition (decreased E-cadherin and β-catenin; increased α-SMA and FSP1); overexpression of Smad7 reverses these changes.","method":"Lentiviral shRNA knockdown and CRISPR/Cas9 knockout in MDCK cells, Western blotting, immunofluorescence for Smad3 localization, Smad7 overexpression rescue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD with defined molecular readouts plus rescue experiment, single lab, multiple orthogonal methods","pmids":["34689106"],"is_preprint":false},{"year":2021,"finding":"NPHP1 deletion in a patient kidney results in loss of cilia in renal tubular cells and defective INPP5E localization to the primary cilium, suggesting NPHP1 is required for ciliary phosphoinositide composition in renal tubular cells.","method":"Immunohistochemistry and electron microscopy on resected patient kidney tissue","journal":"Molecular genetics & genomic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient tissue analysis with IHC and EM, no experimental manipulation of NPHP1 directly","pmids":["33306870"],"is_preprint":false},{"year":2008,"finding":"Targeted disruption of Nphp1 in mice causes male infertility due to defects in spermatid elongation: spermatids detach from Sertoli cells and fail head and tail morphogenesis, demonstrating NPHP1 is required for differentiation of early elongating spermatids and maintenance of Sertoli-spermatid junctions.","method":"Homologous recombination knockout mouse, histology of seminiferous tubules, electron microscopy of sperm ultrastructure","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined cellular phenotype (spermatid detachment, morphogenesis failure) confirmed by EM, single lab","pmids":["18684731"],"is_preprint":false},{"year":2021,"finding":"A near-complete Nphp1 knockout mouse (exon 2-20 deletion) recapitulates renal cyst development, tubular basement membrane thickening, retinal degeneration, and abnormal spermatogenesis; AAV9-mediated re-expression of Nphp1 partially rescues both renal and retinal phenotypes, confirming loss-of-function causality.","method":"CRISPR/Cas9 knockout mouse, histology, AAV9 rescue experiment","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined phenotypes and in vivo gene rescue, single lab","pmids":["34415307"],"is_preprint":false},{"year":2005,"finding":"C. elegans NPHP-1 (ortholog of NPHP1) and NPHP-4 localize to ciliated sensory endings of dendrites and colocalize with PKD-2 in male-specific sensory cilia. Single mutants have intact cilia, but nphp-1; nphp-4 double mutants are response-defective in male sensory behaviors, indicating redundant roles in facilitating ciliary sensory signal transduction.","method":"GFP-tagged protein localization in C. elegans neurons, genetic analysis of single and double mutants, behavioral assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct GFP localization plus genetic epistasis (double mutant), single lab, two orthogonal methods","pmids":["15817158"],"is_preprint":false},{"year":2025,"finding":"Nephrocystin-1 dynamically translocates to the nucleus within 15 minutes of UVC light exposure in NPHP1 WT kidney organoids; NPHP1-depleted kidney organoids exhibit persistent inability to repair DNA lesions and increased senescence and fibrosis, establishing a direct role for nephrocystin-1 in the DNA damage response.","method":"CRISPR/Cas9 NPHP1 knockout iPSC-derived kidney organoids, subcellular fractionation/immunofluorescence time-course after UVC, DNA damage repair assays, senescence and fibrosis assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, novel finding not yet peer-reviewed; localization plus functional consequence but awaiting replication","pmids":["bio_10.1101_2025.06.09.658557"],"is_preprint":true},{"year":2025,"finding":"NPHP1-deficient human iPSC-derived neurons fail to adapt synaptic strength, intrinsic excitability, and ciliary morphology in response to prolonged activity suppression, and display dysregulated baseline network activity and blunted gene expression changes, establishing a role for NPHP1 in neuronal homeostatic plasticity.","method":"CRISPR/Cas9 NPHP1 knockout in human iPSC-derived neurons, electrophysiology, morphological analysis, transcriptomics","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, novel neuronal function, awaiting peer review","pmids":["bio_10.1101_2025.08.27.672341"],"is_preprint":true},{"year":2025,"finding":"In CEP290-null mouse photoreceptors, transition zone proteins AHI1 and NPHP1 are abnormally restricted to the proximal connecting cilium (rather than their normal distribution), while other transition zone proteins (NPHP8, CEP89) are unaffected, indicating that normal NPHP1 distribution within the transition zone depends on CEP290.","method":"Advanced microscopy (super-resolution/immunofluorescence) of CEP290 knockout mouse retina, comparison of multiple transition zone protein localizations","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, localization finding in a different gene's KO model, indirect evidence for NPHP1 spatial regulation","pmids":["bio_10.1101_2025.01.20.633784"],"is_preprint":true},{"year":2025,"finding":"In NPHP1-patient-derived kidney tubular cells, prostaglandin analogues rescue ciliogenesis defects; Eupatilin also partially rescues NPHP1-associated ciliogenesis defects, with transcriptomic analysis suggesting cell cycle inhibition as the mechanism.","method":"Phenotypic screening in patient-derived kidney tubular cells, transcriptomic analysis after Eupatilin treatment","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, cell-based ciliogenesis rescue assay, mechanistic inference from transcriptomics only","pmids":["bio_10.1101_2025.01.15.633139"],"is_preprint":true},{"year":2025,"finding":"In NPHP1-null kidney organoids and nphp1KO MDCK cells, ZONAB expression is increased specifically in renal cyst cells, along with its targets CCND1 and PCNA; ZONAB knockdown inhibits renal cyst formation and tubular dilation and decreases CCND1 and PCNA expression.","method":"CRISPR nphp1KO mice, ZONAB knockdown (siRNA/shRNA), Western blotting, histology (H&E, Masson staining)","journal":"Translational research : the journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with genetic epistasis (knockdown rescue of downstream target), single lab, multiple methods","pmids":["41354125"],"is_preprint":false},{"year":2024,"finding":"Loss of NPHP1 in hiPSC-derived kidney organoids leads to abnormalities in primary cilia and frequent renal cyst formation; transcriptome analysis reveals lower expression of genes related to primary cilia and higher expression of cell cycle genes; cyst formation is rescued by NPHP1 re-expression, linking aberrant proliferation to ciliary dysfunction caused by NPHP1 loss.","method":"Patient-derived and CRISPR-edited hiPSCs differentiated to kidney organoids, cyst formation assay with NPHP1 re-expression rescue, transcriptome analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC disease model with rescue experiment and transcriptomics, single lab, multiple orthogonal methods","pmids":["38989059"],"is_preprint":false},{"year":2025,"finding":"In NPHP1-deficient patient urine-derived renal epithelial cells, bulk RNA-seq reveals altered EGFR signalling, extracellular components, and adherens junctions; EGFR kinase inhibitor AG556 rescues ciliary length and morphology and reverses the disease transcriptional signature more effectively than alprostadil.","method":"Bulk RNA-seq on patient hURECs, AG556 and alprostadil treatment with ciliary morphology readout and transcriptional profiling","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — patient-derived cell assay, single lab, pharmacological rescue without direct manipulation of EGFR-NPHP1 interaction","pmids":["40776899"],"is_preprint":false}],"current_model":"Nephrocystin-1 (NPHP1) is a modular adaptor protein that localizes to the transition zone of primary cilia, where its N-terminal antiparallel coiled-coil domain mediates protein–protein interactions and anti-apoptotic function; it physically interacts with LATS1/2 and Pyk2 (via TMEM237), placing it upstream of Hippo and ERK signalling, and its loss activates TGF-β/Smad-driven EMT, aberrant Hippo/Kibra signalling leading to cyst formation and fibrosis, ZONAB-CCND1/PCNA-driven tubular proliferation, and impaired DNA damage repair with nuclear translocation of nephrocystin-1 after genotoxic stress; in photoreceptors NPHP1 prevents mis-trafficking of inner segment membrane proteins into the outer segment and its distribution within the connecting cilium requires CEP290, while in spermatogenesis it is essential for Sertoli-spermatid junction integrity and spermatid elongation."},"narrative":{"mechanistic_narrative":"NPHP1 (nephrocystin-1) is a modular ciliary adaptor protein that localizes to the transition zone of primary and sensory cilia, where it acts as a gatekeeper of ciliary membrane composition and a hub coupling ciliary integrity to growth- and stress-signalling pathways [PMID:33961633, PMID:15817158]. Its N-terminal coiled-coil folds into a monomeric antiparallel three-stranded coiled coil structurally akin to the BAG domain family and confers resistance to apoptotic stimuli in the full-length protein, providing a structural basis for its protein-interaction and pro-survival functions [PMID:31345020]. At the photoreceptor transition zone NPHP1 prevents inner-segment plasma-membrane proteins (STX3, SNAP25, IMPG2) from infiltrating the outer segment, a barrier function that genetically interacts with Cep290, whose dosage governs the severity of retinal degeneration and the normal distribution of NPHP1 within the connecting cilium [PMID:33961633]. Loss of NPHP1 disrupts ciliogenesis and ciliary phosphoinositide identity and unleashes a coordinated set of pro-cystic, pro-fibrotic programs: physical engagement of the Hippo kinases LATS1/2 normally restrains the pathway, and NPHP1 loss aberrantly activates Kibra-driven Hippo signalling (elevated p-MST1/2, p-LATS, p-YAP) to promote renal cyst formation and fibrosis, with Kibra knockdown reversing these phenotypes [PMID:40968381, PMID:39995111]. In parallel, NPHP1 deficiency activates TGF-β/Smad signalling and epithelial-mesenchymal transition [PMID:34689106] and elevates the transcription factor ZONAB and its proliferative targets CCND1 and PCNA, driving tubular proliferation and cyst expansion [PMID:41354125]. NPHP1 is also required in vivo for spermatid elongation and Sertoli-spermatid junction integrity, and a near-complete knockout mouse recapitulates renal cyst, retinal degeneration, and spermatogenesis defects that are partially rescued by Nphp1 re-expression, establishing loss-of-function causality across its multi-organ ciliopathy phenotype [PMID:18684731, PMID:34415307].","teleology":[{"year":2005,"claim":"Established that NPHP1 is a transition-zone/ciliary-base protein acting redundantly with NPHP4 in ciliary sensory signal transduction, framing it as a ciliary functional module rather than a structural ciliary requirement.","evidence":"GFP-tagged localization and single/double-mutant behavioral genetics in C. elegans sensory neurons","pmids":["15817158"],"confidence":"Medium","gaps":["Redundancy obscures NPHP1's specific molecular role","Did not identify the signal transduced or downstream effectors","Mammalian relevance inferred from orthology"]},{"year":2008,"claim":"Defined an unexpected non-renal requirement for NPHP1 in male fertility, showing its junction/adaptor function operates beyond cilia.","evidence":"Homologous-recombination Nphp1 knockout mouse with seminiferous tubule histology and sperm EM","pmids":["18684731"],"confidence":"Medium","gaps":["Molecular basis of Sertoli-spermatid junction defect not resolved","No interacting partners identified at the junction"]},{"year":2019,"claim":"Provided the first structural insight, showing the N-terminal coiled coil is a monomeric BAG-domain-like fold required for anti-apoptotic activity, rationalizing NPHP1 as a protein-interaction adaptor with a survival function.","evidence":"NMR structure determination, solution biophysics, and anti-apoptosis functional assay with full-length protein","pmids":["31345020"],"confidence":"High","gaps":["Binding partners of the coiled coil not mapped structurally","Mechanism linking the fold to apoptosis resistance unknown"]},{"year":2021,"claim":"Demonstrated NPHP1's transition-zone barrier function in photoreceptors and its genetic dependence on Cep290, explaining the retinal component of the ciliopathy.","evidence":"Nphp1 hypomorph gene-trap mouse, immunofluorescence for mislocalized membrane proteins, and Nphp1×Cep290 genetic epistasis","pmids":["33961633"],"confidence":"Medium","gaps":["Molecular mechanism of the membrane-protein gate not defined","How CEP290 controls NPHP1 distribution unresolved"]},{"year":2021,"claim":"Linked NPHP1 loss to two pro-fibrotic/pro-cystic transcriptional programs (TGF-β/Smad-driven EMT) and confirmed multi-organ loss-of-function causality with in vivo rescue.","evidence":"shRNA/CRISPR knockout MDCK cells with Smad7 rescue; near-complete knockout mouse with AAV9 re-expression rescue","pmids":["34689106","34415307"],"confidence":"Medium","gaps":["Direct molecular link between NPHP1 and TGF-β receptor/Smad machinery not established","Whether EMT is cilium-dependent unclear"]},{"year":2025,"claim":"Identified physical NPHP1-LATS1/2 binding and showed NPHP1 loss aberrantly activates Kibra-driven Hippo signalling to cause cyst and fibrosis, providing a direct signalling mechanism downstream of NPHP1 loss.","evidence":"Co-IP in iPSC kidney organoids and knockout cells/mice, siRNA epistasis, AAV9 Kibra knockdown rescue in vivo","pmids":["40968381","39995111"],"confidence":"Medium","gaps":["Reciprocal validation and structural basis of the NPHP1-LATS interaction limited","How ciliary NPHP1 normally restrains Kibra/Hippo at the molecular level unknown"]},{"year":2025,"claim":"Showed NPHP1 loss elevates ZONAB and its proliferative targets CCND1/PCNA in cyst cells, defining a proliferative axis whose suppression blocks cystogenesis.","evidence":"nphp1 knockout mice and MDCK cells with ZONAB knockdown rescue, Western blotting and histology","pmids":["41354125"],"confidence":"Medium","gaps":["Mechanism by which NPHP1 normally restrains ZONAB not defined","Relationship to Hippo and TGF-β axes not integrated"]},{"year":2025,"claim":"Extended NPHP1 function to a TMEM237-bridged Pyk2/ERK signalling axis in a cancer context, indicating NPHP1 can scaffold growth signalling beyond the kidney.","evidence":"Reciprocal Co-IP, IP-MS, reporter/ChIP, and gain/loss-of-function in hepatocellular carcinoma models in vitro and in vivo","pmids":["37041420"],"confidence":"Medium","gaps":["Relevance to renal/ciliary NPHP1 function unclear","Whether TMEM237-NPHP1-Pyk2 operates at the cilium not addressed"]},{"year":2025,"claim":"Used patient-derived and iPSC models to connect NPHP1 loss to ciliogenesis defects, aberrant cell-cycle/proliferation, EGFR signalling, and DNA damage response, and identified candidate pharmacological rescues.","evidence":"iPSC kidney organoids and patient urine-derived/tubular cells with transcriptomics and drug rescue (prostaglandins, Eupatilin, AG556); UVC time-course nuclear translocation assays (some preprint)","pmids":["38989059","33306870","40776899","bio_10.1101_2025.06.09.658557","bio_10.1101_2025.01.15.633139"],"confidence":"Low","gaps":["Nuclear DNA-damage role awaits peer review and independent replication","EGFR rescue is pharmacological without direct NPHP1-EGFR interaction evidence","Single-patient tissue findings (INPP5E mislocalization) not experimentally manipulated"]},{"year":null,"claim":"How a single transition-zone adaptor mechanistically integrates Hippo, TGF-β/Smad, ZONAB, EGFR, and DNA-damage responses, and whether these converge through ciliary signalling or independent scaffolding interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking NPHP1's structural fold to its multiple signalling outputs","Direct partners for most pathways unmapped","Whether nuclear and ciliary pools of NPHP1 are functionally distinct unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[4,9,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,5,1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,15]}],"complexes":["ciliary transition zone"],"partners":["LATS1","LATS2","TMEM237","PYK2","NPHP4","CEP290"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15259","full_name":"Nephrocystin-1","aliases":["Juvenile nephronophthisis 1 protein"],"length_aa":732,"mass_kda":83.3,"function":"Together with BCAR1 it may play a role in the control of epithelial cell polarity (By similarity). Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling (By similarity). May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development (By similarity). In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis (By similarity)","subcellular_location":"Cell junction; Cell junction, adherens junction; Cell projection, cilium; Cytoplasm, cytoskeleton, cilium axoneme; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/O15259/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPHP1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPHP1","total_profiled":1310},"omim":[{"mim_id":"619468","title":"NEPHRONOPHTHISIS-LIKE NEPHROPATHY 2; NPHPL2","url":"https://www.omim.org/entry/619468"},{"mim_id":"618460","title":"KHAN-KHAN-KATSANIS SYNDROME; 3KS","url":"https://www.omim.org/entry/618460"},{"mim_id":"617781","title":"RETINITIS PIGMENTOSA 80; RP80","url":"https://www.omim.org/entry/617781"},{"mim_id":"617310","title":"ANKYRIN REPEAT AND STERILE ALPHA MOTIF DOMAINS-CONTAINING PROTEIN 3; ANKS3","url":"https://www.omim.org/entry/617310"},{"mim_id":"617271","title":"NEPHRONOPHTHISIS 20; NPHP20","url":"https://www.omim.org/entry/617271"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":36.0},{"tissue":"skeletal muscle","ntpm":34.0}],"url":"https://www.proteinatlas.org/search/NPHP1"},"hgnc":{"alias_symbol":["JBTS4","SLSN1"],"prev_symbol":["NPH1"]},"alphafold":{"accession":"O15259","domains":[{"cath_id":"2.30.30.40","chopping":"155-210","consensus_level":"high","plddt":87.7127,"start":155,"end":210},{"cath_id":"2.60.40.150","chopping":"330-576","consensus_level":"medium","plddt":88.832,"start":330,"end":576},{"cath_id":"-","chopping":"605-732","consensus_level":"medium","plddt":85.1691,"start":605,"end":732},{"cath_id":"1.20.58","chopping":"10-102","consensus_level":"high","plddt":87.6598,"start":10,"end":102}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15259","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15259-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15259-F1-predicted_aligned_error_v6.png","plddt_mean":75.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPHP1","jax_strain_url":"https://www.jax.org/strain/search?query=NPHP1"},"sequence":{"accession":"O15259","fasta_url":"https://rest.uniprot.org/uniprotkb/O15259.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15259/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15259"}},"corpus_meta":[{"pmid":"10411952","id":"PMC_10411952","title":"LOV 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America","url":"https://pubmed.ncbi.nlm.nih.gov/10557359","citation_count":152,"is_preprint":false},{"pmid":"9861055","id":"PMC_9861055","title":"A phytochrome from the fern Adiantum with features of the putative photoreceptor NPH1.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9861055","citation_count":134,"is_preprint":false},{"pmid":"17409309","id":"PMC_17409309","title":"High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations.","date":"2007","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/17409309","citation_count":130,"is_preprint":false},{"pmid":"10712196","id":"PMC_10712196","title":"Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis.","date":"2000","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10712196","citation_count":98,"is_preprint":false},{"pmid":"29654215","id":"PMC_29654215","title":"NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD.","date":"2018","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/29654215","citation_count":85,"is_preprint":false},{"pmid":"24746959","id":"PMC_24746959","title":"Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24746959","citation_count":71,"is_preprint":false},{"pmid":"9856524","id":"PMC_9856524","title":"Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus.","date":"1998","source":"American journal of kidney diseases : the official journal of the National Kidney Foundation","url":"https://pubmed.ncbi.nlm.nih.gov/9856524","citation_count":69,"is_preprint":false},{"pmid":"18684731","id":"PMC_18684731","title":"Targeted disruption of Nphp1 causes male infertility due to defects in the later steps of sperm morphogenesis in mice.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18684731","citation_count":68,"is_preprint":false},{"pmid":"10839884","id":"PMC_10839884","title":"Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis.","date":"2000","source":"The Journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/10839884","citation_count":68,"is_preprint":false},{"pmid":"15817158","id":"PMC_15817158","title":"Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors.","date":"2005","source":"Experimental cell 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structural determination, solution biophysics (monomeric state), functional anti-apoptosis assay with full-length protein\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure determination plus functional validation (anti-apoptotic assay) in a single study with orthogonal methods\",\n      \"pmids\": [\"31345020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM237 interacts with NPHP1 and strengthens the interaction between NPHP1 and Pyk2, triggering phosphorylation of Pyk2 and ERK1/2, thereby promoting hepatocellular carcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation, IP-MS, luciferase reporter, ChIP, gain- and loss-of-function experiments in vitro and in vivo\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and IP-MS with functional readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37041420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPHP1 physically binds LATS1/2 (core Hippo pathway kinases), as demonstrated by co-immunoprecipitation in kidney organoids, and loss of NPHP1 activates the canonical Hippo pathway (elevated Kibra, p-MST1/2, p-LATS, p-YAP), leading to fibrosis.\",\n      \"method\": \"Co-immunoprecipitation in NPHP1-deficient iPSC-derived kidney organoids; siRNA knockdown epistasis; Hippo pathway inhibitor rescue\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, Co-IP plus epistasis rescue, single study\",\n      \"pmids\": [\"40968381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In nphp1 knockout MDCK cells and mice, Kibra and canonical Hippo pathway components (p-MST1/2, p-LATS, p-YAP) are aberrantly upregulated, and Kibra knockdown suppresses Hippo activation, inhibiting renal cyst formation and fibrosis; Nphp1 re-expression reverses Hippo pathway activation in cells.\",\n      \"method\": \"CRISPR knockout cells and mice, siRNA knockdown epistasis, AAV9-mediated Kibra knockdown in vivo, pathway component phosphorylation assays, histology\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with KO and rescue in vitro and in vivo, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39995111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPHP1 is required at the ciliary transition zone to prevent infiltration of inner segment plasma membrane proteins (STX3, SNAP25, IMPG2) into the outer segment during photoreceptor outer segment development; this requirement diminishes after outer segment elongation is complete. Genetic interaction with Cep290 was demonstrated: reduced Cep290 gene dose in Nphp1 mutant mice causes continued retinal degeneration into adulthood.\",\n      \"method\": \"Gene-trap mouse model (Nphp1 hypomorph), immunofluorescence for protein localization, genetic epistasis (Nphp1 × Cep290 double mutant), RT-PCR for splicing analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence, genetic epistasis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33961633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of NPHP1 in MDCK cells activates the TGF-β/Smad signaling pathway (increased Smad2, Smad3, p-Smad3, Smad4; nuclear translocation of Smad3; decreased Smad7) and induces epithelial-mesenchymal transition (decreased E-cadherin and β-catenin; increased α-SMA and FSP1); overexpression of Smad7 reverses these changes.\",\n      \"method\": \"Lentiviral shRNA knockdown and CRISPR/Cas9 knockout in MDCK cells, Western blotting, immunofluorescence for Smad3 localization, Smad7 overexpression rescue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD with defined molecular readouts plus rescue experiment, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34689106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPHP1 deletion in a patient kidney results in loss of cilia in renal tubular cells and defective INPP5E localization to the primary cilium, suggesting NPHP1 is required for ciliary phosphoinositide composition in renal tubular cells.\",\n      \"method\": \"Immunohistochemistry and electron microscopy on resected patient kidney tissue\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient tissue analysis with IHC and EM, no experimental manipulation of NPHP1 directly\",\n      \"pmids\": [\"33306870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Targeted disruption of Nphp1 in mice causes male infertility due to defects in spermatid elongation: spermatids detach from Sertoli cells and fail head and tail morphogenesis, demonstrating NPHP1 is required for differentiation of early elongating spermatids and maintenance of Sertoli-spermatid junctions.\",\n      \"method\": \"Homologous recombination knockout mouse, histology of seminiferous tubules, electron microscopy of sperm ultrastructure\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined cellular phenotype (spermatid detachment, morphogenesis failure) confirmed by EM, single lab\",\n      \"pmids\": [\"18684731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A near-complete Nphp1 knockout mouse (exon 2-20 deletion) recapitulates renal cyst development, tubular basement membrane thickening, retinal degeneration, and abnormal spermatogenesis; AAV9-mediated re-expression of Nphp1 partially rescues both renal and retinal phenotypes, confirming loss-of-function causality.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse, histology, AAV9 rescue experiment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined phenotypes and in vivo gene rescue, single lab\",\n      \"pmids\": [\"34415307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"C. elegans NPHP-1 (ortholog of NPHP1) and NPHP-4 localize to ciliated sensory endings of dendrites and colocalize with PKD-2 in male-specific sensory cilia. Single mutants have intact cilia, but nphp-1; nphp-4 double mutants are response-defective in male sensory behaviors, indicating redundant roles in facilitating ciliary sensory signal transduction.\",\n      \"method\": \"GFP-tagged protein localization in C. elegans neurons, genetic analysis of single and double mutants, behavioral assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct GFP localization plus genetic epistasis (double mutant), single lab, two orthogonal methods\",\n      \"pmids\": [\"15817158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nephrocystin-1 dynamically translocates to the nucleus within 15 minutes of UVC light exposure in NPHP1 WT kidney organoids; NPHP1-depleted kidney organoids exhibit persistent inability to repair DNA lesions and increased senescence and fibrosis, establishing a direct role for nephrocystin-1 in the DNA damage response.\",\n      \"method\": \"CRISPR/Cas9 NPHP1 knockout iPSC-derived kidney organoids, subcellular fractionation/immunofluorescence time-course after UVC, DNA damage repair assays, senescence and fibrosis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, novel finding not yet peer-reviewed; localization plus functional consequence but awaiting replication\",\n      \"pmids\": [\"bio_10.1101_2025.06.09.658557\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPHP1-deficient human iPSC-derived neurons fail to adapt synaptic strength, intrinsic excitability, and ciliary morphology in response to prolonged activity suppression, and display dysregulated baseline network activity and blunted gene expression changes, establishing a role for NPHP1 in neuronal homeostatic plasticity.\",\n      \"method\": \"CRISPR/Cas9 NPHP1 knockout in human iPSC-derived neurons, electrophysiology, morphological analysis, transcriptomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, novel neuronal function, awaiting peer review\",\n      \"pmids\": [\"bio_10.1101_2025.08.27.672341\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In CEP290-null mouse photoreceptors, transition zone proteins AHI1 and NPHP1 are abnormally restricted to the proximal connecting cilium (rather than their normal distribution), while other transition zone proteins (NPHP8, CEP89) are unaffected, indicating that normal NPHP1 distribution within the transition zone depends on CEP290.\",\n      \"method\": \"Advanced microscopy (super-resolution/immunofluorescence) of CEP290 knockout mouse retina, comparison of multiple transition zone protein localizations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, localization finding in a different gene's KO model, indirect evidence for NPHP1 spatial regulation\",\n      \"pmids\": [\"bio_10.1101_2025.01.20.633784\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In NPHP1-patient-derived kidney tubular cells, prostaglandin analogues rescue ciliogenesis defects; Eupatilin also partially rescues NPHP1-associated ciliogenesis defects, with transcriptomic analysis suggesting cell cycle inhibition as the mechanism.\",\n      \"method\": \"Phenotypic screening in patient-derived kidney tubular cells, transcriptomic analysis after Eupatilin treatment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, cell-based ciliogenesis rescue assay, mechanistic inference from transcriptomics only\",\n      \"pmids\": [\"bio_10.1101_2025.01.15.633139\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In NPHP1-null kidney organoids and nphp1KO MDCK cells, ZONAB expression is increased specifically in renal cyst cells, along with its targets CCND1 and PCNA; ZONAB knockdown inhibits renal cyst formation and tubular dilation and decreases CCND1 and PCNA expression.\",\n      \"method\": \"CRISPR nphp1KO mice, ZONAB knockdown (siRNA/shRNA), Western blotting, histology (H&E, Masson staining)\",\n      \"journal\": \"Translational research : the journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with genetic epistasis (knockdown rescue of downstream target), single lab, multiple methods\",\n      \"pmids\": [\"41354125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of NPHP1 in hiPSC-derived kidney organoids leads to abnormalities in primary cilia and frequent renal cyst formation; transcriptome analysis reveals lower expression of genes related to primary cilia and higher expression of cell cycle genes; cyst formation is rescued by NPHP1 re-expression, linking aberrant proliferation to ciliary dysfunction caused by NPHP1 loss.\",\n      \"method\": \"Patient-derived and CRISPR-edited hiPSCs differentiated to kidney organoids, cyst formation assay with NPHP1 re-expression rescue, transcriptome analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC disease model with rescue experiment and transcriptomics, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38989059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In NPHP1-deficient patient urine-derived renal epithelial cells, bulk RNA-seq reveals altered EGFR signalling, extracellular components, and adherens junctions; EGFR kinase inhibitor AG556 rescues ciliary length and morphology and reverses the disease transcriptional signature more effectively than alprostadil.\",\n      \"method\": \"Bulk RNA-seq on patient hURECs, AG556 and alprostadil treatment with ciliary morphology readout and transcriptional profiling\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — patient-derived cell assay, single lab, pharmacological rescue without direct manipulation of EGFR-NPHP1 interaction\",\n      \"pmids\": [\"40776899\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Nephrocystin-1 (NPHP1) is a modular adaptor protein that localizes to the transition zone of primary cilia, where its N-terminal antiparallel coiled-coil domain mediates protein–protein interactions and anti-apoptotic function; it physically interacts with LATS1/2 and Pyk2 (via TMEM237), placing it upstream of Hippo and ERK signalling, and its loss activates TGF-β/Smad-driven EMT, aberrant Hippo/Kibra signalling leading to cyst formation and fibrosis, ZONAB-CCND1/PCNA-driven tubular proliferation, and impaired DNA damage repair with nuclear translocation of nephrocystin-1 after genotoxic stress; in photoreceptors NPHP1 prevents mis-trafficking of inner segment membrane proteins into the outer segment and its distribution within the connecting cilium requires CEP290, while in spermatogenesis it is essential for Sertoli-spermatid junction integrity and spermatid elongation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPHP1 (nephrocystin-1) is a modular ciliary adaptor protein that localizes to the transition zone of primary and sensory cilia, where it acts as a gatekeeper of ciliary membrane composition and a hub coupling ciliary integrity to growth- and stress-signalling pathways [#4, #9]. Its N-terminal coiled-coil folds into a monomeric antiparallel three-stranded coiled coil structurally akin to the BAG domain family and confers resistance to apoptotic stimuli in the full-length protein, providing a structural basis for its protein-interaction and pro-survival functions [#0]. At the photoreceptor transition zone NPHP1 prevents inner-segment plasma-membrane proteins (STX3, SNAP25, IMPG2) from infiltrating the outer segment, a barrier function that genetically interacts with Cep290, whose dosage governs the severity of retinal degeneration and the normal distribution of NPHP1 within the connecting cilium [#4]. Loss of NPHP1 disrupts ciliogenesis and ciliary phosphoinositide identity and unleashes a coordinated set of pro-cystic, pro-fibrotic programs: physical engagement of the Hippo kinases LATS1/2 normally restrains the pathway, and NPHP1 loss aberrantly activates Kibra-driven Hippo signalling (elevated p-MST1/2, p-LATS, p-YAP) to promote renal cyst formation and fibrosis, with Kibra knockdown reversing these phenotypes [#2, #3]. In parallel, NPHP1 deficiency activates TGF-\\u03b2/Smad signalling and epithelial-mesenchymal transition [#5] and elevates the transcription factor ZONAB and its proliferative targets CCND1 and PCNA, driving tubular proliferation and cyst expansion [#14]. NPHP1 is also required in vivo for spermatid elongation and Sertoli-spermatid junction integrity, and a near-complete knockout mouse recapitulates renal cyst, retinal degeneration, and spermatogenesis defects that are partially rescued by Nphp1 re-expression, establishing loss-of-function causality across its multi-organ ciliopathy phenotype [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that NPHP1 is a transition-zone/ciliary-base protein acting redundantly with NPHP4 in ciliary sensory signal transduction, framing it as a ciliary functional module rather than a structural ciliary requirement.\",\n      \"evidence\": \"GFP-tagged localization and single/double-mutant behavioral genetics in C. elegans sensory neurons\",\n      \"pmids\": [\"15817158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy obscures NPHP1's specific molecular role\", \"Did not identify the signal transduced or downstream effectors\", \"Mammalian relevance inferred from orthology\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined an unexpected non-renal requirement for NPHP1 in male fertility, showing its junction/adaptor function operates beyond cilia.\",\n      \"evidence\": \"Homologous-recombination Nphp1 knockout mouse with seminiferous tubule histology and sperm EM\",\n      \"pmids\": [\"18684731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of Sertoli-spermatid junction defect not resolved\", \"No interacting partners identified at the junction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the first structural insight, showing the N-terminal coiled coil is a monomeric BAG-domain-like fold required for anti-apoptotic activity, rationalizing NPHP1 as a protein-interaction adaptor with a survival function.\",\n      \"evidence\": \"NMR structure determination, solution biophysics, and anti-apoptosis functional assay with full-length protein\",\n      \"pmids\": [\"31345020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partners of the coiled coil not mapped structurally\", \"Mechanism linking the fold to apoptosis resistance unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated NPHP1's transition-zone barrier function in photoreceptors and its genetic dependence on Cep290, explaining the retinal component of the ciliopathy.\",\n      \"evidence\": \"Nphp1 hypomorph gene-trap mouse, immunofluorescence for mislocalized membrane proteins, and Nphp1\\u00d7Cep290 genetic epistasis\",\n      \"pmids\": [\"33961633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of the membrane-protein gate not defined\", \"How CEP290 controls NPHP1 distribution unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked NPHP1 loss to two pro-fibrotic/pro-cystic transcriptional programs (TGF-\\u03b2/Smad-driven EMT) and confirmed multi-organ loss-of-function causality with in vivo rescue.\",\n      \"evidence\": \"shRNA/CRISPR knockout MDCK cells with Smad7 rescue; near-complete knockout mouse with AAV9 re-expression rescue\",\n      \"pmids\": [\"34689106\", \"34415307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between NPHP1 and TGF-\\u03b2 receptor/Smad machinery not established\", \"Whether EMT is cilium-dependent unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified physical NPHP1-LATS1/2 binding and showed NPHP1 loss aberrantly activates Kibra-driven Hippo signalling to cause cyst and fibrosis, providing a direct signalling mechanism downstream of NPHP1 loss.\",\n      \"evidence\": \"Co-IP in iPSC kidney organoids and knockout cells/mice, siRNA epistasis, AAV9 Kibra knockdown rescue in vivo\",\n      \"pmids\": [\"40968381\", \"39995111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation and structural basis of the NPHP1-LATS interaction limited\", \"How ciliary NPHP1 normally restrains Kibra/Hippo at the molecular level unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed NPHP1 loss elevates ZONAB and its proliferative targets CCND1/PCNA in cyst cells, defining a proliferative axis whose suppression blocks cystogenesis.\",\n      \"evidence\": \"nphp1 knockout mice and MDCK cells with ZONAB knockdown rescue, Western blotting and histology\",\n      \"pmids\": [\"41354125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NPHP1 normally restrains ZONAB not defined\", \"Relationship to Hippo and TGF-\\u03b2 axes not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NPHP1 function to a TMEM237-bridged Pyk2/ERK signalling axis in a cancer context, indicating NPHP1 can scaffold growth signalling beyond the kidney.\",\n      \"evidence\": \"Reciprocal Co-IP, IP-MS, reporter/ChIP, and gain/loss-of-function in hepatocellular carcinoma models in vitro and in vivo\",\n      \"pmids\": [\"37041420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance to renal/ciliary NPHP1 function unclear\", \"Whether TMEM237-NPHP1-Pyk2 operates at the cilium not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Used patient-derived and iPSC models to connect NPHP1 loss to ciliogenesis defects, aberrant cell-cycle/proliferation, EGFR signalling, and DNA damage response, and identified candidate pharmacological rescues.\",\n      \"evidence\": \"iPSC kidney organoids and patient urine-derived/tubular cells with transcriptomics and drug rescue (prostaglandins, Eupatilin, AG556); UVC time-course nuclear translocation assays (some preprint)\",\n      \"pmids\": [\"38989059\", \"33306870\", \"40776899\", \"bio_10.1101_2025.06.09.658557\", \"bio_10.1101_2025.01.15.633139\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Nuclear DNA-damage role awaits peer review and independent replication\", \"EGFR rescue is pharmacological without direct NPHP1-EGFR interaction evidence\", \"Single-patient tissue findings (INPP5E mislocalization) not experimentally manipulated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single transition-zone adaptor mechanistically integrates Hippo, TGF-\\u03b2/Smad, ZONAB, EGFR, and DNA-damage responses, and whether these converge through ciliary signalling or independent scaffolding interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking NPHP1's structural fold to its multiple signalling outputs\", \"Direct partners for most pathways unmapped\", \"Whether nuclear and ciliary pools of NPHP1 are functionally distinct unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [4, 9, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 5, 1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 15]}\n    ],\n    \"complexes\": [\"ciliary transition zone\"],\n    \"partners\": [\"LATS1\", \"LATS2\", \"TMEM237\", \"PYK2\", \"NPHP4\", \"CEP290\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}