{"gene":"IQCB1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2008,"finding":"NPHP5 (nephrocystin-5) physically interacts with NPHP6 (nephrocystin-6/CEP290); the N-terminal domain of nephrocystin-6 binds nephrocystin-5, with the interacting site mapped to amino acids 696–896 of NPHP6. Synergistic phenotypes from combined zebrafish knockdown and Xenopus rescue experiments establish a genetic interaction between the two proteins in vivo.","method":"Co-immunoprecipitation/pulldown domain mapping, zebrafish morpholino knockdown (synergistic phenotype), Xenopus rescue epistasis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal physical interaction mapped by domain deletion, validated by genetic epistasis in two model organisms","pmids":["18723859"],"is_preprint":false},{"year":2013,"finding":"NPHP5 is a centriolar/transition-zone protein required for an early step of ciliogenesis. Its interaction with Cep290 is necessary for ciliogenesis, while its interaction with calmodulin (CaM) prevents NPHP5 self-aggregation. Disease-causing truncating mutations abolish Cep290 binding and centrosomal localization, thereby blocking cilia formation.","method":"siRNA depletion, co-immunoprecipitation, immunofluorescence localization, disease-mutation functional analysis, pharmacological rescue of ciliogenesis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, KD phenotype, mutant rescue, drug rescue) in a single rigorous study","pmids":["23446637"],"is_preprint":false},{"year":2014,"finding":"NPHP5 contains two separate BBSome-binding sites and interacts with the BBSome to maintain its integrity; depletion of NPHP5 causes dissociation of BBS2 and BBS5 from the BBSome and loss of their ciliary localization. Cep290 (which directly binds NPHP5) additionally controls BBS8 integrity within the BBSome. Loss of individual BBSome subunits completely blocks delivery of ciliary cargos (smoothened, VPAC2, Rab8a), whereas NPHP5 or Cep290 loss selectively impairs cargo delivery.","method":"siRNA depletion, co-immunoprecipitation, immunofluorescence ciliary trafficking assays, cargo localization studies","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple cargo readouts, domain-deletion mutant confirming specific binding site, replicated across NPHP5 and Cep290 contexts","pmids":["25552655"],"is_preprint":false},{"year":2016,"finding":"Genetic knockout of NPHP5 in mice abolishes photoreceptor outer segment formation: Nphp5-/- photoreceptors have aberrant transition zones of reduced diameter and accumulate outer-segment transmembrane proteins in the ER. Basal bodies form but lack fully developed transition zones. NPHP5 is dispensable for ciliogenesis in mouse embryonic fibroblasts and kidney, indicating a photoreceptor-specific requirement.","method":"Germline knockout mouse, electroretinography, ultrastructural analysis (EM), immunofluorescence fractionation, EGFP-CETN2 transition-zone marker","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — clean genetic KO with ultrastructural and functional (ERG) readouts, multiple orthogonal methods","pmids":["27328943"],"is_preprint":false},{"year":2017,"finding":"NPHP5/IQCB1 undergoes cell-cycle-regulated ubiquitination: K63 ubiquitination by the E3 ligase BBS11/TRIM32 in G2/M causes NPHP5 delocalization from the centrosome and cilia loss, while K48/K63 ubiquitination by MARCH7/axotrophin (accumulated at centrosome upon USP9X loss) triggers NPHP5 degradation. The deubiquitinase USP9X is recruited to the centrosome by NPHP5 during G0/G1/S to protect NPHP5 from ubiquitination, thus promoting ciliogenesis.","method":"Co-immunoprecipitation (NPHP5–USP9X, NPHP5–BBS11, NPHP5–MARCH7), ubiquitination assays, siRNA depletion, cell-cycle synchronization, immunofluorescence","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple direct binding partners identified by Co-IP, ubiquitin linkage specificity determined, cell-cycle-dependent mechanism validated by synchronization and depletion experiments","pmids":["28498859"],"is_preprint":false},{"year":2019,"finding":"NPHP5 is a novel component of sub-distal appendages (SDAs) and basal feet (BF) of centrioles/basal bodies, and is specifically required for BF assembly during ciliogenesis. NPHP5 cooperates with a subset of SDA/BF proteins in a defined hierarchical assembly pathway; loss of NPHP5 simultaneously blocks BF assembly and primary ciliogenesis, and these phenotypes can be rescued by manipulating BF assembly pathway components.","method":"siRNA depletion, immunofluorescence co-localization, epistasis by expression rescue, structured-illumination microscopy","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — novel localization with functional consequence demonstrated by KD and rescue, single lab","pmids":["31177295"],"is_preprint":false},{"year":2020,"finding":"EPB41L5 forms a protein complex with IQCB1/NPHP5 and regulates its localization at the ciliary base; EPB41L5 overexpression reduces IQCB1 at the ciliary base while its knockdown increases IQCB1 there. EPB41L5 also decreases IQCB1 interaction with CEP290. Genetic synergy between epb41l5 and iqcb1 in zebrafish supports their functional interaction in controlling ciliary composition.","method":"Co-immunoprecipitation, immunofluorescence localization, zebrafish genetic interaction (epistasis), zebrafish morpholino knockdown","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus localization readout plus zebrafish genetic synergy, single lab","pmids":["32501287"],"is_preprint":false},{"year":2018,"finding":"CNNM4 physically interacts with IQCB1; a truncated CNNM4 protein (R605X) significantly increases the CNNM4–IQCB1 interaction and increases apoptosis, functionally linking the Jalili syndrome gene CNNM4 to IQCB1.","method":"Co-immunoprecipitation, apoptosis assay with truncation mutant","journal":"Molecular genetics and genomics","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with mutant, limited mechanistic follow-up, single lab","pmids":["29322253"],"is_preprint":false},{"year":2022,"finding":"In patient-derived iPSC-RPE and retinal organoids with IQCB1/NPHP5 mutations, CEP290 protein levels are reduced, providing a plausible mechanism for aberrant ciliary gating; patient cells show aberrantly elongated ciliary axonemes and impaired outer segment development with visual pigment mislocalization. AAV-mediated IQCB1 gene augmentation rescues these defects.","method":"iPSC differentiation (RPE, retinal organoids), immunofluorescence, Western blot (CEP290 levels), AAV rescue","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — human patient-derived cells with multiple readouts and genetic rescue, single lab","pmids":["36084637"],"is_preprint":false},{"year":2016,"finding":"In the canine NPHP5-LCA model, rod and cone photoreceptors form a sensory cilium but develop and function abnormally and rapidly degenerate; cone outer segments are absent, indicating ciliary dysfunction. Rod- and rod/cone-expressed genes are significantly downregulated while cone-specific genes are unchanged, and cell-death/survival pathway genes are downregulated.","method":"Canine loss-of-function model, ERG, histology, comparative gene expression profiling","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — large animal KO model with functional (ERG) and ultrastructural readouts plus transcriptomic mechanism","pmids":["27506978"],"is_preprint":false}],"current_model":"IQCB1/NPHP5 encodes nephrocystin-5, a transition-zone and sub-distal appendage/basal foot protein that promotes ciliogenesis by directly binding CEP290 (required for ciliary entry) and the BBSome (maintaining its integrity for selective ciliary cargo delivery); it undergoes cell-cycle-regulated K63/K48 ubiquitination by BBS11/TRIM32 and MARCH7 respectively, which is counteracted by the deubiquitinase USP9X to coordinate cilia assembly and disassembly with the cell cycle, and disease-causing truncating mutations abolish Cep290 binding and centrosomal localization, blocking outer segment formation in photoreceptors."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that IQCB1/NPHP5 physically and genetically interacts with CEP290/NPHP6 revealed the first direct molecular partnership at the ciliary transition zone for this gene, raising the question of what functional role this interaction serves.","evidence":"Co-immunoprecipitation with domain mapping plus synergistic zebrafish morpholino knockdown and Xenopus rescue","pmids":["18723859"],"confidence":"High","gaps":["Whether the interaction is required for ciliogenesis was not tested","Subcellular site of interaction not resolved"]},{"year":2013,"claim":"Demonstrating that IQCB1 localizes to centrioles/transition zone and that its CEP290 interaction is required for an early step of ciliogenesis established IQCB1 as a core ciliogenesis factor and explained why patient truncation mutations—which abolish CEP290 binding—cause ciliopathy.","evidence":"siRNA depletion, disease-mutation functional analysis, calmodulin-binding characterization, pharmacological rescue of ciliogenesis in cultured cells","pmids":["23446637"],"confidence":"High","gaps":["Precise step in ciliogenesis blocked by IQCB1 loss was undefined","Whether IQCB1 has functions beyond CEP290 binding was unknown"]},{"year":2014,"claim":"Showing that IQCB1 maintains BBSome integrity and selective ciliary cargo delivery through two distinct BBSome-binding sites expanded its role from a structural transition-zone component to a regulator of ciliary trafficking.","evidence":"siRNA depletion combined with co-immunoprecipitation and ciliary cargo localization assays for smoothened, VPAC2, and Rab8a","pmids":["25552655"],"confidence":"High","gaps":["How IQCB1 binding maintains BBS2/BBS5 within the BBSome structurally was not resolved","Whether IQCB1 acts as a gatekeeper versus an assembly factor for the BBSome was unclear"]},{"year":2016,"claim":"Genetic knockout studies in mice and a canine model demonstrated that IQCB1 is essential for photoreceptor outer segment formation and function, while being dispensable for ciliogenesis in fibroblasts and kidney, establishing photoreceptor-specific vulnerability and directly modeling Leber congenital amaurosis.","evidence":"Germline knockout mouse with ERG and EM analysis; canine loss-of-function model with ERG, histology, and transcriptomics","pmids":["27328943","27506978"],"confidence":"High","gaps":["Why photoreceptors are uniquely dependent on IQCB1 while other ciliated cells are not","Molecular basis of cone outer segment loss versus rod dysfunction unclear"]},{"year":2017,"claim":"Discovery that IQCB1 undergoes cell-cycle-regulated ubiquitination by BBS11/TRIM32 (K63, G2/M) and MARCH7 (K48/K63), counteracted by USP9X in G0/G1/S, revealed how cilia assembly and disassembly are coupled to cell-cycle progression through regulated IQCB1 stability.","evidence":"Co-immunoprecipitation of IQCB1 with USP9X, BBS11, and MARCH7; ubiquitin-linkage-specific assays; cell-cycle synchronization and siRNA depletion","pmids":["28498859"],"confidence":"High","gaps":["Specific ubiquitinated lysine residues on IQCB1 not mapped","Whether the same ubiquitin regulation operates in photoreceptors in vivo"]},{"year":2019,"claim":"Localization of IQCB1 to sub-distal appendages and basal feet, and demonstration that it is required for basal foot assembly, added a second structural role distinct from its transition-zone function.","evidence":"siRNA depletion with structured-illumination microscopy and epistasis rescue in cultured cells","pmids":["31177295"],"confidence":"Medium","gaps":["Finding from a single lab; independent confirmation of SDA/BF localization needed","Relationship between basal-foot assembly defect and BBSome/cargo trafficking phenotype unknown"]},{"year":2020,"claim":"Identification of EPB41L5 as a negative regulator of IQCB1 at the ciliary base—reducing its abundance and disrupting the IQCB1–CEP290 complex—provided the first upstream modulatory input controlling IQCB1 localization.","evidence":"Co-immunoprecipitation, immunofluorescence quantification, zebrafish genetic interaction","pmids":["32501287"],"confidence":"Medium","gaps":["Mechanism by which EPB41L5 removes IQCB1 from the ciliary base is unresolved","Whether EPB41L5 regulation is relevant in photoreceptors not tested"]},{"year":2022,"claim":"Patient iPSC-derived photoreceptors confirmed that IQCB1 mutations reduce CEP290 protein levels and cause aberrant ciliary elongation and visual pigment mislocalization, and AAV-mediated gene augmentation rescued these defects, validating a therapeutic strategy.","evidence":"iPSC-RPE and retinal organoids from patients, Western blot, immunofluorescence, AAV rescue","pmids":["36084637"],"confidence":"Medium","gaps":["Long-term efficacy and safety of AAV gene augmentation in vivo not established","Whether CEP290 reduction is the sole pathogenic mechanism in patient photoreceptors"]},{"year":null,"claim":"Key unresolved questions include why IQCB1 is essential in photoreceptors but dispensable in other ciliated cell types, what structural basis underlies its simultaneous roles at the transition zone and sub-distal appendages/basal feet, and how its ubiquitin-mediated regulation is coordinated in post-mitotic photoreceptors that lack canonical cell-cycle transitions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the IQCB1–CEP290 or IQCB1–BBSome complex","Photoreceptor-specific versus general ciliary function of IQCB1 not mechanistically explained","Ubiquitin regulation of IQCB1 not tested in post-mitotic neurons"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,3,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,4,5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,3,5]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[3,9,8]}],"complexes":[],"partners":["CEP290","USP9X","TRIM32","MARCH7","EPB41L5","BBS2","BBS5"],"other_free_text":[]},"mechanistic_narrative":"IQCB1 (nephrocystin-5/NPHP5) is a centriolar and ciliary transition-zone protein essential for ciliogenesis and photoreceptor outer segment formation. It directly binds CEP290 through its C-terminal region—an interaction required for ciliary gate assembly and selective cargo delivery—and maintains BBSome integrity by engaging BBS2 and BBS5 through two distinct binding sites, thereby controlling ciliary trafficking of transmembrane cargos such as smoothened and VPAC2 [PMID:18723859, PMID:23446637, PMID:25552655]. IQCB1 stability and centrosomal localization are controlled by cell-cycle-regulated ubiquitination: K63-linked ubiquitination by BBS11/TRIM32 in G2/M triggers its centrosomal delocalization and cilia disassembly, while the deubiquitinase USP9X protects IQCB1 during G0/G1/S to promote ciliogenesis [PMID:28498859]. Disease-causing truncating mutations abolish CEP290 binding and centrosomal targeting, and knockout in mice and dogs eliminates photoreceptor outer segments, establishing IQCB1 loss-of-function as a cause of Senior–Løken syndrome and Leber congenital amaurosis [PMID:27328943, PMID:27506978, PMID:36084637]."},"prefetch_data":{"uniprot":{"accession":"Q15051","full_name":"IQ calmodulin-binding motif-containing protein 1","aliases":["Nephrocystin-5","p53 and DNA damage-regulated IQ motif protein","PIQ"],"length_aa":598,"mass_kda":68.9,"function":"Involved in ciliogenesis. The function in an early step in cilia formation depends on its association with CEP290/NPHP6 (PubMed:21565611, PubMed:23446637). Involved in regulation of the BBSome complex integrity, specifically for presence of BBS2 and BBS5 in the complex, and in ciliary targeting of selected BBSome cargos. May play a role in controlling entry of the BBSome complex to cilia possibly implicating CEP290/NPHP6 (PubMed:25552655)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q15051/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IQCB1","classification":"Not Classified","n_dependent_lines":31,"n_total_lines":1208,"dependency_fraction":0.02566225165562914},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IQCB1","total_profiled":1310},"omim":[{"mim_id":"610142","title":"CENTROSOMAL PROTEIN, 290-KD; CEP290","url":"https://www.omim.org/entry/610142"},{"mim_id":"609254","title":"SENIOR-LOKEN SYNDROME 5; SLSN5","url":"https://www.omim.org/entry/609254"},{"mim_id":"609237","title":"IQ MOTIF-CONTAINING PROTEIN B1; IQCB1","url":"https://www.omim.org/entry/609237"},{"mim_id":"606844","title":"ALMS1 CENTROSOME AND BASAL BODY ASSOCIATED PROTEIN; ALMS1","url":"https://www.omim.org/entry/606844"},{"mim_id":"600053","title":"CYCLIC NUCLEOTIDE-GATED CHANNEL, ALPHA-3; CNGA3","url":"https://www.omim.org/entry/600053"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Microtubules","reliability":"Uncertain"},{"location":"Cytokinetic bridge","reliability":"Uncertain"},{"location":"Mitotic spindle","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IQCB1"},"hgnc":{"alias_symbol":["KIAA0036","NPHP5","SLSN5"],"prev_symbol":[]},"alphafold":{"accession":"Q15051","domains":[{"cath_id":"1.25.10.10","chopping":"9-286","consensus_level":"medium","plddt":85.0168,"start":9,"end":286}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15051","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15051-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15051-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IQCB1","jax_strain_url":"https://www.jax.org/strain/search?query=IQCB1"},"sequence":{"accession":"Q15051","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15051.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15051/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15051"}},"corpus_meta":[{"pmid":"21245082","id":"PMC_21245082","title":"Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21245082","citation_count":102,"is_preprint":false},{"pmid":"20881296","id":"PMC_20881296","title":"IQCB1 mutations in patients with leber congenital amaurosis.","date":"2011","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/20881296","citation_count":95,"is_preprint":false},{"pmid":"25552655","id":"PMC_25552655","title":"Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25552655","citation_count":75,"is_preprint":false},{"pmid":"18723859","id":"PMC_18723859","title":"Genetic and physical interaction between the NPHP5 and NPHP6 gene products.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18723859","citation_count":67,"is_preprint":false},{"pmid":"23446637","id":"PMC_23446637","title":"Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23446637","citation_count":60,"is_preprint":false},{"pmid":"21220633","id":"PMC_21220633","title":"Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior-Loken syndrome.","date":"2011","source":"Archives of ophthalmology (Chicago, Ill. : 1960)","url":"https://pubmed.ncbi.nlm.nih.gov/21220633","citation_count":55,"is_preprint":false},{"pmid":"21901789","id":"PMC_21901789","title":"Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21901789","citation_count":53,"is_preprint":false},{"pmid":"27506978","id":"PMC_27506978","title":"Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27506978","citation_count":40,"is_preprint":false},{"pmid":"24045995","id":"PMC_24045995","title":"IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds.","date":"2013","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/24045995","citation_count":39,"is_preprint":false},{"pmid":"28498859","id":"PMC_28498859","title":"USP9X counteracts differential ubiquitination of NPHP5 by MARCH7 and BBS11 to regulate ciliogenesis.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28498859","citation_count":35,"is_preprint":false},{"pmid":"27328943","id":"PMC_27328943","title":"Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation.","date":"2016","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/27328943","citation_count":34,"is_preprint":false},{"pmid":"33781914","id":"PMC_33781914","title":"Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33781914","citation_count":29,"is_preprint":false},{"pmid":"36084637","id":"PMC_36084637","title":"In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells.","date":"2022","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36084637","citation_count":26,"is_preprint":false},{"pmid":"28322220","id":"PMC_28322220","title":"Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes).","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28322220","citation_count":19,"is_preprint":false},{"pmid":"29322253","id":"PMC_29322253","title":"Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1.","date":"2018","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/29322253","citation_count":15,"is_preprint":false},{"pmid":"32088401","id":"PMC_32088401","title":"Transient pupillary light reflex in CEP290- or NPHP5-associated Leber congenital amaurosis: Latency as a potential outcome measure of cone 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CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/31177295","citation_count":8,"is_preprint":false},{"pmid":"25984213","id":"PMC_25984213","title":"Senior-Loken syndrome secondary to NPHP5/IQCB1 mutation in an Iranian family.","date":"2011","source":"NDT plus","url":"https://pubmed.ncbi.nlm.nih.gov/25984213","citation_count":5,"is_preprint":false},{"pmid":"38522724","id":"PMC_38522724","title":"IQCB1 (NPHP5)-Retinopathy: Clinical and Genetic Characterization and Natural History.","date":"2024","source":"American journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/38522724","citation_count":4,"is_preprint":false},{"pmid":"32501287","id":"PMC_32501287","title":"Epb41l5 interacts with Iqcb1 and regulates ciliary function in zebrafish embryos.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/32501287","citation_count":3,"is_preprint":false},{"pmid":"40263280","id":"PMC_40263280","title":"Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome.","date":"2025","source":"NPJ genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40263280","citation_count":1,"is_preprint":false},{"pmid":"41316455","id":"PMC_41316455","title":"Senior-Løken syndrome with IQCB1/NPHP5 mutation in an adult: a case report.","date":"2025","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/41316455","citation_count":0,"is_preprint":false},{"pmid":"40331022","id":"PMC_40331022","title":"A Novel NPHP5 Gene Mutation in Three Siblings With Nephronophthisis Without Retinitis Pigmentosa: A Case Report.","date":"2025","source":"Case reports in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40331022","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.15.633139","title":"Evaluation of Prostaglandin Receptor Agonists and Eupatilin in the Context of Nephronophthisis","date":"2025-01-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.15.633139","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14158,"output_tokens":2739,"usd":0.041779},"stage2":{"model":"claude-opus-4-6","input_tokens":6063,"output_tokens":2477,"usd":0.13836},"total_usd":0.180139,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"NPHP5 (nephrocystin-5) physically interacts with NPHP6 (nephrocystin-6/CEP290); the N-terminal domain of nephrocystin-6 binds nephrocystin-5, with the interacting site mapped to amino acids 696–896 of NPHP6. Synergistic phenotypes from combined zebrafish knockdown and Xenopus rescue experiments establish a genetic interaction between the two proteins in vivo.\",\n      \"method\": \"Co-immunoprecipitation/pulldown domain mapping, zebrafish morpholino knockdown (synergistic phenotype), Xenopus rescue epistasis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal physical interaction mapped by domain deletion, validated by genetic epistasis in two model organisms\",\n      \"pmids\": [\"18723859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NPHP5 is a centriolar/transition-zone protein required for an early step of ciliogenesis. Its interaction with Cep290 is necessary for ciliogenesis, while its interaction with calmodulin (CaM) prevents NPHP5 self-aggregation. Disease-causing truncating mutations abolish Cep290 binding and centrosomal localization, thereby blocking cilia formation.\",\n      \"method\": \"siRNA depletion, co-immunoprecipitation, immunofluorescence localization, disease-mutation functional analysis, pharmacological rescue of ciliogenesis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, KD phenotype, mutant rescue, drug rescue) in a single rigorous study\",\n      \"pmids\": [\"23446637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NPHP5 contains two separate BBSome-binding sites and interacts with the BBSome to maintain its integrity; depletion of NPHP5 causes dissociation of BBS2 and BBS5 from the BBSome and loss of their ciliary localization. Cep290 (which directly binds NPHP5) additionally controls BBS8 integrity within the BBSome. Loss of individual BBSome subunits completely blocks delivery of ciliary cargos (smoothened, VPAC2, Rab8a), whereas NPHP5 or Cep290 loss selectively impairs cargo delivery.\",\n      \"method\": \"siRNA depletion, co-immunoprecipitation, immunofluorescence ciliary trafficking assays, cargo localization studies\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple cargo readouts, domain-deletion mutant confirming specific binding site, replicated across NPHP5 and Cep290 contexts\",\n      \"pmids\": [\"25552655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic knockout of NPHP5 in mice abolishes photoreceptor outer segment formation: Nphp5-/- photoreceptors have aberrant transition zones of reduced diameter and accumulate outer-segment transmembrane proteins in the ER. Basal bodies form but lack fully developed transition zones. NPHP5 is dispensable for ciliogenesis in mouse embryonic fibroblasts and kidney, indicating a photoreceptor-specific requirement.\",\n      \"method\": \"Germline knockout mouse, electroretinography, ultrastructural analysis (EM), immunofluorescence fractionation, EGFP-CETN2 transition-zone marker\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean genetic KO with ultrastructural and functional (ERG) readouts, multiple orthogonal methods\",\n      \"pmids\": [\"27328943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NPHP5/IQCB1 undergoes cell-cycle-regulated ubiquitination: K63 ubiquitination by the E3 ligase BBS11/TRIM32 in G2/M causes NPHP5 delocalization from the centrosome and cilia loss, while K48/K63 ubiquitination by MARCH7/axotrophin (accumulated at centrosome upon USP9X loss) triggers NPHP5 degradation. The deubiquitinase USP9X is recruited to the centrosome by NPHP5 during G0/G1/S to protect NPHP5 from ubiquitination, thus promoting ciliogenesis.\",\n      \"method\": \"Co-immunoprecipitation (NPHP5–USP9X, NPHP5–BBS11, NPHP5–MARCH7), ubiquitination assays, siRNA depletion, cell-cycle synchronization, immunofluorescence\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple direct binding partners identified by Co-IP, ubiquitin linkage specificity determined, cell-cycle-dependent mechanism validated by synchronization and depletion experiments\",\n      \"pmids\": [\"28498859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPHP5 is a novel component of sub-distal appendages (SDAs) and basal feet (BF) of centrioles/basal bodies, and is specifically required for BF assembly during ciliogenesis. NPHP5 cooperates with a subset of SDA/BF proteins in a defined hierarchical assembly pathway; loss of NPHP5 simultaneously blocks BF assembly and primary ciliogenesis, and these phenotypes can be rescued by manipulating BF assembly pathway components.\",\n      \"method\": \"siRNA depletion, immunofluorescence co-localization, epistasis by expression rescue, structured-illumination microscopy\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — novel localization with functional consequence demonstrated by KD and rescue, single lab\",\n      \"pmids\": [\"31177295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EPB41L5 forms a protein complex with IQCB1/NPHP5 and regulates its localization at the ciliary base; EPB41L5 overexpression reduces IQCB1 at the ciliary base while its knockdown increases IQCB1 there. EPB41L5 also decreases IQCB1 interaction with CEP290. Genetic synergy between epb41l5 and iqcb1 in zebrafish supports their functional interaction in controlling ciliary composition.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, zebrafish genetic interaction (epistasis), zebrafish morpholino knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus localization readout plus zebrafish genetic synergy, single lab\",\n      \"pmids\": [\"32501287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CNNM4 physically interacts with IQCB1; a truncated CNNM4 protein (R605X) significantly increases the CNNM4–IQCB1 interaction and increases apoptosis, functionally linking the Jalili syndrome gene CNNM4 to IQCB1.\",\n      \"method\": \"Co-immunoprecipitation, apoptosis assay with truncation mutant\",\n      \"journal\": \"Molecular genetics and genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with mutant, limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"29322253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In patient-derived iPSC-RPE and retinal organoids with IQCB1/NPHP5 mutations, CEP290 protein levels are reduced, providing a plausible mechanism for aberrant ciliary gating; patient cells show aberrantly elongated ciliary axonemes and impaired outer segment development with visual pigment mislocalization. AAV-mediated IQCB1 gene augmentation rescues these defects.\",\n      \"method\": \"iPSC differentiation (RPE, retinal organoids), immunofluorescence, Western blot (CEP290 levels), AAV rescue\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human patient-derived cells with multiple readouts and genetic rescue, single lab\",\n      \"pmids\": [\"36084637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In the canine NPHP5-LCA model, rod and cone photoreceptors form a sensory cilium but develop and function abnormally and rapidly degenerate; cone outer segments are absent, indicating ciliary dysfunction. Rod- and rod/cone-expressed genes are significantly downregulated while cone-specific genes are unchanged, and cell-death/survival pathway genes are downregulated.\",\n      \"method\": \"Canine loss-of-function model, ERG, histology, comparative gene expression profiling\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large animal KO model with functional (ERG) and ultrastructural readouts plus transcriptomic mechanism\",\n      \"pmids\": [\"27506978\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IQCB1/NPHP5 encodes nephrocystin-5, a transition-zone and sub-distal appendage/basal foot protein that promotes ciliogenesis by directly binding CEP290 (required for ciliary entry) and the BBSome (maintaining its integrity for selective ciliary cargo delivery); it undergoes cell-cycle-regulated K63/K48 ubiquitination by BBS11/TRIM32 and MARCH7 respectively, which is counteracted by the deubiquitinase USP9X to coordinate cilia assembly and disassembly with the cell cycle, and disease-causing truncating mutations abolish Cep290 binding and centrosomal localization, blocking outer segment formation in photoreceptors.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IQCB1 (nephrocystin-5/NPHP5) is a centriolar and ciliary transition-zone protein essential for ciliogenesis and photoreceptor outer segment formation. It directly binds CEP290 through its C-terminal region—an interaction required for ciliary gate assembly and selective cargo delivery—and maintains BBSome integrity by engaging BBS2 and BBS5 through two distinct binding sites, thereby controlling ciliary trafficking of transmembrane cargos such as smoothened and VPAC2 [PMID:18723859, PMID:23446637, PMID:25552655]. IQCB1 stability and centrosomal localization are controlled by cell-cycle-regulated ubiquitination: K63-linked ubiquitination by BBS11/TRIM32 in G2/M triggers its centrosomal delocalization and cilia disassembly, while the deubiquitinase USP9X protects IQCB1 during G0/G1/S to promote ciliogenesis [PMID:28498859]. Disease-causing truncating mutations abolish CEP290 binding and centrosomal targeting, and knockout in mice and dogs eliminates photoreceptor outer segments, establishing IQCB1 loss-of-function as a cause of Senior–Løken syndrome and Leber congenital amaurosis [PMID:27328943, PMID:27506978, PMID:36084637].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that IQCB1/NPHP5 physically and genetically interacts with CEP290/NPHP6 revealed the first direct molecular partnership at the ciliary transition zone for this gene, raising the question of what functional role this interaction serves.\",\n      \"evidence\": \"Co-immunoprecipitation with domain mapping plus synergistic zebrafish morpholino knockdown and Xenopus rescue\",\n      \"pmids\": [\"18723859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the interaction is required for ciliogenesis was not tested\",\n        \"Subcellular site of interaction not resolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that IQCB1 localizes to centrioles/transition zone and that its CEP290 interaction is required for an early step of ciliogenesis established IQCB1 as a core ciliogenesis factor and explained why patient truncation mutations—which abolish CEP290 binding—cause ciliopathy.\",\n      \"evidence\": \"siRNA depletion, disease-mutation functional analysis, calmodulin-binding characterization, pharmacological rescue of ciliogenesis in cultured cells\",\n      \"pmids\": [\"23446637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise step in ciliogenesis blocked by IQCB1 loss was undefined\",\n        \"Whether IQCB1 has functions beyond CEP290 binding was unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that IQCB1 maintains BBSome integrity and selective ciliary cargo delivery through two distinct BBSome-binding sites expanded its role from a structural transition-zone component to a regulator of ciliary trafficking.\",\n      \"evidence\": \"siRNA depletion combined with co-immunoprecipitation and ciliary cargo localization assays for smoothened, VPAC2, and Rab8a\",\n      \"pmids\": [\"25552655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How IQCB1 binding maintains BBS2/BBS5 within the BBSome structurally was not resolved\",\n        \"Whether IQCB1 acts as a gatekeeper versus an assembly factor for the BBSome was unclear\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic knockout studies in mice and a canine model demonstrated that IQCB1 is essential for photoreceptor outer segment formation and function, while being dispensable for ciliogenesis in fibroblasts and kidney, establishing photoreceptor-specific vulnerability and directly modeling Leber congenital amaurosis.\",\n      \"evidence\": \"Germline knockout mouse with ERG and EM analysis; canine loss-of-function model with ERG, histology, and transcriptomics\",\n      \"pmids\": [\"27328943\", \"27506978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why photoreceptors are uniquely dependent on IQCB1 while other ciliated cells are not\",\n        \"Molecular basis of cone outer segment loss versus rod dysfunction unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that IQCB1 undergoes cell-cycle-regulated ubiquitination by BBS11/TRIM32 (K63, G2/M) and MARCH7 (K48/K63), counteracted by USP9X in G0/G1/S, revealed how cilia assembly and disassembly are coupled to cell-cycle progression through regulated IQCB1 stability.\",\n      \"evidence\": \"Co-immunoprecipitation of IQCB1 with USP9X, BBS11, and MARCH7; ubiquitin-linkage-specific assays; cell-cycle synchronization and siRNA depletion\",\n      \"pmids\": [\"28498859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific ubiquitinated lysine residues on IQCB1 not mapped\",\n        \"Whether the same ubiquitin regulation operates in photoreceptors in vivo\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Localization of IQCB1 to sub-distal appendages and basal feet, and demonstration that it is required for basal foot assembly, added a second structural role distinct from its transition-zone function.\",\n      \"evidence\": \"siRNA depletion with structured-illumination microscopy and epistasis rescue in cultured cells\",\n      \"pmids\": [\"31177295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Finding from a single lab; independent confirmation of SDA/BF localization needed\",\n        \"Relationship between basal-foot assembly defect and BBSome/cargo trafficking phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of EPB41L5 as a negative regulator of IQCB1 at the ciliary base—reducing its abundance and disrupting the IQCB1–CEP290 complex—provided the first upstream modulatory input controlling IQCB1 localization.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence quantification, zebrafish genetic interaction\",\n      \"pmids\": [\"32501287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which EPB41L5 removes IQCB1 from the ciliary base is unresolved\",\n        \"Whether EPB41L5 regulation is relevant in photoreceptors not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Patient iPSC-derived photoreceptors confirmed that IQCB1 mutations reduce CEP290 protein levels and cause aberrant ciliary elongation and visual pigment mislocalization, and AAV-mediated gene augmentation rescued these defects, validating a therapeutic strategy.\",\n      \"evidence\": \"iPSC-RPE and retinal organoids from patients, Western blot, immunofluorescence, AAV rescue\",\n      \"pmids\": [\"36084637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Long-term efficacy and safety of AAV gene augmentation in vivo not established\",\n        \"Whether CEP290 reduction is the sole pathogenic mechanism in patient photoreceptors\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include why IQCB1 is essential in photoreceptors but dispensable in other ciliated cell types, what structural basis underlies its simultaneous roles at the transition zone and sub-distal appendages/basal feet, and how its ubiquitin-mediated regulation is coordinated in post-mitotic photoreceptors that lack canonical cell-cycle transitions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the IQCB1–CEP290 or IQCB1–BBSome complex\",\n        \"Photoreceptor-specific versus general ciliary function of IQCB1 not mechanistically explained\",\n        \"Ubiquitin regulation of IQCB1 not tested in post-mitotic neurons\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [3, 9, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CEP290\",\n      \"USP9X\",\n      \"TRIM32\",\n      \"MARCH7\",\n      \"EPB41L5\",\n      \"BBS2\",\n      \"BBS5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}