Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0090090 negative regulation of canonical Wnt signaling pathway	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation inferred from phylogeny. Human NPHP4 has been implicated in Wnt signaling regulation, and the mammalian TZ has roles in compartmentalizing signaling molecules. However, direct evidence for NPHP-4 involvement in Wnt signaling in C. elegans is limited. Reason: While human NPHP4 has been linked to Wnt signaling regulation and TZ proteins can modulate ciliary signaling, the core function of C. elegans NPHP-4 is in TZ structure and ciliary gating rather than specific signaling pathway regulation. This may represent a conserved but secondary function. Supporting Evidence: file:worm/nphp-4/nphp-4-deep-research-falcon.md model: Edison Scientific Literature
GO:0035869 ciliary transition zone	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation supported by extensive experimental evidence. NPHP-4 localizes specifically to the TZ in C. elegans sensory neurons (PMID:21422230, PMID:18316409, PMID:21689635). Reason: Core localization supported by multiple IDA studies. The TZ is the primary site of NPHP-4 function. Supporting Evidence: PMID:21422230 MKS/MKSR and NPHP proteins localize specifically to the ciliary TZ PMID:18316409 NPHP-1 and NPHP-4 localize to TZs of male-specific CEM cilia
GO:0097730 non-motile cilium	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation supported by experimental evidence. C. elegans sensory cilia are non-motile primary cilia, and NPHP-4 localizes to these structures (PMID:15817158, PMID:18316409). Reason: Accurate cellular component annotation. NPHP-4 is present in sensory cilia of C. elegans, which are non-motile. This is broader than TZ localization and captures the overall ciliary context. Supporting Evidence: PMID:15817158 GFP-tagged NPHP-1 and NPHP-4 proteins localize to ciliated sensory endings of dendrites
GO:0036064 ciliary basal body	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation. NPHP-4 localizes primarily to the TZ, which is adjacent to but distinct from the basal body. Some studies describe TZ proteins as "basal body" associated due to co-isolation (PMID:21422230). Reason: The TZ is often co-isolated with the basal body, and NPHP-4 is found at the proximal ciliary region. While TZ is the more precise localization, basal body is not incorrect given the structural continuity. Supported by IDA evidence from PMID:27623382 and PMID:18316409. Supporting Evidence: PMID:21422230 The TZ is an underappreciated ciliary subcompartment, often incorrectly presumed to be one and the same with the adjacent BB
GO:0097546 ciliary base	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation. Ciliary base encompasses the TZ and basal body region. NPHP-4 localizes to this region (PMID:18316409, PMID:21422230). Reason: Appropriate broader CC term that accurately captures NPHP-4 localization at the proximal ciliary region.
GO:1904491 protein localization to ciliary transition zone	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation supported by experimental evidence. NPHP-4 functions with MKS-5 to localize other TZ proteins (PMID:21422230). Reason: Core function of NPHP-4 as part of the NPHP module. NPHP-4 is involved in establishing the TZ protein complex and recruiting/localizing other proteins to the TZ. Supported by IGI evidence from PMID:21422230. Supporting Evidence: PMID:21422230 MKS-5 is a central component required for docking/anchoring MKS and NPHP protein modules
GO:0005856 cytoskeleton	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: IEA annotation from InterPro. Cilia are microtubule-based structures, and TZ proteins interact with the axonemal cytoskeleton. Reason: While technically not wrong (cilia are cytoskeletal structures), this is too broad and uninformative. The more specific ciliary component annotations are preferred.
GO:0090090 negative regulation of canonical Wnt signaling pathway	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: IEA annotation from InterPro, duplicate of IBA annotation. Limited direct evidence in C. elegans. Reason: Duplicate annotation by different method. The Wnt signaling role is likely secondary to core ciliary gating function.
GO:0097730 non-motile cilium	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro. Supported by experimental IDA evidence. Reason: Valid broader annotation consistent with more specific experimental evidence.
GO:0036064 ciliary basal body	IDA PMID:27623382 A Conserved Role for Girdin in Basal Body Positioning and Ci...	ACCEPT	Summary: IDA annotation from a study on Girdin's role in basal body positioning. NPHP-4 was used as a marker/reference for basal body/TZ localization. Reason: Direct experimental observation of NPHP-4 at basal body region. Consistent with other IDA annotations. Supporting Evidence: PMID:27623382 Girdin localizes to the proximal regions of centrioles and regulates BB positioning and ciliogenesis
GO:0016358 dendrite development	IGI PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci...	KEEP AS NON CORE	Summary: IGI annotation with TMEM-107 (H2L2K0). TMEM-107 functions redundantly with NPHP-4, and double mutants show defects in dendrite structure in addition to ciliary defects. Reason: The primary function is in cilia, but dendrite development is affected in double mutants with MKS module genes, likely as a secondary consequence of TZ/ciliary defects. This is consistent with the functional redundancy between NPHP and MKS modules. Supporting Evidence: PMID:26595381 TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors
GO:1905515 non-motile cilium assembly	IMP PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci...	ACCEPT	Summary: IMP annotation. Loss of function results in ciliary assembly defects, particularly when combined with MKS module mutations. Reason: Core function of NPHP-4. The NPHP module works with the MKS module to establish the TZ and enable ciliogenesis. Supporting Evidence: PMID:26595381 TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity
GO:1905515 non-motile cilium assembly	IGI PMID:26595381 TMEM107 recruits ciliopathy proteins to subdomains of the ci...	ACCEPT	Summary: IGI annotation with TMEM-107 (H2L2K0). nphp-4;tmem-107 double mutants have severe ciliary assembly defects. Reason: Strong genetic interaction evidence supporting NPHP-4's role in cilium assembly. Supporting Evidence: PMID:26595381 Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors
GO:1905515 non-motile cilium assembly	IGI PMID:26863025 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS...	ACCEPT	Summary: IGI annotation with OSM-3 (C8JQP7). The osm-3(yhw66);nphp-4(tm925) double mutant shows synthetic dye-filling defects and loss of distal ciliary segments. Reason: Important genetic interaction demonstrating NPHP-4's role in regulating OSM-3 function and ciliary distal segment formation. Supporting Evidence: PMID:26863025 nphp-4(tm925);osm-3(yhw66) double mutants lack distal segments and are dye-filling (Dyf) and osmotic avoidance (Osm) defective PMID:26863025 in addition to regulating cilia protein entry or exit, NPHP-4 influences localization and function of a distal ciliary kinesin
GO:1905515 non-motile cilium assembly	IGI PMID:26982032 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Tr...	ACCEPT	Summary: IGI annotation from MKS5/CEP290 transition zone assembly study. nphp-4 interacts genetically with cep-290 and mks module genes. Reason: Supports NPHP-4's role in TZ assembly pathway, working in parallel with the CEP290-dependent MKS module assembly. Supporting Evidence: PMID:26982032 cep-290;nphp-4 animals fail to uptake the lipophilic dye DiI, a phenotype rescued by low-level expression of the CEP-290::GFP construct
GO:1905515 non-motile cilium assembly	IGI PMID:22152675 TMEM237 is mutated in individuals with a Joubert syndrome re...	ACCEPT	Summary: IGI annotation with JBTS-14/TMEM237. jbts-14;nphp-4 double mutants have ciliary defects consistent with functional redundancy. Reason: Part of the extensive genetic interaction network between NPHP and MKS module proteins in controlling TZ function and ciliogenesis. Supporting Evidence: PMID:22152675 Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis
GO:1904491 protein localization to ciliary transition zone	IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: IGI annotation with MKS-5. NPHP-4 is part of the NPHP module that is anchored to the TZ by MKS-5, and functions to localize other proteins. Reason: Key functional role of NPHP-4 in the TZ protein localization hierarchy. Supporting Evidence: PMID:21422230 MKS-5 is a central component required for docking/anchoring MKS and NPHP protein modules
GO:1905515 non-motile cilium assembly	IGI PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: IGI annotation based on genetic interactions with multiple MKS module genes (mks-1, mks-2, mks-3, mks-5, mks-6, mksr-1, mksr-2). Double mutants have severe ciliary defects including loss of membrane-TZ attachments and axoneme extension defects. Reason: Comprehensive genetic interaction study establishing the modular organization of TZ proteins and their collective role in ciliogenesis. Supporting Evidence: PMID:21422230 MKS/MKSR and NPHP modules are collectively required for two essential aspects of ciliogenesis, namely membrane anchoring of the BB/TZ and formation of an intact TZ region PMID:21422230 Joint disruption of an MKS/MKSR protein and NPHP-4 results in BB/TZ membrane association defects
GO:0023041 neuronal signal transduction	IC PMID:15817158 Functional characterization of the C. elegans nephrocystins ...	KEEP AS NON CORE	Summary: IC annotation inferred from localization in sensory cilia. nphp-1;nphp-4 double mutant males show sensory behavior defects consistent with impaired signal transduction. Reason: While NPHP-4 is required for sensory neuron function, the primary defect is in ciliary structure/gating rather than direct signal transduction. The behavioral phenotypes are likely secondary to ciliary gating defects that affect signaling molecule compartmentalization. Supporting Evidence: PMID:15817158 We propose that NPHP-1 and NPHP-4 proteins play important and redundant roles in facilitating ciliary sensory signal transduction
GO:0034606 response to hermaphrodite contact	IGI PMID:15817158 Functional characterization of the C. elegans nephrocystins ...	KEEP AS NON CORE	Summary: IGI annotation with NPHP-1. nphp-1;nphp-4 double mutant males are defective in response to hermaphrodite contact during mating. Reason: Behavioral phenotype that reflects ciliary sensory function rather than core molecular function. Important for understanding organismal role but secondary to TZ structural function. Supporting Evidence: PMID:15817158 nphp-1; nphp-4 double, but not single, mutant males are response defective
GO:0034607 turning behavior involved in mating	IGI PMID:15817158 Functional characterization of the C. elegans nephrocystins ...	KEEP AS NON CORE	Summary: IGI annotation with NPHP-1. nphp-1;nphp-4 double mutant males show mating behavior defects. Reason: Male-specific sensory behavior dependent on ciliary function. Secondary phenotype reflecting ciliary gating defects. Supporting Evidence: PMID:15817158 nphp-1; nphp-4 double, but not single, mutant males are response defective
GO:0097730 non-motile cilium	IDA PMID:15817158 Functional characterization of the C. elegans nephrocystins ...	ACCEPT	Summary: IDA showing NPHP-4::GFP localization to sensory cilia. First characterization of C. elegans nephrocystins. Reason: Direct experimental observation of ciliary localization in multiple sensory neuron types. Supporting Evidence: PMID:15817158 GFP-tagged NPHP-1 and NPHP-4 proteins localize to ciliated sensory endings of dendrites and colocalize with PKD-2 in male-specific sensory cilia
GO:0035869 ciliary transition zone	IDA PMID:21689635 Caenorhabditis elegans ciliary protein NPHP-8, the homologue...	ACCEPT	Summary: IDA showing NPHP-4 colocalization with NPHP-8 at the TZ. NPHP-8 depends on NPHP-4 for proper localization. Reason: Direct visualization of TZ localization, consistent with other studies. Supporting Evidence: PMID:21689635 NPHP-8 co-localized with NPHP-4 at the transition zone at the base of cilia
GO:0035869 ciliary transition zone	IDA PMID:21422230 MKS and NPHP modules cooperate to establish basal body/trans...	ACCEPT	Summary: IDA from comprehensive TZ protein study. High-resolution imaging of NPHP-4 localization at the TZ. Reason: Key study establishing TZ as a distinct compartment and NPHP-4 as a core TZ-localized protein. Supporting Evidence: PMID:21422230 MKS/MKSR and NPHP proteins localize specifically to the ciliary TZ
GO:0008340 determination of adult lifespan	IMP PMID:19208769 Functional interactions between the ciliopathy-associated Me...	KEEP AS NON CORE	Summary: IMP annotation from MKS1-related proteins study. Double mutants of mks/mksr genes (which interact with nphp genes) show increased lifespan due to abnormal insulin-IGF-I signaling. Reason: Pleiotropic phenotype that may result from altered ciliary signaling. Not a core function of NPHP-4 but represents downstream physiological consequence of ciliary dysfunction. Supporting Evidence: PMID:19208769 we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling
GO:0008104 intracellular protein localization	IGI PMID:18316409 The Caenorhabditis elegans nephrocystins act as global modif...	MODIFY	Summary: IGI annotation with NPHP-1. nphp-1;nphp-4 double mutants show abnormal localization of IFT components including OSM-6 and BBS proteins. Reason: This is too broad. The annotation should more specifically reflect the role in regulating ciliary access and localization of specific IFT components. Proposed replacements: intraciliary transport protein localization to ciliary transition zone Supporting Evidence: PMID:18316409 loss of both NPHP-1 and NPHP-4 but not NPHP-1 alone leads to the abnormal ciliary localization of the IFT-B polypeptide OSM-6, the OSM-3-kinesin, and the BBS proteins BBS-7 and BBS-8
GO:0036064 ciliary basal body	IDA PMID:18316409 The Caenorhabditis elegans nephrocystins act as global modif...	ACCEPT	Summary: IDA from detailed ultrastructural study of nephrocystin function. NPHP-4 localizes to basal body/TZ region. Reason: Comprehensive study with electron microscopy and fluorescence imaging confirming localization at the ciliary base region. Supporting Evidence: PMID:18316409 NPHP-1 and NPHP-4 localize to TZs of male-specific CEM cilia
GO:0097730 non-motile cilium	IDA PMID:18316409 The Caenorhabditis elegans nephrocystins act as global modif...	ACCEPT	Summary: IDA showing localization in sensory cilia across multiple neuron types. Reason: Consistent with other IDA studies showing ciliary localization. Supporting Evidence: PMID:18316409 NPHP-1 and NPHP-4 localize to TZs of male-specific CEM cilia
GO:1905515 non-motile cilium assembly	IMP PMID:18316409 The Caenorhabditis elegans nephrocystins act as global modif...	ACCEPT	Summary: IMP annotation from study showing nphp-4 mutants have ultrastructural defects in ciliary B tubules and IFT transport abnormalities. Reason: Core function demonstrated by loss-of-function analysis with ultrastructural characterization. Supporting Evidence: PMID:18316409 nphp-4 mutants have B tubule defects in amphid channel cilia PMID:18316409 We propose that NPHP-1 and NPHP-4 act globally at the TZ to regulate ciliary access of the IFT machinery, axonemal structural components, and signaling molecules
GO:0035177 larval foraging behavior	IMP PMID:18337471 Functional redundancy of the B9 proteins and nephrocystins i...	KEEP AS NON CORE	Summary: IMP annotation from study on B9 proteins and nephrocystins. nphp-4 mutants with B9 protein mutations have foraging behavior defects. Reason: Behavioral phenotype reflecting sensory function. The foraging defect is likely due to chemosensory impairment from ciliary dysfunction rather than a direct role in behavior per se. Supporting Evidence: PMID:18337471 the B9 proteins function redundantly with the nephrocystins to regulate the formation and/or maintenance of cilia and dendrites in the amphid and phasmid ciliated sensory neurons
GO:0030674 protein-macromolecule adaptor activity	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations.

Core Functions

NPHP-4 is a core component of the NPHP module at the ciliary transition zone, where it functions to establish the ciliary gate and regulate protein access to the ciliary compartment. Multiple IDA studies demonstrate specific localization to the TZ (PMID:21422230, PMID:21689635, PMID:18316409, PMID:15817158).

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

non-motile cilium assembly protein localization to ciliary transition zone

Cellular Locations:

ciliary transition zone non-motile cilium

Supporting Evidence:

PMID:21422230
MKS/MKSR and NPHP proteins localize specifically to the ciliary TZ
PMID:18316409
We propose that NPHP-1 and NPHP-4 act globally at the TZ to regulate ciliary access of the IFT machinery, axonemal structural components, and signaling molecules

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

PMID:15817158

Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors

NPHP-1 and NPHP-4 are expressed in a subset of sensory neurons

"Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors."
GFP-tagged proteins localize to ciliated sensory endings

"Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors."
The cilia of single mutants are intact

"Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors."
nphp-1;nphp-4 double mutant males are response defective

"Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors."
NPHP-1 and NPHP-4 play redundant roles in ciliary sensory signal transduction

"Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors."

PMID:18316409

The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure

NPHP-1 and NPHP-4 localize to ciliary transition zones

"The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure."
Loss of nephrocystins causes changes in localization of specific ciliary components

"The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure."
nphp-4 mutations cause B tubule defects in amphid channel cilia

"The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure."
NPHP-4 regulates ciliary localization of OSM-6, OSM-3, and BBS proteins

"The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure."
Nephrocystins act globally at the TZ to regulate ciliary access

"The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure."

PMID:18337471

Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis

B9 proteins function redundantly with nephrocystins

"Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis."
Combined mutations cause cilia and dendrite defects

"Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis."
B9 proteins form a complex at the base of cilia

"Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis."

PMID:19208769

Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins

MKS-1, MKSR-1, MKSR-2 localize to transition zones

"Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins."
Their localization is largely co-dependent

"Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins."
mks/mksr mutant combinations show increased lifespan phenotype

"Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins."

PMID:21422230

MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis

NPHP-4 is part of the NPHP module at the TZ

"MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis."
MKS and NPHP modules work together for TZ function

"MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis."
TZ proteins establish basal body membrane attachments

"MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis."
TZ proteins restrict accumulation of nonciliary components in cilia

"MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis."
MKS-5 is central for anchoring both modules

"MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis."

PMID:21689635

Caenorhabditis elegans ciliary protein NPHP-8, the homologue of human RPGRIP1L, is required for ciliogenesis and chemosensation.

NPHP-8 colocalizes with NPHP-4 at the transition zone

"Caenorhabditis elegans ciliary protein NPHP-8, the homologue of human RPGRIP1L, is required for ciliogenesis and chemosensation."

PMID:22152675

TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone

JBTS-14/TMEM237 genetically interacts with nphp-4

"TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone."
Double mutants have basal body-TZ anchoring defects

"TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone."
Both require RPGRIP1L/MKS-5 for proper TZ localization

"TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone."

PMID:26595381

TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome

TMEM-107 functions redundantly with NPHP-4

"TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome."
Double mutants have TZ docking and Y-link assembly defects

"TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome."
TMEM-107 is part of the MKS module

"TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome."

PMID:26863025

A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4

Screen identified mks-1, mks-2, mks-5 as nphp-4 interactors

"A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4."
Novel osm-3(yhw66) allele shows specific interaction with nphp-4

"A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4."
Double mutants lack distal segments and are Dyf

"A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4."
NPHP-4 influences localization and function of OSM-3 kinesin

"A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4."

PMID:26982032

MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone

CEP-290 is required for MKS module assembly

"MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone."
MKS-5 is central to TZ assembly pathway

"MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone."
cep-290;nphp-4 double mutants fail to dye-fill

"MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone."

PMID:27623382

A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis

Girdin localizes to proximal centrioles

"A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis."
Girdin regulates basal body positioning

"A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis."
NPHP-4 used as marker for basal body region

"A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis."

file:worm/nphp-4/nphp-4-deep-research-falcon.md

Deep research report on nphp-4

Suggested Experiments

Experiment: Proximity proteomics (BioID/APEX) to identify direct NPHP-4 interacting partners

Experiment: Super-resolution microscopy to determine precise subdomain localization within the TZ

Experiment: Structure-function analysis to identify domains required for TZ localization vs function

📚 Additional Documentation

Deep Research Falcon

(nphp-4-deep-research-falcon.md)

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template_file: templates/gene_research_go_focused.md
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organism: worm
gene_id: nphp-4
gene_symbol: nphp-4
uniprot_accession: G5ECP0
protein_description: 'SubName: Full=NePHronoPhthisis (Human kidney disease) homolog
{ECO:0000313|EMBL:CAB04654.3}; SubName: Full=Nephrocystin-4-like protein {ECO:0000313|EMBL:AAX56914.1};'
gene_info: Name=nphp-4 {ECO:0000313|EMBL:CAB04654.3, ECO:0000313|WormBase:R13H4.1};
ORFNames=CELE_R13H4.1 {ECO:0000313|EMBL:CAB04654.3}, R13H4.1 {ECO:0000313|WormBase:R13H4.1};
organism_full: Caenorhabditis elegans.
protein_family: Not specified in UniProt
protein_domains: NPHP4. (IPR029775)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: G5ECP0
Protein Description: SubName: Full=NePHronoPhthisis (Human kidney disease) homolog {ECO:0000313|EMBL:CAB04654.3}; SubName: Full=Nephrocystin-4-like protein {ECO:0000313|EMBL:AAX56914.1};
Gene Information: Name=nphp-4 {ECO:0000313|EMBL:CAB04654.3, ECO:0000313|WormBase:R13H4.1}; ORFNames=CELE_R13H4.1 {ECO:0000313|EMBL:CAB04654.3}, R13H4.1 {ECO:0000313|WormBase:R13H4.1};
Organism (full): Caenorhabditis elegans.
Protein Family: Not specified in UniProt
Key Domains: NPHP4. (IPR029775)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "nphp-4" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'nphp-4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene nphp-4 (gene ID: nphp-4, UniProt: G5ECP0) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: G5ECP0
Protein Description: SubName: Full=NePHronoPhthisis (Human kidney disease) homolog {ECO:0000313|EMBL:CAB04654.3}; SubName: Full=Nephrocystin-4-like protein {ECO:0000313|EMBL:AAX56914.1};
Gene Information: Name=nphp-4 {ECO:0000313|EMBL:CAB04654.3, ECO:0000313|WormBase:R13H4.1}; ORFNames=CELE_R13H4.1 {ECO:0000313|EMBL:CAB04654.3}, R13H4.1 {ECO:0000313|WormBase:R13H4.1};
Organism (full): Caenorhabditis elegans.
Protein Family: Not specified in UniProt
Key Domains: NPHP4. (IPR029775)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "nphp-4" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene nphp-4 (gene ID: nphp-4, UniProt: G5ECP0) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research plan and identity verification
- Target identity: nphp-4 encodes NPHP-4 (Nephrocystin-4 homolog) in Caenorhabditis elegans (ORF R13H4.1; WormBase CELE_R13H4.1). UniProt G5ECP0 matches this identity. Literature consistently places NPHP-4 at the ciliary transition zone (TZ) as part of the NPHP module, with strong genetic interactions with MKS module components. No conflicting gene symbol usage was found within C. elegans (park2022compositionorganizationand pages 6-8, masyukova2011assessingthepathogenic pages 2-2).

Key concepts and definitions with current understanding
- Ciliary transition zone and modules: The transition zone acts as a diffusion/selectivity barrier that establishes ciliary compartmentalization. In C. elegans, TZ proteins segregate into two cooperating modules, MKS and NPHP. CEP-290 and MKS-5 (RPGRIP1L) serve central assembly roles for the MKS module; NPHP-4 and NPHP-1 constitute the core NPHP module. Synthetic phenotypes arise when mutations spanning the two modules are combined (e.g., mks;nphp), underscoring functional redundancy and cooperativity of the gate (EMBO Reports review, Nov 2022; https://doi.org/10.15252/embr.202255420) (park2022compositionorganizationand pages 6-8).
- NPHP-4 localization and role: NPHP-4 localizes to the C. elegans ciliary TZ in amphid and phasmid neurons and is required for proper TZ localization of NPHP-1. As a TZ scaffold/adaptor, NPHP-4 supports gate integrity and contributes to anchoring NPHP-1 at the TZ (Human Molecular Genetics, Aug 2011; https://doi.org/10.1093/hmg/ddr198) (masyukova2011assessingthepathogenic pages 2-2, masyukova2011assessingthepathogenic pages 4-4).

Recent developments and latest research (priority 2023–2024)
- Sustained extracellular vesicle (EV) release requires NPHP-4: Live imaging of PKD-2-labeled EVs showed that cilia sustain EV release for ~2 hours. NPHP-4 is dispensable for initial release but required for sustained EV release, and nphp-4 mutants show diminished ciliary base PKD-2 pools, linking the TZ directly to prolonged EV dynamics (bioRxiv, Nov 2023; https://doi.org/10.1101/2023.11.01.565151) (masyukova2011assessingthepathogenic pages 6-7).
- Functional redundancy with RPI-1/DCDC2: C. elegans RPI-1 (DCDC2 ortholog) localizes to the axoneme and shows genetic redundancy with NPHP-4 in controlling cilia length and placement; rpi-1; nphp-4 double mutants exhibit ectopic projections and additive ciliogenesis defects (Turkish Journal of Biology, Jan 2023; https://doi.org/10.55730/1300-0152.2642) (masyukova2016ascreenfor pages 18-19).
- Cilia trafficking and drug resistance screens: A G3 study identified 24 novel anthelmintic survival-associated genes and, among known ciliary genes, observed that nphp-4(tm925) can show incomplete penetrance of resistance phenotypes—implicating amphid cilia structure/gating (including NPHP-4) in macrocyclic lactone resistance (G3, Jan 2024; https://doi.org/10.1093/g3journal/jkae009) (masyukova2011assessingthepathogenic pages 7-7).
- IFT/BBSome context and TZ integrity: Work on WDR31 places TZ integrity (including NPHP-4 context) as crucial for regulating IFT and BBSome trafficking, with combined mutations causing IFT component accumulation and leakage of non-ciliary proteins (Life Science Alliance, May 2023; https://doi.org/10.26508/lsa.202201844) (park2022compositionorganizationand pages 6-8).
- Broader 2023 context: Recent studies leveraged NPHP-4 as a canonical TZ marker in dissecting G protein signaling in ciliogenesis, further reinforcing its role in demarcating the gate (PLOS Genetics, Nov 2023; https://doi.org/10.1371/journal.pgen.1011015) (park2022compositionorganizationand pages 6-8).

Current applications and real-world implementations
- Variant interpretation for ciliopathies: C. elegans nphp-4 provides an in vivo platform to functionally assess human NPHP4 missense variants. Six of eight human NPHP4 alleles tested showed functional defects in C. elegans behavioral and ciliary assays, with some altering NPHP-4 and NPHP-1 localization, enabling refinement of variant pathogenicity (Human Molecular Genetics, Aug 2011; https://doi.org/10.1093/hmg/ddr198) (masyukova2011assessingthepathogenic pages 6-7, masyukova2011assessingthepathogenic pages 4-4).
- Sensitized genetic backgrounds for pathway mapping: nphp-4 mutants serve as sensitized backgrounds to uncover TZ assembly factors and trafficking regulators (e.g., OSM-3 modifiers), facilitating discovery of novel MKS alleles and motor regulation nodes relevant to ciliogenesis (PLOS Genetics, Feb 2016; https://doi.org/10.1371/journal.pgen.1005841) (masyukova2016ascreenfor pages 2-4, masyukova2016ascreenfor pages 18-19).
- Drug-resistance mechanism modeling: Because amphid cilia influence anthelmintic uptake/signaling, nphp-4 mutants contribute to dissecting mechanisms underlying macrocyclic lactone resistance with translational relevance to parasitic nematodes (G3, Jan 2024; https://doi.org/10.1093/g3journal/jkae009) (masyukova2011assessingthepathogenic pages 7-7).

Expert opinions and analysis from authoritative sources
- Assembly hierarchies and module cooperation: Reviews and comprehensive mechanistic studies place CEP-290 and MKS-5 as central assembly factors, with MKS and NPHP modules cooperating to build a functional TZ gate. NPHP-4 occupies the NPHP module and is required to position NPHP-1; CEP-290 genetically interacts with nphp-4 and acts as a key organizer of MKS components (EMBO Reports, Nov 2022; PLOS Biology, Mar 2016) (park2022compositionorganizationand pages 6-8, li2016mks5andcep290 pages 18-20).
- Structural roles within TZ: Ultrastructural analyses indicate that single nphp-4 mutants can exhibit modest Y-link defects, whereas MKS–NPHP double mutants often display near-complete Y-link loss, detachment of the ciliary membrane, and severe ciliogenesis defects, highlighting NPHP-4’s structural contribution that is buffered by module redundancy (JCB, Jul 2015; PLOS Biology, Mar 2016) (schouteden2015theciliarytransition pages 2-3, li2016mks5andcep290 pages 18-20).

Relevant statistics and data from recent and foundational studies
- Variant functional assessment: In C. elegans, 6/8 tested human NPHP4 missense mutations impaired cilia-dependent foraging; several also failed to rescue synthetic defects in mksr-2;nphp-4 backgrounds, indicating module-spanning sensitivity (Human Molecular Genetics, Aug 2011; https://doi.org/10.1093/hmg/ddr198) (masyukova2011assessingthepathogenic pages 6-7, masyukova2011assessingthepathogenic pages 2-2).
- Genetic screen scale: An EMS enhancer screen starting in nphp-4 generated 118 transmissible Dyf lines, with outcrossing yielding 29 characterized double mutants; multiple lines disrupted MKS complex formation/localization (PLOS Genetics, Feb 2016; https://doi.org/10.1371/journal.pgen.1005841) (masyukova2016ascreenfor pages 2-4).
- EV release kinetics: Cilia sustain PKD-2 EV release for approximately two hours; nphp-4 is required for sustained (but not initial) release, evidencing a TZ-dependent mechanism maintaining prolonged EV output (bioRxiv, Nov 2023; https://doi.org/10.1101/2023.11.01.565151) (masyukova2011assessingthepathogenic pages 6-7).
- Anthelmintic resistance gene set: A 2024 screen identified 24 novel anthelmintic survival-associated genes and documented incomplete penetrance of resistance phenotypes in some nphp-4(tm925) individuals, linking TZ/IFT function to drug responses (G3, Jan 2024; https://doi.org/10.1093/g3journal/jkae009) (masyukova2011assessingthepathogenic pages 7-7).

Primary function, processes, and localization of NPHP-4 in C. elegans
- Localization: NPHP-4 is a core TZ protein in amphid and phasmid cilia and is required for NPHP-1 localization at the TZ. In some mutant contexts, NPHP-4 localization within the TZ is altered by loss of upstream assembly factors (e.g., MKS-5), consistent with hierarchical assembly dependencies (Human Molecular Genetics, Aug 2011; PLOS Genetics, Feb 2016) (masyukova2011assessingthepathogenic pages 2-2, masyukova2016ascreenfor pages 18-19).
- Structural/gating role: NPHP-4 contributes to the TZ “gate” that restricts entry/exit of proteins. In single mutants, gating/ultrastructural defects are generally modest but become severe in MKS–NPHP double mutants, with near-complete Y-link loss and membrane detachment, underscoring its structural role buffered by module cooperativity (PLOS Biology, Mar 2016; JCB, Jul 2015; EMBO Reports, Nov 2022) (li2016mks5andcep290 pages 18-20, schouteden2015theciliarytransition pages 2-3, park2022compositionorganizationand pages 6-8).
- Genetic network and epistasis: NPHP-4 genetically interacts with multiple MKS module proteins (MKS-1, MKS-2, MKS-3, MKSR/B9 proteins) and with CEP-290. CEP-290 is placed as a central organizer of the MKS module and shows genetic interaction with nphp-4; NPHP-4 is essential for NPHP-1 positioning within the NPHP module (PLOS Biology, Mar 2016; EMBO Reports, Nov 2022; Human Molecular Genetics, Aug 2011) (li2016mks5andcep290 pages 18-20, park2022compositionorganizationand pages 6-8, masyukova2011assessingthepathogenic pages 2-2).
- Effects on trafficking and motors: nphp-4 mutants show OSM-3 kinesin mislocalization/accumulation at the ciliary base and specific genetic interactions with osm-3 alleles that compromise distal segment assembly, suggesting that NPHP-4 influences motor access or regulation at the gate. Mild increases in OSM-3 velocity were also observed in nphp-4 single mutants (PLOS Genetics, Feb 2016; JCS, Jun 2012; https://doi.org/10.1371/journal.pgen.1005841; https://doi.org/10.1242/jcs.095539) (masyukova2016ascreenfor pages 18-19, warburtonpitt2012ciliogenesisincaenorhabditis pages 7-8).
- ARL-13 and PKD-2 context: CEP-290 is required to prevent ARL-13 from leaking out of cilia and to block inappropriate membrane protein entry—defining TZ gating in which NPHP-4 participates via module cooperativity. Separately, sustained EV release of PKD-2 from cilia requires NPHP-4, showing an NPHP-4–dependent role for maintaining the ciliary cargo pool/base for extended EV secretion (PLOS Biology, Mar 2016; bioRxiv, Nov 2023) (li2016mks5andcep290 pages 18-20, masyukova2011assessingthepathogenic pages 6-7).
- Phenotypic spectrum: Single nphp-4 mutants often display mild cilia functional/morphological defects, whereas double mutants with MKS genes show severe synthetic Dyf phenotypes and ciliogenesis failure including loss of stable TZ–membrane attachments. Behavioral readouts (foraging) and dye-filling are sensitive quantitative assays used across studies (Human Molecular Genetics, Aug 2011; PLOS Genetics, Feb 2016) (masyukova2011assessingthepathogenic pages 2-2, masyukova2011assessingthepathogenic pages 7-7, masyukova2016ascreenfor pages 18-19).

Open questions and future directions
- Precise biochemical interfaces: While localization dependencies with NPHP-1 and assembly interactions with CEP-290/MKS-5 are clear, high-resolution biochemical/structural definitions of NPHP-4 binding interfaces within the TZ remain to be fully elucidated in vivo (park2022compositionorganizationand pages 6-8, li2016mks5andcep290 pages 18-20).
- Mechanistic link to EV biogenesis: The requirement for NPHP-4 in sustained EV release suggests emergent roles for the TZ in cargo retention/replenishment and membrane mechanics over long durations; how NPHP-4 coordinates with lipid or cytoskeletal elements at the TZ warrants further study (masyukova2011assessingthepathogenic pages 6-7).
- Translational modeling: Given contributions to anthelmintic resistance and ciliary gate function, nphp-4 provides a sensitized genetic background to dissect drug uptake and signaling, potentially informing parasite control strategies (masyukova2011assessingthepathogenic pages 7-7).

Key study summary table
| Year | Citation (authors, journal) | Model / assay | Key finding on NPHP-4 | Interaction / module context | Notable phenotypes (Dyf, cilia defects, EV release, drug resistance) | URL / DOI | Publication date |
|---:|---|---|---|---|---|---|---|
| 2011 | Masyukova et al., Human Molecular Genetics (NPHP‑4 missense modelling) (masyukova2011assessingthepathogenic pages 4-4) | C. elegans transgenics; dye‑filling, foraging, fluorescence localization | NPHP‑4 localizes to the ciliary transition zone (TZ) and is required for proper TZ localization of NPHP‑1; human NPHP4 missense alleles tested in vivo | Core NPHP module; genetic interaction with MKS (e.g., mksr‑2/B9) | Foraging defects; synthetic Dyf and ciliogenesis defects in nphp‑4; mks double mutants; variant-specific mislocalization (e.g., F903S, T1101M) | https://doi.org/10.1093/hmg/ddr198 | Aug 2011 |
| 2012 | Warburton‑Pitt et al., Journal of Cell Science (warburtonpitt2012ciliogenesisincaenorhabditis pages 7-8) | C. elegans genetics, cilia morphology, IFT assays | nphp‑2 (Inversin) interacts genetically with TZ proteins; NPHP‑4 TZ localization does not depend on nphp‑2 | NPHP and MKS modules interplay; links to middle‑segment regulators | nphp‑2; nphp‑4 double mutants show exacerbated cilia placement/length/orientation defects; modest OSM‑3 velocity changes in nphp‑4 | https://doi.org/10.1242/jcs.095539 | Jun 2012 |
| 2015 | Jensen et al., EMBO Journal (Formation of the TZ by MKS5/Rpgrip1L) (park2022compositionorganizationand pages 6-8) | C. elegans TZ assembly studies; localization & hierarchy assays | Defines MKS5/CEP290 assembly pathway for TZ; places NPHP proteins relative to MKS assembly factors | CEP‑290 / MKS5‑dependent assembly; NPHP module distinct but interdependent | Loss of assembly factors perturbs gating and TZ ultrastructure; NPHP proteins (including NPHP‑4) show module‑dependent localization defects | https://doi.org/10.15252/embj.201488044 | Oct 2015 |
| 2015 | Schouteden et al., Journal of Cell Biology (schouteden2015theciliarytransition pages 2-3) | C. elegans TEM and genetic analyses of TZ | TZ required for cell adhesion; CCEP‑290 occupies central TZ position and cooperates with MKSR/NPHP proteins | CEP‑290, MKSR, NPHP (including NPHP‑4) cooperate for TZ ultrastructure | ccep-290;nphp-4 and triple mutants cause severe TZ ultrastructural loss; axoneme–membrane detachment in combined mutants | https://doi.org/10.1083/jcb.201501013 | Jul 2015 |
| 2016 | Li et al., PLOS Biology (MKS5 & CEP290 assembly pathway) (li2016mks5andcep290 pages 18-20) | C. elegans genetics, localization, functional assays | CEP‑290 is a central assembly factor for MKS module; nphp‑4 has modest single‑mutant Y‑link defects but strong synthetic defects in MKS–NPHP double mutants | Places CEP‑290 with MKS, shows cep‑290 ↔ nphp‑4 genetic interactions; hierarchy with MKS5/RPGRIP1L | Various MKS‑NPHP double mutants (e.g., mks‑2;nphp‑4) show near‑complete loss of Y‑links and severe cilia defects | https://doi.org/10.1371/journal.pbio.1002416 | Mar 2016 |
| 2016 | Masyukova et al., PLOS Genetics (modifier screen) (masyukova2016ascreenfor pages 18-19) | EMS enhancer screen in nphp‑4(tm925); dye‑filling and MKS‑3::GFP localization | Identified novel MKS alleles; uncovered specific genetic interaction between osm‑3 (kinesin) and nphp‑4 | nphp‑4 sensitizes to MKS loss; genetic interaction with OSM‑3 affects distal segment assembly | nphp‑4 mutants show OSM‑3 accumulation at dendrite/base; osm‑3 alleles + nphp‑4 produce distal segment loss and Dyf phenotypes | https://doi.org/10.1371/journal.pgen.1005841 | Feb 2016 |
| 2022 | Park & Leroux, EMBO Reports (review: TZ composition & mechanisms) (park2022compositionorganizationand pages 6-8) | Review (synthesis of C. elegans and vertebrate TZ literature) | Synthesizes module model (MKS vs NPHP), hierarchical dependencies (CEP‑290, MKS5), and NPHP‑4 role in TZ organization | Summarizes NPHP module (NPHP‑1/4) vs MKS module and CEP‑290 placement | Review of phenotypes: module single mutants vs synthetic double mutants (Dyf, mislocalization); provides contemporary conceptual model | https://doi.org/10.15252/embr.202255420 | Nov 2022 |
| 2023 | Dobbelaere et al., The EMBO Journal (phylogenetic profiling) (park2022compositionorganizationand pages 6-8) | Comparative genomics + C. elegans mutant analysis | Identified conserved ciliogenesis genes; places TZ players (e.g., NPHP‑4) within conserved cilium‑assembly networks | Supports conservation of NPHP/MKS genetic modules across species | C. elegans mutants combining TZ components (e.g., ccep‑290;nphp‑4) show combined phenotypes (shortened cilia, dendrite effects) | https://doi.org/10.15252/embj.2023113616 | Jun 2023 |
| 2023 | Kaplan, Turkish Journal of Biology (RPI‑1 / DCDC2 redundancy with NPHP‑4) (masyukova2016ascreenfor pages 18-19) | C. elegans fluorescent cilia markers, null mutants | Reports functional redundancy between RPI‑1 (DCDC2 ortholog) and NPHP‑4 in controlling cilia length and position | Genetic redundancy: RPI‑1 (axonemal) vs NPHP‑4 (TZ) influencing overlapping ciliogenesis outputs | rpi‑1; nphp‑4 double mutants show ectopic projections and additive cilia defects | https://doi.org/10.55730/1300-0152.2642 | Jan 2023 |
| 2023 | Campagna et al., PLOS Genetics (RIC‑8 / cilia morphogenesis) () | C. elegans localization and genetic pathway analysis | Uses NPHP‑4 as a TZ marker; shows TZ demarcates gating linked to cilia morphology pathways | NPHP‑4 used as canonical TZ marker; links TZ gating to signaling modules (RIC‑8 → Gα pathway) | TZ marker (NPHP‑4::GFP) used to show TZ integrity in morphogenesis mutants; cilia morphological defects when pathway perturbed | https://doi.org/10.1371/journal.pgen.1011015 | Nov 2023 |
| 2023 | Cevik et al., Life Science Alliance (WDR31 / IFT & BBSome) (schouteden2015theciliarytransition pages 2-3) | C. elegans & zebrafish genetics, IFT trafficking assays | Notes that loss of NPHP‑4 alone is mild but combined loss with other TZ regulators produces strong IFT/BBSome transport defects | Places NPHP‑4 within context of TZ integrity controlling IFT/BBSome entry/exit | Combined mutants (wdr‑31; rpi‑2; elmd‑1 and loss of nphp‑4 in other studies) show IFT component accumulation and non‑ciliary protein leakage | https://doi.org/10.26508/lsa.202201844 | May 2023 |
| 2024 | Brinzer et al., G3 (IFT, trafficking & anthelmintic resistance) (masyukova2011assessingthepathogenic pages 7-7) | C. elegans forward genetics & resistance screens | Links cilia/IFT components to macrocyclic lactone resistance; nphp‑4(tm925) shows incomplete penetrance of resistance phenotype in some assays | TZ/IFT components (including nphp‑4) influence drug uptake/resistance via amphid cilia function | nphp‑4 mutants exhibited variable resistance phenotypes; implicates cilia defects in altered drug sensitivity | https://doi.org/10.1093/g3journal/jkae009 | Jan 2024 |
| 2024 | Wang et al., bioRxiv (ciliary EV release dynamics) (masyukova2011assessingthepathogenic pages 6-7) | Live imaging of ciliary EV release in C. elegans sensory neurons | Identifies NPHP‑4 requirement for sustained (but not initial) ciliary EV release of PKD‑2; links TZ integrity to prolonged EV release | NPHP‑4 (TZ) required for sustained EV release; connects TZ gating to EV biogenesis/maintenance | nphp‑4 mutants show diminished sustained PKD‑2 EV release and reduced ciliary base PKD‑2 pools; implicates TZ in EV dynamics | https://doi.org/10.1101/2023.11.01.565151 | Nov 2023 |

Table: Compact summary table of primary and review studies on C. elegans NPHP‑4 covering localization, interactions (NPHP/MKS/CEP‑290/OSM‑3), phenotypes, and 2023–2024 developments; each row cites context IDs from the gathered evidence for traceability.

Acknowledgment of symbol ambiguity check
- The gene symbol “nphp-4” can refer to orthologs in other species, but all cited studies here concern Caenorhabditis elegans or general TZ mechanisms anchored by C. elegans data. The organism, ORF (R13H4.1), and module/domain context match UniProt G5ECP0 and WormBase entries (park2022compositionorganizationand pages 6-8, masyukova2011assessingthepathogenic pages 2-2).

References

(park2022compositionorganizationand pages 6-8): Kwangjin Park and Michel R Leroux. Composition, organization and mechanisms of the transition zone, a gate for the cilium. EMBO reports, Nov 2022. URL: https://doi.org/10.15252/embr.202255420, doi:10.15252/embr.202255420. This article has 71 citations and is from a highest quality peer-reviewed journal.
(masyukova2011assessingthepathogenic pages 2-2): Svetlana V. Masyukova, Marlene E. Winkelbauer, Corey L. Williams, Jay N. Pieczynski, and Bradley K. Yoder. Assessing the pathogenic potential of human nephronophthisis disease-associated nphp-4 missense mutations in c. elegans. Human molecular genetics, 20 15:2942-54, Aug 2011. URL: https://doi.org/10.1093/hmg/ddr198, doi:10.1093/hmg/ddr198. This article has 13 citations and is from a domain leading peer-reviewed journal.
(masyukova2011assessingthepathogenic pages 4-4): Svetlana V. Masyukova, Marlene E. Winkelbauer, Corey L. Williams, Jay N. Pieczynski, and Bradley K. Yoder. Assessing the pathogenic potential of human nephronophthisis disease-associated nphp-4 missense mutations in c. elegans. Human molecular genetics, 20 15:2942-54, Aug 2011. URL: https://doi.org/10.1093/hmg/ddr198, doi:10.1093/hmg/ddr198. This article has 13 citations and is from a domain leading peer-reviewed journal.
(masyukova2011assessingthepathogenic pages 6-7): Svetlana V. Masyukova, Marlene E. Winkelbauer, Corey L. Williams, Jay N. Pieczynski, and Bradley K. Yoder. Assessing the pathogenic potential of human nephronophthisis disease-associated nphp-4 missense mutations in c. elegans. Human molecular genetics, 20 15:2942-54, Aug 2011. URL: https://doi.org/10.1093/hmg/ddr198, doi:10.1093/hmg/ddr198. This article has 13 citations and is from a domain leading peer-reviewed journal.
(masyukova2016ascreenfor pages 18-19): Svetlana V. Masyukova, Dawn E. Landis, Scott J. Henke, Corey L. Williams, Jay N. Pieczynski, Kelly N. Roszczynialski, Jannese E. Covington, Erik B. Malarkey, and Bradley K. Yoder. A screen for modifiers of cilia phenotypes reveals novel mks alleles and uncovers a specific genetic interaction between osm-3 and nphp-4. PLOS Genetics, 12:e1005841, Feb 2016. URL: https://doi.org/10.1371/journal.pgen.1005841, doi:10.1371/journal.pgen.1005841. This article has 20 citations and is from a domain leading peer-reviewed journal.
(masyukova2011assessingthepathogenic pages 7-7): Svetlana V. Masyukova, Marlene E. Winkelbauer, Corey L. Williams, Jay N. Pieczynski, and Bradley K. Yoder. Assessing the pathogenic potential of human nephronophthisis disease-associated nphp-4 missense mutations in c. elegans. Human molecular genetics, 20 15:2942-54, Aug 2011. URL: https://doi.org/10.1093/hmg/ddr198, doi:10.1093/hmg/ddr198. This article has 13 citations and is from a domain leading peer-reviewed journal.
(masyukova2016ascreenfor pages 2-4): Svetlana V. Masyukova, Dawn E. Landis, Scott J. Henke, Corey L. Williams, Jay N. Pieczynski, Kelly N. Roszczynialski, Jannese E. Covington, Erik B. Malarkey, and Bradley K. Yoder. A screen for modifiers of cilia phenotypes reveals novel mks alleles and uncovers a specific genetic interaction between osm-3 and nphp-4. PLOS Genetics, 12:e1005841, Feb 2016. URL: https://doi.org/10.1371/journal.pgen.1005841, doi:10.1371/journal.pgen.1005841. This article has 20 citations and is from a domain leading peer-reviewed journal.
(li2016mks5andcep290 pages 18-20): Chunmei Li, Victor L. Jensen, Kwangjin Park, Julie Kennedy, Francesc R. Garcia-Gonzalo, Marta Romani, Roberta De Mori, Ange-Line Bruel, Dominique Gaillard, Bérénice Doray, Estelle Lopez, Jean-Baptiste Rivière, Laurence Faivre, Christel Thauvin-Robinet, Jeremy F. Reiter, Oliver E. Blacque, Enza Maria Valente, and Michel R. Leroux. Mks5 and cep290 dependent assembly pathway of the ciliary transition zone. PLOS Biology, 14:e1002416, Mar 2016. URL: https://doi.org/10.1371/journal.pbio.1002416, doi:10.1371/journal.pbio.1002416. This article has 165 citations and is from a highest quality peer-reviewed journal.
(schouteden2015theciliarytransition pages 2-3): Clementine Schouteden, Daniel Serwas, Mate Palfy, and Alexander Dammermann. The ciliary transition zone functions in cell adhesion but is dispensable for axoneme assembly in c. elegans. The Journal of Cell Biology, 210:947-956, Jul 2015. URL: https://doi.org/10.1083/jcb.201501013, doi:10.1083/jcb.201501013. This article has 75 citations.
(warburtonpitt2012ciliogenesisincaenorhabditis pages 7-8): Simon R. F. Warburton-Pitt, Andrew R. Jauregui, Chunmei Li, Juan Wang, M. Leroux, and M. Barr. Ciliogenesis in caenorhabditis elegans requires genetic interactions between ciliary middle segment localized nphp-2 (inversin) and transition zone-associated proteins. Journal of Cell Science, 125:2592-2603, Jun 2012. URL: https://doi.org/10.1242/jcs.095539, doi:10.1242/jcs.095539. This article has 57 citations and is from a domain leading peer-reviewed journal.

Citations

park2022compositionorganizationand pages 6-8
masyukova2011assessingthepathogenic pages 6-7
masyukova2016ascreenfor pages 18-19
masyukova2011assessingthepathogenic pages 7-7
masyukova2016ascreenfor pages 2-4
masyukova2011assessingthepathogenic pages 4-4
warburtonpitt2012ciliogenesisincaenorhabditis pages 7-8
schouteden2015theciliarytransition pages 2-3
masyukova2011assessingthepathogenic pages 2-2
https://doi.org/10.15252/embr.202255420
https://doi.org/10.1093/hmg/ddr198
https://doi.org/10.1101/2023.11.01.565151
https://doi.org/10.55730/1300-0152.2642
https://doi.org/10.1093/g3journal/jkae009
https://doi.org/10.26508/lsa.202201844
https://doi.org/10.1371/journal.pgen.1011015
https://doi.org/10.1371/journal.pgen.1005841
https://doi.org/10.1371/journal.pgen.1005841;
https://doi.org/10.1242/jcs.095539
https://doi.org/10.15252/embj.201488044
https://doi.org/10.1083/jcb.201501013
https://doi.org/10.1371/journal.pbio.1002416
https://doi.org/10.15252/embj.2023113616
https://doi.org/10.15252/embr.202255420,
https://doi.org/10.1093/hmg/ddr198,
https://doi.org/10.1371/journal.pgen.1005841,
https://doi.org/10.1371/journal.pbio.1002416,
https://doi.org/10.1083/jcb.201501013,
https://doi.org/10.1242/jcs.095539,

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id: G5ECP0
gene_symbol: nphp-4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: NPHP-4 is the C. elegans ortholog of human nephrocystin-4 (NPHP4), 
  a protein that localizes to the ciliary transition zone (TZ) and ciliary basal
  body. Together with NPHP-1, NPHP-4 forms the NPHP module at the TZ, which acts
  redundantly with the MKS module to establish basal body membrane associations,
  regulate TZ Y-link formation, and establish the ciliary diffusion barrier 
  (gate). Single nphp-4 mutants have relatively mild cilia defects, but nphp-4 
  mutants in combination with mutations in MKS module genes (mks-1, mks-2, 
  mks-5, mks-6) exhibit severe ciliary phenotypes including loss of dye-filling,
  defective TZ ultrastructure, and impaired ciliogenesis. NPHP-4 regulates 
  ciliary access of specific IFT components including OSM-6 and BBS proteins, 
  and shows a specific genetic interaction with the kinesin OSM-3. Expression is
  in ciliated sensory neurons, and the protein functions in sensory signal 
  transduction required for male mating behaviors and chemosensation.
existing_annotations:
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation inferred from phylogeny. Human NPHP4 has been 
      implicated in Wnt signaling regulation, and the mammalian TZ has roles in 
      compartmentalizing signaling molecules. However, direct evidence for 
      NPHP-4 involvement in Wnt signaling in C. elegans is limited.
    action: KEEP_AS_NON_CORE
    reason: While human NPHP4 has been linked to Wnt signaling regulation and TZ
      proteins can modulate ciliary signaling, the core function of C. elegans 
      NPHP-4 is in TZ structure and ciliary gating rather than specific 
      signaling pathway regulation. This may represent a conserved but secondary
      function.
    supported_by:
    - reference_id: file:worm/nphp-4/nphp-4-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0035869
    label: ciliary transition zone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation supported by extensive experimental evidence. NPHP-4
      localizes specifically to the TZ in C. elegans sensory neurons 
      (PMID:21422230, PMID:18316409, PMID:21689635).
    action: ACCEPT
    reason: Core localization supported by multiple IDA studies. The TZ is the 
      primary site of NPHP-4 function.
    supported_by:
    - reference_id: PMID:21422230
      supporting_text: MKS/MKSR and NPHP proteins localize specifically to the 
        ciliary TZ
    - reference_id: PMID:18316409
      supporting_text: NPHP-1 and NPHP-4 localize to TZs of male-specific CEM 
        cilia
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation supported by experimental evidence. C. elegans 
      sensory cilia are non-motile primary cilia, and NPHP-4 localizes to these 
      structures (PMID:15817158, PMID:18316409).
    action: ACCEPT
    reason: Accurate cellular component annotation. NPHP-4 is present in sensory
      cilia of C. elegans, which are non-motile. This is broader than TZ 
      localization and captures the overall ciliary context.
    supported_by:
    - reference_id: PMID:15817158
      supporting_text: GFP-tagged NPHP-1 and NPHP-4 proteins localize to 
        ciliated sensory endings of dendrites
- term:
    id: GO:0036064
    label: ciliary basal body
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation. NPHP-4 localizes primarily to the TZ, which is 
      adjacent to but distinct from the basal body. Some studies describe TZ 
      proteins as "basal body" associated due to co-isolation (PMID:21422230).
    action: ACCEPT
    reason: The TZ is often co-isolated with the basal body, and NPHP-4 is found
      at the proximal ciliary region. While TZ is the more precise localization,
      basal body is not incorrect given the structural continuity. Supported by 
      IDA evidence from PMID:27623382 and PMID:18316409.
    supported_by:
    - reference_id: PMID:21422230
      supporting_text: The TZ is an underappreciated ciliary subcompartment, 
        often incorrectly presumed to be one and the same with the adjacent BB
- term:
    id: GO:0097546
    label: ciliary base
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation. Ciliary base encompasses the TZ and basal body 
      region. NPHP-4 localizes to this region (PMID:18316409, PMID:21422230).
    action: ACCEPT
    reason: Appropriate broader CC term that accurately captures NPHP-4 
      localization at the proximal ciliary region.
- term:
    id: GO:1904491
    label: protein localization to ciliary transition zone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation supported by experimental evidence. NPHP-4 functions
      with MKS-5 to localize other TZ proteins (PMID:21422230).
    action: ACCEPT
    reason: Core function of NPHP-4 as part of the NPHP module. NPHP-4 is 
      involved in establishing the TZ protein complex and recruiting/localizing 
      other proteins to the TZ. Supported by IGI evidence from PMID:21422230.
    supported_by:
    - reference_id: PMID:21422230
      supporting_text: MKS-5 is a central component required for 
        docking/anchoring MKS and NPHP protein modules
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation from InterPro. Cilia are microtubule-based 
      structures, and TZ proteins interact with the axonemal cytoskeleton.
    action: MARK_AS_OVER_ANNOTATED
    reason: While technically not wrong (cilia are cytoskeletal structures), 
      this is too broad and uninformative. The more specific ciliary component 
      annotations are preferred.
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation from InterPro, duplicate of IBA annotation. Limited 
      direct evidence in C. elegans.
    action: KEEP_AS_NON_CORE
    reason: Duplicate annotation by different method. The Wnt signaling role is 
      likely secondary to core ciliary gating function.
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation from InterPro. Supported by experimental IDA 
      evidence.
    action: ACCEPT
    reason: Valid broader annotation consistent with more specific experimental 
      evidence.
- term:
    id: GO:0036064
    label: ciliary basal body
  evidence_type: IDA
  original_reference_id: PMID:27623382
  review:
    summary: IDA annotation from a study on Girdin's role in basal body 
      positioning. NPHP-4 was used as a marker/reference for basal body/TZ 
      localization.
    action: ACCEPT
    reason: Direct experimental observation of NPHP-4 at basal body region. 
      Consistent with other IDA annotations.
    supported_by:
    - reference_id: PMID:27623382
      supporting_text: Girdin localizes to the proximal regions of centrioles 
        and regulates BB positioning and ciliogenesis
- term:
    id: GO:0016358
    label: dendrite development
  evidence_type: IGI
  original_reference_id: PMID:26595381
  review:
    summary: IGI annotation with TMEM-107 (H2L2K0). TMEM-107 functions 
      redundantly with NPHP-4, and double mutants show defects in dendrite 
      structure in addition to ciliary defects.
    action: KEEP_AS_NON_CORE
    reason: The primary function is in cilia, but dendrite development is 
      affected in double mutants with MKS module genes, likely as a secondary 
      consequence of TZ/ciliary defects. This is consistent with the functional 
      redundancy between NPHP and MKS modules.
    supported_by:
    - reference_id: PMID:26595381
      supporting_text: TMEM-107 controls ciliary composition and functions 
        redundantly with NPHP-4 to regulate cilium integrity, TZ docking and 
        assembly of membrane to microtubule Y-link connectors
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IMP
  original_reference_id: PMID:26595381
  review:
    summary: IMP annotation. Loss of function results in ciliary assembly 
      defects, particularly when combined with MKS module mutations.
    action: ACCEPT
    reason: Core function of NPHP-4. The NPHP module works with the MKS module 
      to establish the TZ and enable ciliogenesis.
    supported_by:
    - reference_id: PMID:26595381
      supporting_text: TMEM-107 controls ciliary composition and functions 
        redundantly with NPHP-4 to regulate cilium integrity
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IGI
  original_reference_id: PMID:26595381
  review:
    summary: IGI annotation with TMEM-107 (H2L2K0). nphp-4;tmem-107 double 
      mutants have severe ciliary assembly defects.
    action: ACCEPT
    reason: Strong genetic interaction evidence supporting NPHP-4's role in 
      cilium assembly.
    supported_by:
    - reference_id: PMID:26595381
      supporting_text: Mechanistic studies in Caenorhabditis elegans showed that
        TMEM-107 controls ciliary composition and functions redundantly with 
        NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane
        to microtubule Y-link connectors
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IGI
  original_reference_id: PMID:26863025
  review:
    summary: IGI annotation with OSM-3 (C8JQP7). The osm-3(yhw66);nphp-4(tm925) 
      double mutant shows synthetic dye-filling defects and loss of distal 
      ciliary segments.
    action: ACCEPT
    reason: Important genetic interaction demonstrating NPHP-4's role in 
      regulating OSM-3 function and ciliary distal segment formation.
    supported_by:
    - reference_id: PMID:26863025
      supporting_text: nphp-4(tm925);osm-3(yhw66) double mutants lack distal 
        segments and are dye-filling (Dyf) and osmotic avoidance (Osm) defective
    - reference_id: PMID:26863025
      supporting_text: in addition to regulating cilia protein entry or exit, 
        NPHP-4 influences localization and function of a distal ciliary kinesin
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IGI
  original_reference_id: PMID:26982032
  review:
    summary: IGI annotation from MKS5/CEP290 transition zone assembly study. 
      nphp-4 interacts genetically with cep-290 and mks module genes.
    action: ACCEPT
    reason: Supports NPHP-4's role in TZ assembly pathway, working in parallel 
      with the CEP290-dependent MKS module assembly.
    supported_by:
    - reference_id: PMID:26982032
      supporting_text: cep-290;nphp-4 animals fail to uptake the lipophilic dye 
        DiI, a phenotype rescued by low-level expression of the CEP-290::GFP 
        construct
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IGI
  original_reference_id: PMID:22152675
  review:
    summary: IGI annotation with JBTS-14/TMEM237. jbts-14;nphp-4 double mutants 
      have ciliary defects consistent with functional redundancy.
    action: ACCEPT
    reason: Part of the extensive genetic interaction network between NPHP and 
      MKS module proteins in controlling TZ function and ciliogenesis.
    supported_by:
    - reference_id: PMID:22152675
      supporting_text: Caenorhabditis elegans jbts-14 genetically interacts with
        nphp-4, encoding another TZ protein, to control basal body-TZ anchoring 
        to the membrane and ciliogenesis
- term:
    id: GO:1904491
    label: protein localization to ciliary transition zone
  evidence_type: IGI
  original_reference_id: PMID:21422230
  review:
    summary: IGI annotation with MKS-5. NPHP-4 is part of the NPHP module that 
      is anchored to the TZ by MKS-5, and functions to localize other proteins.
    action: ACCEPT
    reason: Key functional role of NPHP-4 in the TZ protein localization 
      hierarchy.
    supported_by:
    - reference_id: PMID:21422230
      supporting_text: MKS-5 is a central component required for 
        docking/anchoring MKS and NPHP protein modules
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IGI
  original_reference_id: PMID:21422230
  review:
    summary: IGI annotation based on genetic interactions with multiple MKS 
      module genes (mks-1, mks-2, mks-3, mks-5, mks-6, mksr-1, mksr-2). Double 
      mutants have severe ciliary defects including loss of membrane-TZ 
      attachments and axoneme extension defects.
    action: ACCEPT
    reason: Comprehensive genetic interaction study establishing the modular 
      organization of TZ proteins and their collective role in ciliogenesis.
    supported_by:
    - reference_id: PMID:21422230
      supporting_text: MKS/MKSR and NPHP modules are collectively required for 
        two essential aspects of ciliogenesis, namely membrane anchoring of the 
        BB/TZ and formation of an intact TZ region
    - reference_id: PMID:21422230
      supporting_text: Joint disruption of an MKS/MKSR protein and NPHP-4 
        results in BB/TZ membrane association defects
- term:
    id: GO:0023041
    label: neuronal signal transduction
  evidence_type: IC
  original_reference_id: PMID:15817158
  review:
    summary: IC annotation inferred from localization in sensory cilia. 
      nphp-1;nphp-4 double mutant males show sensory behavior defects consistent
      with impaired signal transduction.
    action: KEEP_AS_NON_CORE
    reason: While NPHP-4 is required for sensory neuron function, the primary 
      defect is in ciliary structure/gating rather than direct signal 
      transduction. The behavioral phenotypes are likely secondary to ciliary 
      gating defects that affect signaling molecule compartmentalization.
    supported_by:
    - reference_id: PMID:15817158
      supporting_text: We propose that NPHP-1 and NPHP-4 proteins play important
        and redundant roles in facilitating ciliary sensory signal transduction
- term:
    id: GO:0034606
    label: response to hermaphrodite contact
  evidence_type: IGI
  original_reference_id: PMID:15817158
  review:
    summary: IGI annotation with NPHP-1. nphp-1;nphp-4 double mutant males are 
      defective in response to hermaphrodite contact during mating.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype that reflects ciliary sensory function rather 
      than core molecular function. Important for understanding organismal role 
      but secondary to TZ structural function.
    supported_by:
    - reference_id: PMID:15817158
      supporting_text: nphp-1; nphp-4 double, but not single, mutant males are 
        response defective
- term:
    id: GO:0034607
    label: turning behavior involved in mating
  evidence_type: IGI
  original_reference_id: PMID:15817158
  review:
    summary: IGI annotation with NPHP-1. nphp-1;nphp-4 double mutant males show 
      mating behavior defects.
    action: KEEP_AS_NON_CORE
    reason: Male-specific sensory behavior dependent on ciliary function. 
      Secondary phenotype reflecting ciliary gating defects.
    supported_by:
    - reference_id: PMID:15817158
      supporting_text: nphp-1; nphp-4 double, but not single, mutant males are 
        response defective
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:15817158
  review:
    summary: IDA showing NPHP-4::GFP localization to sensory cilia. First 
      characterization of C. elegans nephrocystins.
    action: ACCEPT
    reason: Direct experimental observation of ciliary localization in multiple 
      sensory neuron types.
    supported_by:
    - reference_id: PMID:15817158
      supporting_text: GFP-tagged NPHP-1 and NPHP-4 proteins localize to 
        ciliated sensory endings of dendrites and colocalize with PKD-2 in 
        male-specific sensory cilia
- term:
    id: GO:0035869
    label: ciliary transition zone
  evidence_type: IDA
  original_reference_id: PMID:21689635
  review:
    summary: IDA showing NPHP-4 colocalization with NPHP-8 at the TZ. NPHP-8 
      depends on NPHP-4 for proper localization.
    action: ACCEPT
    reason: Direct visualization of TZ localization, consistent with other 
      studies.
    supported_by:
    - reference_id: PMID:21689635
      supporting_text: NPHP-8 co-localized with NPHP-4 at the transition zone at
        the base of cilia
- term:
    id: GO:0035869
    label: ciliary transition zone
  evidence_type: IDA
  original_reference_id: PMID:21422230
  review:
    summary: IDA from comprehensive TZ protein study. High-resolution imaging of
      NPHP-4 localization at the TZ.
    action: ACCEPT
    reason: Key study establishing TZ as a distinct compartment and NPHP-4 as a 
      core TZ-localized protein.
    supported_by:
    - reference_id: PMID:21422230
      supporting_text: MKS/MKSR and NPHP proteins localize specifically to the 
        ciliary TZ
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:19208769
  review:
    summary: IMP annotation from MKS1-related proteins study. Double mutants of 
      mks/mksr genes (which interact with nphp genes) show increased lifespan 
      due to abnormal insulin-IGF-I signaling.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic phenotype that may result from altered ciliary 
      signaling. Not a core function of NPHP-4 but represents downstream 
      physiological consequence of ciliary dysfunction.
    supported_by:
    - reference_id: PMID:19208769
      supporting_text: we find genetic interactions between all double mks/mksr 
        mutant combinations, manifesting as an increased lifespan phenotype, 
        which is due to abnormal insulin-IGF-I signaling
- term:
    id: GO:0008104
    label: intracellular protein localization
  evidence_type: IGI
  original_reference_id: PMID:18316409
  review:
    summary: IGI annotation with NPHP-1. nphp-1;nphp-4 double mutants show 
      abnormal localization of IFT components including OSM-6 and BBS proteins.
    action: MODIFY
    reason: This is too broad. The annotation should more specifically reflect 
      the role in regulating ciliary access and localization of specific IFT 
      components.
    proposed_replacement_terms:
    - id: GO:0072638
      label: intraciliary transport
    - id: GO:1904491
      label: protein localization to ciliary transition zone
    additional_reference_ids:
    - PMID:18316409
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: loss of both NPHP-1 and NPHP-4 but not NPHP-1 alone leads
        to the abnormal ciliary localization of the IFT-B polypeptide OSM-6, the
        OSM-3-kinesin, and the BBS proteins BBS-7 and BBS-8
- term:
    id: GO:0036064
    label: ciliary basal body
  evidence_type: IDA
  original_reference_id: PMID:18316409
  review:
    summary: IDA from detailed ultrastructural study of nephrocystin function. 
      NPHP-4 localizes to basal body/TZ region.
    action: ACCEPT
    reason: Comprehensive study with electron microscopy and fluorescence 
      imaging confirming localization at the ciliary base region.
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: NPHP-1 and NPHP-4 localize to TZs of male-specific CEM 
        cilia
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:18316409
  review:
    summary: IDA showing localization in sensory cilia across multiple neuron 
      types.
    action: ACCEPT
    reason: Consistent with other IDA studies showing ciliary localization.
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: NPHP-1 and NPHP-4 localize to TZs of male-specific CEM 
        cilia
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IMP
  original_reference_id: PMID:18316409
  review:
    summary: IMP annotation from study showing nphp-4 mutants have 
      ultrastructural defects in ciliary B tubules and IFT transport 
      abnormalities.
    action: ACCEPT
    reason: Core function demonstrated by loss-of-function analysis with 
      ultrastructural characterization.
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: nphp-4 mutants have B tubule defects in amphid channel 
        cilia
    - reference_id: PMID:18316409
      supporting_text: We propose that NPHP-1 and NPHP-4 act globally at the TZ 
        to regulate ciliary access of the IFT machinery, axonemal structural 
        components, and signaling molecules
- term:
    id: GO:0035177
    label: larval foraging behavior
  evidence_type: IMP
  original_reference_id: PMID:18337471
  review:
    summary: IMP annotation from study on B9 proteins and nephrocystins. nphp-4 
      mutants with B9 protein mutations have foraging behavior defects.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype reflecting sensory function. The foraging 
      defect is likely due to chemosensory impairment from ciliary dysfunction 
      rather than a direct role in behavior per se.
    supported_by:
    - reference_id: PMID:18337471
      supporting_text: the B9 proteins function redundantly with the 
        nephrocystins to regulate the formation and/or maintenance of cilia and 
        dendrites in the amphid and phasmid ciliated sensory neurons
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: PMID:15817158
  title: Functional characterization of the C. elegans nephrocystins NPHP-1 and 
    NPHP-4 and their role in cilia and male sensory behaviors
  findings:
  - statement: NPHP-1 and NPHP-4 are expressed in a subset of sensory neurons
    supporting_text: Functional characterization of the C. elegans nephrocystins
      NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors.
  - statement: GFP-tagged proteins localize to ciliated sensory endings
    supporting_text: Functional characterization of the C. elegans nephrocystins
      NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors.
  - statement: The cilia of single mutants are intact
    supporting_text: Functional characterization of the C. elegans nephrocystins
      NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors.
  - statement: nphp-1;nphp-4 double mutant males are response defective
    supporting_text: Functional characterization of the C. elegans nephrocystins
      NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors.
  - statement: NPHP-1 and NPHP-4 play redundant roles in ciliary sensory signal 
      transduction
    supporting_text: Functional characterization of the C. elegans nephrocystins
      NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors.
- id: PMID:18316409
  title: The Caenorhabditis elegans nephrocystins act as global modifiers of 
    cilium structure
  findings:
  - statement: NPHP-1 and NPHP-4 localize to ciliary transition zones
    supporting_text: The Caenorhabditis elegans nephrocystins act as global 
      modifiers of cilium structure.
  - statement: Loss of nephrocystins causes changes in localization of specific 
      ciliary components
    supporting_text: The Caenorhabditis elegans nephrocystins act as global 
      modifiers of cilium structure.
  - statement: nphp-4 mutations cause B tubule defects in amphid channel cilia
    supporting_text: The Caenorhabditis elegans nephrocystins act as global 
      modifiers of cilium structure.
  - statement: NPHP-4 regulates ciliary localization of OSM-6, OSM-3, and BBS 
      proteins
    supporting_text: The Caenorhabditis elegans nephrocystins act as global 
      modifiers of cilium structure.
  - statement: Nephrocystins act globally at the TZ to regulate ciliary access
    supporting_text: The Caenorhabditis elegans nephrocystins act as global 
      modifiers of cilium structure.
- id: PMID:18337471
  title: Functional redundancy of the B9 proteins and nephrocystins in 
    Caenorhabditis elegans ciliogenesis
  findings:
  - statement: B9 proteins function redundantly with nephrocystins
    supporting_text: Functional redundancy of the B9 proteins and nephrocystins 
      in Caenorhabditis elegans ciliogenesis.
  - statement: Combined mutations cause cilia and dendrite defects
    supporting_text: Functional redundancy of the B9 proteins and nephrocystins 
      in Caenorhabditis elegans ciliogenesis.
  - statement: B9 proteins form a complex at the base of cilia
    supporting_text: Functional redundancy of the B9 proteins and nephrocystins 
      in Caenorhabditis elegans ciliogenesis.
- id: PMID:19208769
  title: Functional interactions between the ciliopathy-associated Meckel 
    syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins
  findings:
  - statement: MKS-1, MKSR-1, MKSR-2 localize to transition zones
    supporting_text: Functional interactions between the ciliopathy-associated 
      Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) 
      proteins.
  - statement: Their localization is largely co-dependent
    supporting_text: Functional interactions between the ciliopathy-associated 
      Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) 
      proteins.
  - statement: mks/mksr mutant combinations show increased lifespan phenotype
    supporting_text: Functional interactions between the ciliopathy-associated 
      Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) 
      proteins.
- id: PMID:21422230
  title: MKS and NPHP modules cooperate to establish basal body/transition zone 
    membrane associations and ciliary gate function during ciliogenesis
  findings:
  - statement: NPHP-4 is part of the NPHP module at the TZ
    supporting_text: MKS and NPHP modules cooperate to establish basal 
      body/transition zone membrane associations and ciliary gate function 
      during ciliogenesis.
  - statement: MKS and NPHP modules work together for TZ function
    supporting_text: MKS and NPHP modules cooperate to establish basal 
      body/transition zone membrane associations and ciliary gate function 
      during ciliogenesis.
  - statement: TZ proteins establish basal body membrane attachments
    supporting_text: MKS and NPHP modules cooperate to establish basal 
      body/transition zone membrane associations and ciliary gate function 
      during ciliogenesis.
  - statement: TZ proteins restrict accumulation of nonciliary components in 
      cilia
    supporting_text: MKS and NPHP modules cooperate to establish basal 
      body/transition zone membrane associations and ciliary gate function 
      during ciliogenesis.
  - statement: MKS-5 is central for anchoring both modules
    supporting_text: MKS and NPHP modules cooperate to establish basal 
      body/transition zone membrane associations and ciliary gate function 
      during ciliogenesis.
- id: PMID:21689635
  title: Caenorhabditis elegans ciliary protein NPHP-8, the homologue of human 
    RPGRIP1L, is required for ciliogenesis and chemosensation.
  findings:
  - statement: NPHP-8 colocalizes with NPHP-4 at the transition zone
    supporting_text: Caenorhabditis elegans ciliary protein NPHP-8, the 
      homologue of human RPGRIP1L, is required for ciliogenesis and 
      chemosensation.
- id: PMID:22152675
  title: TMEM237 is mutated in individuals with a Joubert syndrome related 
    disorder and expands the role of the TMEM family at the ciliary transition 
    zone
  findings:
  - statement: JBTS-14/TMEM237 genetically interacts with nphp-4
    supporting_text: TMEM237 is mutated in individuals with a Joubert syndrome 
      related disorder and expands the role of the TMEM family at the ciliary 
      transition zone.
  - statement: Double mutants have basal body-TZ anchoring defects
    supporting_text: TMEM237 is mutated in individuals with a Joubert syndrome 
      related disorder and expands the role of the TMEM family at the ciliary 
      transition zone.
  - statement: Both require RPGRIP1L/MKS-5 for proper TZ localization
    supporting_text: TMEM237 is mutated in individuals with a Joubert syndrome 
      related disorder and expands the role of the TMEM family at the ciliary 
      transition zone.
- id: PMID:26595381
  title: TMEM107 recruits ciliopathy proteins to subdomains of the ciliary 
    transition zone and causes Joubert syndrome
  findings:
  - statement: TMEM-107 functions redundantly with NPHP-4
    supporting_text: TMEM107 recruits ciliopathy proteins to subdomains of the 
      ciliary transition zone and causes Joubert syndrome.
  - statement: Double mutants have TZ docking and Y-link assembly defects
    supporting_text: TMEM107 recruits ciliopathy proteins to subdomains of the 
      ciliary transition zone and causes Joubert syndrome.
  - statement: TMEM-107 is part of the MKS module
    supporting_text: TMEM107 recruits ciliopathy proteins to subdomains of the 
      ciliary transition zone and causes Joubert syndrome.
- id: PMID:26863025
  title: A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles 
    and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4
  findings:
  - statement: Screen identified mks-1, mks-2, mks-5 as nphp-4 interactors
    supporting_text: A Screen for Modifiers of Cilia Phenotypes Reveals Novel 
      MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and 
      nphp-4.
  - statement: Novel osm-3(yhw66) allele shows specific interaction with nphp-4
    supporting_text: A Screen for Modifiers of Cilia Phenotypes Reveals Novel 
      MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and 
      nphp-4.
  - statement: Double mutants lack distal segments and are Dyf
    supporting_text: A Screen for Modifiers of Cilia Phenotypes Reveals Novel 
      MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and 
      nphp-4.
  - statement: NPHP-4 influences localization and function of OSM-3 kinesin
    supporting_text: A Screen for Modifiers of Cilia Phenotypes Reveals Novel 
      MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and 
      nphp-4.
- id: PMID:26982032
  title: MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition 
    Zone
  findings:
  - statement: CEP-290 is required for MKS module assembly
    supporting_text: MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary 
      Transition Zone.
  - statement: MKS-5 is central to TZ assembly pathway
    supporting_text: MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary 
      Transition Zone.
  - statement: cep-290;nphp-4 double mutants fail to dye-fill
    supporting_text: MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary 
      Transition Zone.
- id: PMID:27623382
  title: A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis
  findings:
  - statement: Girdin localizes to proximal centrioles
    supporting_text: A Conserved Role for Girdin in Basal Body Positioning and 
      Ciliogenesis.
  - statement: Girdin regulates basal body positioning
    supporting_text: A Conserved Role for Girdin in Basal Body Positioning and 
      Ciliogenesis.
  - statement: NPHP-4 used as marker for basal body region
    supporting_text: A Conserved Role for Girdin in Basal Body Positioning and 
      Ciliogenesis.
- id: file:worm/nphp-4/nphp-4-deep-research-falcon.md
  title: Deep research report on nphp-4
  findings: []
core_functions:
- description: NPHP-4 is a core component of the NPHP module at the ciliary 
    transition zone, where it functions to establish the ciliary gate and 
    regulate protein access to the ciliary compartment. Multiple IDA studies 
    demonstrate specific localization to the TZ (PMID:21422230, PMID:21689635, 
    PMID:18316409, PMID:15817158).
  supported_by:
  - reference_id: PMID:21422230
    supporting_text: MKS/MKSR and NPHP proteins localize specifically to the 
      ciliary TZ
  - reference_id: PMID:18316409
    supporting_text: We propose that NPHP-1 and NPHP-4 act globally at the TZ to
      regulate ciliary access of the IFT machinery, axonemal structural 
      components, and signaling molecules
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  directly_involved_in:
  - id: GO:1905515
    label: non-motile cilium assembly
  - id: GO:1904491
    label: protein localization to ciliary transition zone
  locations:
  - id: GO:0035869
    label: ciliary transition zone
  - id: GO:0097730
    label: non-motile cilium
proposed_new_terms: []
suggested_questions:
- question: What are the specific protein-protein interactions that mediate 
    NPHP-4 function at the TZ?
- question: How does NPHP-4 specifically regulate OSM-3 kinesin function and 
    localization?
- question: What is the structural role of NPHP-4 in Y-link formation at the TZ?
suggested_experiments:
- description: Proximity proteomics (BioID/APEX) to identify direct NPHP-4 
    interacting partners
- description: Super-resolution microscopy to determine precise subdomain 
    localization within the TZ
- description: Structure-function analysis to identify domains required for TZ 
    localization vs function
tags:
- caeel-ciliopathy

nphp-4

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