nphp-1

UniProt ID: O17972
Organism: Caenorhabditis elegans
Review Status: COMPLETE
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Gene Description

NPHP-1 is the C. elegans ortholog of human nephrocystin-1 (NPHP1), a protein mutated in nephronophthisis. It localizes specifically to the ciliary transition zone (TZ) in sensory neurons and functions as part of the NPHP module that works redundantly with the MKS module to establish the ciliary gate. NPHP-1 plays important roles in ciliary structure, sensory signal transduction, and male mating behaviors. The protein contains an SH3 domain and requires NPHP-4 for proper TZ localization. Together with NPHP-4, it regulates ciliary access of IFT machinery components, axonemal structural proteins, and signaling molecules.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: IBA annotation based on phylogenetic analysis. While NPHP-1 is predominantly localized to the ciliary transition zone, cytoplasmic localization is plausible as the protein must transit through the cytoplasm. However, this is a generic term that does not capture the protein's specific and functionally relevant localization at the transition zone.
Reason: The annotation is not incorrect but does not represent the core localization of NPHP-1. The protein's critical function is at the transition zone. Cytoplasmic localization may represent transit or a minor pool, but the more informative and functionally relevant localizations are the TZ-related terms.
Supporting Evidence:
file:worm/nphp-1/nphp-1-deep-research-falcon.md
model: Edison Scientific Literature
GO:0005929 cilium
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation based on phylogenetic analysis. NPHP-1 localizes to the ciliary transition zone, which is a subdomain of the cilium. Multiple studies demonstrate TZ-specific localization in C. elegans [PMID:15817158, PMID:18316409, PMID:21422230].
Reason: While the more specific term 'ciliary transition zone' (GO:0035869) better captures NPHP-1's localization, this broader term is accurate since the TZ is part of the cilium. The IBA annotation aligns with experimental evidence showing ciliary localization.
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.
PMID:18316409
GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization
GO:0090251 protein localization involved in establishment of planar polarity
IBA
GO_REF:0000033 		UNDECIDED
Summary: IBA annotation based on phylogenetic inference. This annotation likely derives from mammalian data where NPHP1 has been implicated in planar cell polarity pathways. There is no direct evidence for this function in C. elegans.
Reason: While this may be a conserved function based on phylogenetic analysis, there is no direct experimental evidence for a role in planar polarity in C. elegans. The IBA annotation is reasonable given conservation, but without C. elegans-specific data, this remains speculative.
GO:0030030 cell projection organization
IEA
GO_REF:0000043 		ACCEPT
Summary: IEA annotation based on UniProtKB keyword mapping (cilium biogenesis/degradation). NPHP-1 is involved in cilium structure and organization, particularly through its role at the transition zone.
Reason: The annotation is supported by experimental evidence showing that nphp-1 mutants have defects in CEM cilia morphology [PMID:18316409]. NPHP-1 and NPHP-4 act globally at the TZ to regulate ciliary structure, and loss causes cell type-specific phenotypes in cilia organization.
Supporting Evidence:
PMID:18316409
nphp-1 and nphp-4 are important modulators of ciliary ultrastructure, with defects resulting in a broad phenotypic spectrum
GO:0036064 ciliary basal body
IDA
PMID:27623382
A Conserved Role for Girdin in Basal Body Positioning and Ci... 		MODIFY
Summary: IDA annotation from a study on Girdin's role in basal body positioning. The paper examines various ciliary proteins including NPHP-1 localization. However, multiple C. elegans studies show NPHP-1 specifically localizes to the transition zone rather than the basal body proper [PMID:18316409, PMID:21422230].
Reason: In C. elegans, the basal body and transition zone are distinct regions. Multiple detailed studies using GFP-tagged NPHP-1 show specific localization to the transition zone, not the basal body. The transition zone is adjacent to but distinct from the basal body region where IFT proteins concentrate. This annotation should be modified to reflect TZ localization.
Proposed replacements: ciliary transition zone
Supporting Evidence:
PMID:18316409
GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization
PMID:21422230
we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB)
GO:0035869 ciliary transition zone
IDA
PMID:26595381
TMEM107 recruits ciliopathy proteins to subdomains of the ci... 		ACCEPT
Summary: Direct experimental evidence from a study on TMEM107 and ciliopathy proteins. NPHP-1 TZ localization is well-established across multiple C. elegans studies.
Reason: This is the core localization for NPHP-1. Multiple studies demonstrate specific TZ localization using fluorescently tagged proteins [PMID:15817158, PMID:18316409, PMID:21422230, PMID:26595381]. NPHP-1 is part of the NPHP module that localizes to and functions at the transition zone.
Supporting Evidence:
PMID:26595381
nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins
PMID:21422230
NPHP-1 and NPHP-4 localize to the TZ in mks-5 mutants, but to a subregion smaller than that occupied in N2
GO:0003674 molecular_function
ND
GO_REF:0000015 		ACCEPT
Summary: ND (No biological Data) annotation indicating no molecular function is annotated. This is a placeholder annotation used when no experimental data defines a specific molecular function.
Reason: Despite extensive characterization of NPHP-1's cellular role, no specific molecular function (e.g., enzyme activity, specific binding activity) has been experimentally determined. The protein contains an SH3 domain which suggests protein-protein interaction capability, but no specific molecular function has been annotated with experimental evidence. The ND annotation is appropriate.
GO:0097546 ciliary base
IDA
PMID:25335890
Ciliopathy proteins establish a bipartite signaling compartm... 		ACCEPT
Summary: IDA annotation from a study on ciliopathy proteins in AFD thermosensory neurons. The study examines how ciliary proteins establish signaling compartments.
Reason: The ciliary base encompasses the transition zone and basal body region. NPHP-1 localization to this region is well-documented. This broader term is accurate as an annotation alongside the more specific TZ term.
Supporting Evidence:
PMID:25335890
proteins associated with Bardet-Biedl syndrome (BBS), Meckel syndrome and nephronophthisis at its base
GO:0023041 neuronal signal transduction
IC
PMID:15817158
Functional characterization of the C. elegans nephrocystins ... 		ACCEPT
Summary: IC (Inferred by Curator) annotation inferring a role in neuronal signal transduction based on localization to non-motile cilia in sensory neurons and mating behavior phenotypes.
Reason: NPHP-1 localizes to sensory cilia in neurons and contributes to sensory behaviors. The double mutant nphp-1;nphp-4 shows response defects, supporting a role in sensory signal transduction. The IC inference from localization and behavioral phenotypes is reasonable.
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 ... 		ACCEPT
Summary: IGI (Inferred from Genetic Interaction) annotation based on interaction with nphp-4. Double mutant nphp-1;nphp-4 males show defects in response behaviors during mating.
Reason: The annotation captures the redundant role of NPHP-1 and NPHP-4 in male mating behaviors. While single mutants have mild phenotypes, the double mutant shows clear behavioral defects.
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: Turning-behaviour defects seen in nphp-1;nphp-4 double mutants are downstream of impaired ciliary signalling in male-specific sensory neurons, not a direct molecular function of NPHP-1.
Reason: Ciliary gene; the mating-turning behaviour is a distal phenotypic consequence of cilium dysfunction; non-core per the behaviour-annotation rubric.
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 annotation showing NPHP-1 localizes to non-motile (primary/sensory) cilia. C. elegans sensory neurons have non-motile cilia, and NPHP-1 localizes to these structures.
Reason: All C. elegans sensory cilia are non-motile (9+0 configuration), and NPHP-1 is expressed in and localizes to ciliated sensory neurons. This is a correct and well-supported annotation.
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:21422230
MKS and NPHP modules cooperate to establish basal body/trans... 		ACCEPT
Summary: IDA annotation from the comprehensive study on MKS and NPHP modules at the transition zone. This paper provides detailed characterization of NPHP-1 TZ localization and function.
Reason: This is a core localization for NPHP-1 supported by extensive experimental evidence. The study uses fluorophore-tagged proteins and demonstrates NPHP-1 specifically localizes to the TZ region. Duplicate with PMID:26595381 annotation but from different reference.
Supporting Evidence:
PMID:21422230
Using fluorescently tagged proteins, we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB).
GO:0008340 determination of adult lifespan
IMP
PMID:19208769
Functional interactions between the ciliopathy-associated Me... 		KEEP AS NON CORE
Summary: IMP annotation based on lifespan phenotype in double mutants. The study on MKS1-related proteins found that mks/mksr double mutants with nphp mutations show increased lifespan due to abnormal insulin-IGF-I signaling.
Reason: This is a pleiotropic phenotype likely resulting from disrupted ciliary function affecting sensory signaling pathways that regulate lifespan (insulin/IGF-1 signaling). Not a core function of NPHP-1 but rather a consequence of ciliary/sensory 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 indicating NPHP-1 participates in regulating protein localization within the cell, specifically at the ciliary transition zone.
Reason: This annotation is too general. NPHP-1 specifically functions at the TZ to regulate ciliary access of IFT components and other proteins. A more specific term related to ciliary protein localization or ciliary gate function would be more appropriate.
Supporting Evidence:
PMID:18316409
In conclusion, 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.
PMID:21422230
the two modules restrict inappropriate accumulation of membrane-associated proteins inside cilia
GO:0097730 non-motile cilium
IDA
PMID:18316409
The Caenorhabditis elegans nephrocystins act as global modif... 		ACCEPT
Summary: IDA annotation confirming localization to non-motile cilia based on comprehensive characterization of nephrocystin function in C. elegans.
Reason: Duplicate of annotation from PMID:15817158 but from different reference. Both support NPHP-1 localization to non-motile sensory cilia. Valid annotation.
Supporting Evidence:
PMID:18316409
C. elegans nphp-1 and nphp-4 orthologues are expressed in the ciliated sensory nervous system
GO:1905515 non-motile cilium assembly
IMP
PMID:18316409
The Caenorhabditis elegans nephrocystins act as global modif... 		ACCEPT
Summary: IMP annotation based on ciliary assembly defects observed in nephrocystin mutants. The study shows NPHP-1 and NPHP-4 are important for proper cilium assembly and structure.
Reason: UniProt states NPHP-1 may be necessary for initial assembly of the cilium. The Jauregui 2008 study demonstrates that NPHP-1 and NPHP-4 act at the TZ to regulate ciliary components, and double mutants have ciliary structure defects. NPHP-1 contributes to cilium assembly through its role at the TZ.
Supporting Evidence:
PMID:18316409
nphp-1 and nphp-4 are important modulators of ciliary ultrastructure, with defects resulting in a broad phenotypic spectrum
PMID:21422230
MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension

Core Functions

NPHP-1 is a transition zone scaffold protein that functions as part of the NPHP module. It localizes specifically to the ciliary transition zone where it contributes to establishing the ciliary gate and regulating cilium assembly. The protein works redundantly with NPHP-4 and cooperates with the MKS module to anchor the basal body/TZ to the membrane.

Directly Involved In:
non-motile cilium assembly neuronal signal transduction
Cellular Locations:
ciliary transition zone
Supporting Evidence:
  • PMID:21422230
    Using fluorescently tagged proteins, we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB).
  • PMID:18316409
    GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization

References

GO_REF:0000015
Use of the ND evidence code for Gene Ontology (GO) terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
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 localizes to ciliated sensory endings of dendrites
    "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."
  • NPHP-1 and NPHP-4 colocalize with PKD-2 in male-specific sensory cilia
    "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."
  • nphp-1;nphp-4 double mutant males are response defective
    "nphp-1; nphp-4 double, but not single, mutant males are response defective."
  • NPHP-1 and NPHP-4 play redundant roles in ciliary sensory signal transduction
    "We propose that NPHP-1 and NPHP-4 proteins play important and redundant roles in facilitating ciliary sensory signal transduction."
PMID:18316409
The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure.
  • NPHP-1 and NPHP-4 localize to ciliary transition zones
    "GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization"
  • NPHP-1 requires NPHP-4 for TZ localization
    "GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization"
  • NPHP-1 and NPHP-4 regulate ciliary access of IFT machinery and signaling molecules
    "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"
  • Loss of NPHP-1 and NPHP-4 causes changes in localization of specific ciliary components
    "In conclusion, 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."
  • nphp-1 mutants have stunted or misshaped CEM cilia
    "In nphp-1 mutants, CEM cilia are stunted or misshaped"
PMID:19208769
Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins.
  • MKS/MKSR proteins localize to transition zones/basal bodies of sensory cilia
    "MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia"
  • Genetic interactions between mks/mksr mutants manifest as increased lifespan due to abnormal insulin-IGF-I signaling
    "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"
PMID:21422230
MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis.
  • NPHP-1 and NPHP-4 localize to the transition zone
    "Using fluorescently tagged proteins, we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB)."
  • NPHP-1 and NPHP-4 are part of the NPHP module
    "we group MKS-1, MKSR-1, MKSR-2, MKS-3, and MKS-6 into an MKS/MKSR module and NPHP-1 and NPHP-4 into an NPHP module"
  • NPHP and MKS modules cooperate for BB/TZ membrane associations
    "MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension"
  • TZ proteins establish a ciliary gate that restricts protein accumulation in cilia
    "the two modules restrict inappropriate accumulation of membrane-associated proteins inside cilia"
PMID:25335890
Ciliopathy proteins establish a bipartite signaling compartment in a C. elegans thermosensory neuron.
  • Ciliopathy proteins including nephronophthisis proteins localize to the ciliary base
    "proteins associated with Bardet-Biedl syndrome (BBS), Meckel syndrome and nephronophthisis at its base"
PMID:26595381
TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome.
  • TMEM-107 functions redundantly with NPHP-4 to regulate cilium integrity
    "nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins"
  • TZ proteins organize recruitment of ciliopathy proteins
    "nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins"
PMID:27623382
A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis.
PMID:15659564
Expression and phenotype analysis of the nephrocystin-1 and nephrocystin-4 homologs in Caenorhabditis elegans.
file:worm/nphp-1/nphp-1-deep-research-falcon.md
Deep research report on nphp-1

Suggested Questions for Experts

Q: What is the precise molecular function of the SH3 domain in NPHP-1?

Q: Does NPHP-1 directly participate in Y-link formation at the transition zone?

Q: Are there specific protein-protein interactions mediated by NPHP-1 that are essential for ciliary gate function?

Suggested Experiments

Experiment: Identify direct binding partners of NPHP-1 using immunoprecipitation or proximity labeling approaches

Hypothesis: NPHP-1 interacts with specific TZ proteins through its SH3 domain

Experiment: Determine if the SH3 domain is required for TZ localization using domain deletion constructs

Hypothesis: The SH3 domain mediates protein-protein interactions required for TZ anchoring

Experiment: Examine whether NPHP-1 is a structural component of Y-links using immuno-EM

Hypothesis: NPHP-1 may be a direct structural component of Y-link connectors

Tags

caeel-ciliopathy

Deep Research

Falcon

(nphp-1-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 26 citations 2025-12-29T15:35:32.162205

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.

Research plan and verification
We verified the target as Caenorhabditis elegans nphp-1 (UniProt O17972), encoding a nephrocystin-1-like protein in the nephrocystin-1 family with an SH3 domain and additional interaction motifs; literature consistently localizes C. elegans NPHP-1 to the ciliary transition zone (TZ) in ciliated sensory neurons and functionally groups it with the NPHP module (notably NPHP-4), matching the UniProt description and domain annotations (Dec 2005 Journal of Cell Science; Mar 2008 J Cell Biol; May 2008 Mol Biol Cell) (winkelbauer2005thec.elegans pages 1-2, jauregui2008thecaenorhabditiselegans pages 1-2, williams2008functionalredundancyof pages 1-2).

Key concepts and definitions with current understanding
- Identity and family: nphp-1 encodes the C. elegans ortholog of human NPHP1, a ciliopathy protein; NPHP-1 contains interaction modules including an SH3 region and a nephrocystin homology domain, consistent with an adaptor/scaffold role rather than an enzyme or transporter (Dec 2005, J Cell Sci, doi:10.1242/jcs.02665) (winkelbauer2005thec.elegans pages 1-2).
- Subcellular localization: In vivo, NPHP-1 concentrates at the ciliary transition zone (base of cilia/basal body–TZ region) in ciliated sensory neurons and is excluded from distal axoneme; its TZ localization depends on NPHP-4 (Aug 2011, Hum Mol Genet, doi:10.1093/hmg/ddr198; Dec 2005, J Cell Sci) (masyukova2011assessingthepathogenic pages 2-2, winkelbauer2005thec.elegans pages 1-2).
- Primary function: NPHP-1 functions as a TZ adaptor/modifier that regulates gatekeeping of protein access, impacting intraflagellar transport (IFT) cargo entry and axonemal composition; single mutants often have mild or subtle ultrastructural phenotypes, indicating NPHP-1 modulates rather than absolutely drives ciliogenesis (Mar 2008, J Cell Biol, doi:10.1083/jcb.200707090) (jauregui2008thecaenorhabditiselegans pages 1-2).
- Pathway/module context: NPHP-1 and NPHP-4 comprise the NPHP module at the TZ; this module cooperates and shows genetic redundancy with MKS module proteins (e.g., MKS-1, MKSR-1/2, MKS-3, MKS-5/RPGRIP1L, CEP-290/MKS4) and interfaces with IFT/BBS components; modular interactions underpin TZ assembly and gating (Nov 2015, PLoS Genet, doi:10.1371/journal.pgen.1005627; Mar 2016, PLoS Biol, doi:10.1371/journal.pbio.1002416; Jun 2012, J Cell Sci, doi:10.1242/jcs.095539) (masyukova2016ascreenfor pages 26-27, warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2).

Recent developments and latest research (emphasis 2023–2024)
- Transition zone as gated compartment and modular organization: Recent reviews synthesize advances that define the TZ as a ringed, modular diffusion barrier whose integrity and selectivity are conferred by MKS and NPHP complexes; these frameworks contextualize NPHP-1’s adaptor role in maintaining ciliary compartmentalization (Apr 2023, Nature Reviews Genetics, doi:10.1038/s41576-023-00587-9) (williams2008functionalredundancyof pages 11-11).
- Methodological advances: Super-resolution and expansion microscopy now resolve TZ architecture at tens-of-nanometers to sub-10 nm scales, enabling precise mapping of TZ adaptors like NPHP-1 within discrete rings and nanodomains; these methods support re-interpretation of prior localization and interaction data in C. elegans and mammals (Jan 2024, Laser & Optoelectronics Progress, doi:10.3788/lop232684) (zhen2024superresolutionfluorescencemicroscopy pages 1-3).
- Broader ciliopathy synthesis: Contemporary nephrology-focused reviews highlight actin–TZ crosstalk and reiterate the cooperative role of NPHP and MKS modules in TZ integrity and ciliogenesis, aligning with C. elegans genetic paradigms that placed NPHP-1/4 as gate modifiers (Jan 2024, Frontiers in Nephrology, doi:10.3389/fneph.2023.1331847) (williams2008functionalredundancyof pages 11-11).
- Additional genetic landscape updates: A 2023 study on DCDC2 (RPI-1)–NPHP-4 redundancy in C. elegans reinforces the modular, partially redundant nature of TZ and ciliary biogenesis networks within which NPHP-1 operates, supporting an adaptor network with distributed robustness (Jan 2023, Turkish Journal of Biology, doi:10.55730/1300-0152.2642) (williams2008functionalredundancyof pages 11-11).

Primary experimental evidence in C. elegans for function and localization
- TZ localization and dependency: NPHP-1 and NPHP-4 localize to the TZ and require DAF-19 (RFX) transcriptional regulation; NPHP-4 is required for correct TZ localization of NPHP-1 (Dec 2005, J Cell Sci; Aug 2011, Hum Mol Genet) (winkelbauer2005thec.elegans pages 1-2, masyukova2011assessingthepathogenic pages 2-2).
- Adaptor/gatekeeper function: Loss of NPHP-1/4 changes localization of specific ciliary components and induces subtle ultrastructural axonemal defects; nphp-4 mutants show B-tubule defects that perturb IFT, supporting a role for the NPHP-1/4 module in regulating cargo access and axonemal integrity at the TZ (Mar 2008, J Cell Biol) (jauregui2008thecaenorhabditiselegans pages 1-2).
- Genetic interactions with MKS and other complexes: NPHP-1/4 display synthetic interactions with MKS genes (mks-1, mks-3, mks-5/RPGRIP1L, mksr-1/2, mks-6), indicating cooperative parallel pathways that support TZ assembly, basal body/TZ membrane anchoring, and ciliogenesis (May 2008, Mol Biol Cell; Jun 2012, J Cell Sci; Mar 2016, PLoS Biol) (williams2008functionalredundancyof pages 1-2, warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2).
- Interactions with IFT motors and BBSome context: A modifier screen in worms uncovered a specific genetic interaction between the IFT kinesin OSM-3 and nphp-4, implicating the NPHP module in coordinating distal segment assembly and IFT motor function; this genetic cross-talk supports the idea that NPHP-1, via the NPHP module, interfaces with IFT and BBS-dependent trafficking at the TZ gate (Feb 2016, PLoS Genet, doi:10.1371/journal.pgen.1005841; Nov 2015, PLoS Genet) (masyukova2016ascreenfor pages 26-27).
- Conservation with human NPHP1: Mammalian NPHP1 and NPHP4 physically interact, and cross-species studies converge on conserved TZ localization and gating functions, reinforcing use of C. elegans to model human NPHP1 biology (Jun 2012, J Cell Sci; reviews cited therein) (warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2).

Phenotypes and quantitative readouts in C. elegans
- Cilia structure and ultrastructure: nphp-1 or nphp-4 single mutants typically retain gross cilia by dye filling, yet transmission electron microscopy reveals axonemal abnormalities (e.g., B-tubule defects in amphid channel cilia) and altered IFT dynamics in nphp-4 mutants; double or specific sensitized backgrounds show stronger ciliogenesis defects, including truncated axonemes and dendrite attachment issues (Mar 2008, J Cell Biol; May 2008, Mol Biol Cell) (jauregui2008thecaenorhabditiselegans pages 1-2, williams2008functionalredundancyof pages 1-2).
- Sensory function: Behavioral assays show chemosensory deficits and male sensory behavioral changes consistent with impaired ciliary signaling when the NPHP module is perturbed (Dec 2005, J Cell Sci) (winkelbauer2005thec.elegans pages 1-2).
- Genetic interaction statistics/examples: Screens in nphp-4 backgrounds identified ≥10 loci that exacerbate NPHP phenotypes, including multiple MKS genes and the osm-3 kinesin; dyf/osm behavioral penetrance rises markedly in double mutants compared to single mutants, illustrating quantitative genetic modifiers (Feb 2016, PLoS Genet) (masyukova2016ascreenfor pages 26-27).

Subcellular context and assembly pathway
- TZ hierarchy and assembly: C. elegans studies place MKS-5 (RPGRIP1L) and CEP-290 as central assembly factors establishing TZ architecture, with NPHP and MKS modules showing interdependent, yet partially separable, localization dependencies; within this pathway, NPHP-1/4 act as early NPHP-module components engaged in gating and membrane anchoring functions (Mar 2016, PLoS Biol) (warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2).

Expert opinions and authoritative analyses
- Cross-disciplinary reviews conclude the TZ comprises modular complexes (NPHP and MKS) forming diffusion barriers essential for ciliary signaling, and that gene–gene interactions between modules (including with BBS/IFT) shape penetrance and expressivity in ciliopathies; C. elegans genetics is highlighted for revealing conserved module logic applicable to human disease (Apr 2023, Nat Rev Genet; Jan 2024, Frontiers in Nephrology) (williams2008functionalredundancyof pages 11-11).
- Imaging method reviews emphasize that super-resolution modalities now robustly resolve TZ rings and substructures, providing the technical basis to refine NPHP-1 spatial models in vivo (Jan 2024, Laser & Optoelectronics Progress) (zhen2024superresolutionfluorescencemicroscopy pages 1-3).

Current applications and real-world implementations
- Variant interpretation and functional modeling: C. elegans is used to functionally assess human nephronophthisis alleles (e.g., NPHP4) with in vivo phenotyping of TZ localization and cilia function; dependency of NPHP-1 localization on NPHP-4 in worm informs variant pathogenicity frameworks and cross-species conservation (Aug 2011, Hum Mol Genet) (masyukova2011assessingthepathogenic pages 2-2).
- Systems genetics of ciliopathies: Worm genetic interaction maps (NPHP–MKS–IFT/BBS) are applied conceptually to interpret human oligogenic cases and modifiers in nephronophthisis and related ciliopathies (Nov 2015, PLoS Genet; Mar 2016, PLoS Biol) (masyukova2016ascreenfor pages 26-27, warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2).
- Imaging pipelines: The application of SRM/expansion microscopy to TZ architecture underpins diagnostic imaging development and enables hypothesis-driven mapping of pathogenic variants impacting NPHP/MKS rings, relevant to research translation (Jan 2024, Laser & Optoelectronics Progress) (zhen2024superresolutionfluorescencemicroscopy pages 1-3).

URLs and publication dates (selection)
- Winkelbauer et al., J Cell Sci, published Dec 2005 (online Nov 15, 2005): https://doi.org/10.1242/jcs.02665 (winkelbauer2005thec.elegans pages 1-2)
- Jauregui et al., J Cell Biol, Mar 3, 2008: https://doi.org/10.1083/jcb.200707090 (jauregui2008thecaenorhabditiselegans pages 1-2)
- Williams et al., Mol Biol Cell, May 2008 (published online Mar 12, 2008): https://doi.org/10.1091/mbc.E07-10-1070 (williams2008functionalredundancyof pages 1-2)
- Warburton‑Pitt et al., J Cell Sci, Jun 2012: https://doi.org/10.1242/jcs.095539 (warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2)
- Yee et al., PLoS Genet, Nov 2015: https://doi.org/10.1371/journal.pgen.1005627 (masyukova2016ascreenfor pages 26-27)
- Li et al., PLoS Biol, Mar 2016: https://doi.org/10.1371/journal.pbio.1002416 (warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2)
- Masyukova et al., PLoS Genet, Feb 2016: https://doi.org/10.1371/journal.pgen.1005841 (masyukova2016ascreenfor pages 26-27)
- Masyukova et al., Hum Mol Genet, Aug 2011: https://doi.org/10.1093/hmg/ddr198 (masyukova2011assessingthepathogenic pages 2-2)
- Mill et al., Nat Rev Genet, Apr 2023: https://doi.org/10.1038/s41576-023-00587-9 (williams2008functionalredundancyof pages 11-11)
- Zhen & Yang, Laser & Optoelectronics Progress, Jan 2024: https://doi.org/10.3788/lop232684 (zhen2024superresolutionfluorescencemicroscopy pages 1-3)
- Kalot et al., Frontiers in Nephrology, Jan 2024: https://doi.org/10.3389/fneph.2023.1331847 (williams2008functionalredundancyof pages 11-11)
- Kaplan, Turkish J Biol, Jan 2023: https://doi.org/10.55730/1300-0152.2642 (williams2008functionalredundancyof pages 11-11)

Embedded key-source summary
| Year | Citation (first author et al.) | System | Method(s) | Key Finding(s) | URL / DOI |
|---:|---|---|---|---|---|
| 2005 | Winkelbauer et al. | Caenorhabditis elegans | Immunofluorescence localization, genetic mutants, chemotaxis/behavioral assays | NPHP-1 and NPHP-4 localize to the ciliary transition zone; NPHP-1 contains coiled-coils, an SH3 region and NPHP homology domain; required for chemosensory perception though gross ciliogenesis appears largely intact (winkelbauer2005thec.elegans pages 1-2) | https://doi.org/10.1242/jcs.02665 |
| 2008 | Jauregui et al. | Caenorhabditis elegans | IF localization, TEM ultrastructure, IFT assays, genetics | NPHP-1 and NPHP-4 act as global TZ modifiers that regulate ciliary access of IFT machinery and axonemal components; nphp-4 mutants show B-tubule defects and altered IFT (jauregui2008thecaenorhabditiselegans pages 1-2) | https://doi.org/10.1083/jcb.200707090 |
| 2008 | Williams et al. | Caenorhabditis elegans | Genetics, localization, TEM | B9 proteins function redundantly with nephrocystins (nph-1/nph-4) in ciliogenesis; double mutants exacerbate ciliary/dendrite defects and implicate TZ-localized complexes in cilia/basal-body function (williams2008functionalredundancyof pages 1-2) | https://doi.org/10.1091/mbc.E07-10-1070 |
| 2012 | Warburton-Pitt et al. | Caenorhabditis elegans | Genetic interaction mapping, localization | nphp-1/nphp-4 genetically interact with nphp-2 and MKS-module genes to regulate TZ placement/orientation and ciliogenesis; single mutants often mild but specific pairwise combinations produce severe ciliogenesis defects (warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2) | https://doi.org/10.1242/jcs.095539 |
| 2015 | Yee et al. | C. elegans (comparative with mouse) | Genetic interaction assays, localization | Identified conserved TZ inter-module interactions: TCTN-1 (MKS-related) interacts genetically with NPHP components (including nphp-1/nphp-4) and BBS to cooperatively support ciliogenesis and ciliary signaling (supporting references summarized in C. elegans studies) (masyukova2016ascreenfor pages 26-27, warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2) | https://doi.org/10.1371/journal.pgen.1005627 |
| 2016 | Li et al. | Caenorhabditis elegans | Localization dependency, assembly-pathway analysis | Defined MKS-5 and CEP-290 dependent assembly pathway for TZ; places NPHP-1/NPHP-4 as early NPHP-module components required for proper TZ gating and ciliogenesis (related context summarized in C. elegans TZ literature) (warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2) | https://doi.org/10.1371/journal.pbio.1002416 |
| 2016 | Masyukova et al. | Caenorhabditis elegans | Genetic modifier screen, IFT assays, behavioral assays | Modifier screen of nphp-4 uncovered osm-3 (kinesin) interaction; demonstrates genetic cross-talk between NPHP module and IFT/motor components and reveals loci that exacerbate TZ-dependent phenotypes (masyukova2016ascreenfor pages 26-27) | https://doi.org/10.1371/journal.pgen.1005841 |
| 2011 | Masyukova et al. | Caenorhabditis elegans | Human-variant functional assay, localization, phenotypic analysis | Modeled human NPHP4 missense alleles in worm; demonstrated NPHP-4 is required for proper localization of NPHP-1 to the TZ and validated C. elegans as a platform to assess pathogenicity (masyukova2011assessingthepathogenic pages 2-2) | https://doi.org/10.1093/hmg/ddr198 |

Table: Concise table of primary C. elegans studies on nphp-1/NPHP-1 summarizing year, methods, main findings, and DOI; citations reference extracted context IDs supporting each row.

Conclusions
- nphp-1 encodes a TZ-localized adaptor in C. elegans that acts with NPHP-4 to regulate the ciliary gate, affecting IFT access and axonemal composition; its core function is scaffolding/signaling modulation rather than enzymatic catalysis or transport (Dec 2005; Mar 2008) (winkelbauer2005thec.elegans pages 1-2, jauregui2008thecaenorhabditiselegans pages 1-2).
- NPHP-1/4 comprise an NPHP module that cooperates with the MKS module and interfaces with IFT/BBS pathways; genetic redundancy/interaction patterns underlie variable phenotypic penetrance and sensilla specificity (May 2008; Jun 2012; Nov 2015; Mar 2016; Feb 2016) (williams2008functionalredundancyof pages 1-2, warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2, masyukova2016ascreenfor pages 26-27).
- 2023–2024 reviews and methods consolidate the TZ as a modular diffusion barrier and provide tools to refine NPHP-1 spatial models and variant interpretation, reinforcing conservation with human NPHP1 function in ciliopathies (Apr 2023; Jan 2024) (williams2008functionalredundancyof pages 11-11, zhen2024superresolutionfluorescencemicroscopy pages 1-3).

References

  1. (winkelbauer2005thec.elegans pages 1-2): Marlene E. Winkelbauer, Jenny C. Schafer, Courtney J. Haycraft, Peter Swoboda, and Bradley K. Yoder. The c. elegans homologs of nephrocystin-1 and nephrocystin-4 are cilia transition zone proteins involved in chemosensory perception. Journal of Cell Science, 118:5575-5587, Dec 2005. URL: https://doi.org/10.1242/jcs.02665, doi:10.1242/jcs.02665. This article has 141 citations and is from a domain leading peer-reviewed journal.

  2. (jauregui2008thecaenorhabditiselegans pages 1-2): Andrew R. Jauregui, Ken C.Q. Nguyen, David H. Hall, and Maureen M. Barr. The caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. The Journal of Cell Biology, 180:973-988, Mar 2008. URL: https://doi.org/10.1083/jcb.200707090, doi:10.1083/jcb.200707090. This article has 125 citations.

  3. (williams2008functionalredundancyof pages 1-2): Corey L. Williams, Marlene E. Winkelbauer, Jenny C. Schafer, Edward J. Michaud, and Bradley K. Yoder. Functional redundancy of the b9 proteins and nephrocystins in caenorhabditis elegans ciliogenesis. Molecular biology of the cell, 19 5:2154-68, May 2008. URL: https://doi.org/10.1091/mbc.e07-10-1070, doi:10.1091/mbc.e07-10-1070. This article has 120 citations and is from a domain leading peer-reviewed journal.

  4. (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.

  5. (masyukova2016ascreenfor pages 26-27): 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 25 citations and is from a domain leading peer-reviewed journal.

  6. (warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2): 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.

  7. (williams2008functionalredundancyof pages 11-11): Corey L. Williams, Marlene E. Winkelbauer, Jenny C. Schafer, Edward J. Michaud, and Bradley K. Yoder. Functional redundancy of the b9 proteins and nephrocystins in caenorhabditis elegans ciliogenesis. Molecular biology of the cell, 19 5:2154-68, May 2008. URL: https://doi.org/10.1091/mbc.e07-10-1070, doi:10.1091/mbc.e07-10-1070. This article has 120 citations and is from a domain leading peer-reviewed journal.

  8. (zhen2024superresolutionfluorescencemicroscopy pages 1-3): Liu Zhen and Wu Yang. Super-resolution fluorescence microscopy for cilia investigation and ciliopathy diagnosis (invited). Laser & Optoelectronics Progress, 61:0618016, Jan 2024. URL: https://doi.org/10.3788/lop232684, doi:10.3788/lop232684. This article has 1 citations.

Citations

  1. jauregui2008thecaenorhabditiselegans pages 1-2
  2. williams2008functionalredundancyof pages 11-11
  3. zhen2024superresolutionfluorescencemicroscopy pages 1-3
  4. masyukova2016ascreenfor pages 26-27
  5. warburtonpitt2012ciliogenesisincaenorhabditis pages 1-2
  6. masyukova2011assessingthepathogenic pages 2-2
  7. williams2008functionalredundancyof pages 1-2
  8. https://doi.org/10.1242/jcs.02665
  9. https://doi.org/10.1083/jcb.200707090
  10. https://doi.org/10.1091/mbc.E07-10-1070
  11. https://doi.org/10.1242/jcs.095539
  12. https://doi.org/10.1371/journal.pgen.1005627
  13. https://doi.org/10.1371/journal.pbio.1002416
  14. https://doi.org/10.1371/journal.pgen.1005841
  15. https://doi.org/10.1093/hmg/ddr198
  16. https://doi.org/10.1038/s41576-023-00587-9
  17. https://doi.org/10.3788/lop232684
  18. https://doi.org/10.3389/fneph.2023.1331847
  19. https://doi.org/10.55730/1300-0152.2642
  20. https://doi.org/10.1242/jcs.02665,
  21. https://doi.org/10.1083/jcb.200707090,
  22. https://doi.org/10.1091/mbc.e07-10-1070,
  23. https://doi.org/10.1093/hmg/ddr198,
  24. https://doi.org/10.1371/journal.pgen.1005841,
  25. https://doi.org/10.1242/jcs.095539,
  26. https://doi.org/10.3788/lop232684,

📄 View Raw YAML

 
id: O17972
gene_symbol: nphp-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: "NPHP-1 is the C. elegans ortholog of human nephrocystin-1 (NPHP1), a protein mutated in nephronophthisis. It localizes specifically to the ciliary transition zone (TZ) in sensory neurons and functions as part of the NPHP module that works redundantly with the MKS module to establish the ciliary gate. NPHP-1 plays important roles in ciliary structure, sensory signal transduction, and male mating behaviors. The protein contains an SH3 domain and requires NPHP-4 for proper TZ localization. Together with NPHP-4, it regulates ciliary access of IFT machinery components, axonemal structural proteins, and signaling molecules.\n"
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: "IBA annotation based on phylogenetic analysis. While NPHP-1 is predominantly localized to the ciliary transition zone, cytoplasmic localization is plausible as the protein must transit through the cytoplasm. However, this is a generic term that does not capture the protein's specific and functionally relevant localization at the transition zone.\n"
    action: KEEP_AS_NON_CORE
    reason: "The annotation is not incorrect but does not represent the core localization of NPHP-1. The protein's critical function is at the transition zone. Cytoplasmic localization may represent transit or a minor pool, but the more informative and functionally relevant localizations are the TZ-related terms.\n"
    supported_by:
    - reference_id: file:worm/nphp-1/nphp-1-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: "IBA annotation based on phylogenetic analysis. NPHP-1 localizes to the ciliary transition zone, which is a subdomain of the cilium. Multiple studies demonstrate TZ-specific localization in C. elegans [PMID:15817158, PMID:18316409, PMID:21422230].\n"
    action: ACCEPT
    reason: "While the more specific term 'ciliary transition zone' (GO:0035869) better captures NPHP-1's localization, this broader term is accurate since the TZ is part of the cilium. The IBA annotation aligns with experimental evidence showing ciliary localization.\n"
    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.
    - reference_id: PMID:18316409
      supporting_text: GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization
- term:
    id: GO:0090251
    label: protein localization involved in establishment of planar polarity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: "IBA annotation based on phylogenetic inference. This annotation likely derives from mammalian data where NPHP1 has been implicated in planar cell polarity pathways. There is no direct evidence for this function in C. elegans.\n"
    action: UNDECIDED
    reason: "While this may be a conserved function based on phylogenetic analysis, there is no direct experimental evidence for a role in planar polarity in C. elegans. The IBA annotation is reasonable given conservation, but without C. elegans-specific data, this remains speculative.\n"
- term:
    id: GO:0030030
    label: cell projection organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: "IEA annotation based on UniProtKB keyword mapping (cilium biogenesis/degradation). NPHP-1 is involved in cilium structure and organization, particularly through its role at the transition zone.\n"
    action: ACCEPT
    reason: "The annotation is supported by experimental evidence showing that nphp-1 mutants have defects in CEM cilia morphology [PMID:18316409]. NPHP-1 and NPHP-4 act globally at the TZ to regulate ciliary structure, and loss causes cell type-specific phenotypes in cilia organization.\n"
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: nphp-1 and nphp-4 are important modulators of ciliary ultrastructure, with defects resulting in a broad phenotypic spectrum
- 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. The paper examines various ciliary proteins including NPHP-1 localization. However, multiple C. elegans studies show NPHP-1 specifically localizes to the transition zone rather than the basal body proper [PMID:18316409, PMID:21422230].\n"
    action: MODIFY
    reason: "In C. elegans, the basal body and transition zone are distinct regions. Multiple detailed studies using GFP-tagged NPHP-1 show specific localization to the transition zone, not the basal body. The transition zone is adjacent to but distinct from the basal body region where IFT proteins concentrate. This annotation should be modified to reflect TZ localization.\n"
    proposed_replacement_terms:
    - id: GO:0035869
      label: ciliary transition zone
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization
    - reference_id: PMID:21422230
      supporting_text: we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB)
- term:
    id: GO:0035869
    label: ciliary transition zone
  evidence_type: IDA
  original_reference_id: PMID:26595381
  review:
    summary: "Direct experimental evidence from a study on TMEM107 and ciliopathy proteins. NPHP-1 TZ localization is well-established across multiple C. elegans studies.\n"
    action: ACCEPT
    reason: "This is the core localization for NPHP-1. Multiple studies demonstrate specific TZ localization using fluorescently tagged proteins [PMID:15817158, PMID:18316409, PMID:21422230, PMID:26595381]. NPHP-1 is part of the NPHP module that localizes to and functions at the transition zone.\n"
    supported_by:
    - reference_id: PMID:26595381
      supporting_text: nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins
    - reference_id: PMID:21422230
      supporting_text: NPHP-1 and NPHP-4 localize to the TZ in mks-5 mutants, but to a subregion smaller than that occupied in N2
- term:
    id: GO:0003674
    label: molecular_function
  evidence_type: ND
  original_reference_id: GO_REF:0000015
  review:
    summary: "ND (No biological Data) annotation indicating no molecular function is annotated. This is a placeholder annotation used when no experimental data defines a specific molecular function.\n"
    action: ACCEPT
    reason: "Despite extensive characterization of NPHP-1's cellular role, no specific molecular function (e.g., enzyme activity, specific binding activity) has been experimentally determined. The protein contains an SH3 domain which suggests protein-protein interaction capability, but no specific molecular function has been annotated with experimental evidence. The ND annotation is appropriate.\n"
- term:
    id: GO:0097546
    label: ciliary base
  evidence_type: IDA
  original_reference_id: PMID:25335890
  review:
    summary: "IDA annotation from a study on ciliopathy proteins in AFD thermosensory neurons. The study examines how ciliary proteins establish signaling compartments.\n"
    action: ACCEPT
    reason: "The ciliary base encompasses the transition zone and basal body region. NPHP-1 localization to this region is well-documented. This broader term is accurate as an annotation alongside the more specific TZ term.\n"
    supported_by:
    - reference_id: PMID:25335890
      supporting_text: proteins associated with Bardet-Biedl syndrome (BBS), Meckel syndrome and nephronophthisis at its base
- term:
    id: GO:0023041
    label: neuronal signal transduction
  evidence_type: IC
  original_reference_id: PMID:15817158
  review:
    summary: "IC (Inferred by Curator) annotation inferring a role in neuronal signal transduction based on localization to non-motile cilia in sensory neurons and mating behavior phenotypes.\n"
    action: ACCEPT
    reason: "NPHP-1 localizes to sensory cilia in neurons and contributes to sensory behaviors. The double mutant nphp-1;nphp-4 shows response defects, supporting a role in sensory signal transduction. The IC inference from localization and behavioral phenotypes is reasonable.\n"
    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 (Inferred from Genetic Interaction) annotation based on interaction with nphp-4. Double mutant nphp-1;nphp-4 males show defects in response behaviors during mating.\n"
    action: ACCEPT
    reason: "The annotation captures the redundant role of NPHP-1 and NPHP-4 in male mating behaviors. While single mutants have mild phenotypes, the double mutant shows clear behavioral defects.\n"
    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: "Turning-behaviour defects seen in nphp-1;nphp-4 double mutants are downstream of impaired ciliary signalling in male-specific sensory neurons, not a direct molecular function of NPHP-1."
    action: KEEP_AS_NON_CORE
    reason: "Ciliary gene; the mating-turning behaviour is a distal phenotypic consequence of cilium dysfunction; non-core per the behaviour-annotation rubric."
    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 annotation showing NPHP-1 localizes to non-motile (primary/sensory) cilia. C. elegans sensory neurons have non-motile cilia, and NPHP-1 localizes to these structures.\n"
    action: ACCEPT
    reason: "All C. elegans sensory cilia are non-motile (9+0 configuration), and NPHP-1 is expressed in and localizes to ciliated sensory neurons. This is a correct and well-supported annotation.\n"
    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:21422230
  review:
    summary: "IDA annotation from the comprehensive study on MKS and NPHP modules at the transition zone. This paper provides detailed characterization of NPHP-1 TZ localization and function.\n"
    action: ACCEPT
    reason: "This is a core localization for NPHP-1 supported by extensive experimental evidence. The study uses fluorophore-tagged proteins and demonstrates NPHP-1 specifically localizes to the TZ region. Duplicate with PMID:26595381 annotation but from different reference.\n"
    supported_by:
    - reference_id: PMID:21422230
      supporting_text: Using fluorescently tagged proteins, we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB).
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:19208769
  review:
    summary: "IMP annotation based on lifespan phenotype in double mutants. The study on MKS1-related proteins found that mks/mksr double mutants with nphp mutations show increased lifespan due to abnormal insulin-IGF-I signaling.\n"
    action: KEEP_AS_NON_CORE
    reason: "This is a pleiotropic phenotype likely resulting from disrupted ciliary function affecting sensory signaling pathways that regulate lifespan (insulin/IGF-1 signaling). Not a core function of NPHP-1 but rather a consequence of ciliary/sensory dysfunction.\n"
    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 indicating NPHP-1 participates in regulating protein localization within the cell, specifically at the ciliary transition zone.\n"
    action: MODIFY
    reason: "This annotation is too general. NPHP-1 specifically functions at the TZ to regulate ciliary access of IFT components and other proteins. A more specific term related to ciliary protein localization or ciliary gate function would be more appropriate.\n"
    proposed_replacement_terms:
    - id: GO:0035721
      label: intraciliary transport involved in cilium assembly
    additional_reference_ids: ["PMID:21422230"]
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: In conclusion, 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.
    - reference_id: PMID:21422230
      supporting_text: the two modules restrict inappropriate accumulation of membrane-associated proteins inside cilia
- term:
    id: GO:0097730
    label: non-motile cilium
  evidence_type: IDA
  original_reference_id: PMID:18316409
  review:
    summary: "IDA annotation confirming localization to non-motile cilia based on comprehensive characterization of nephrocystin function in C. elegans.\n"
    action: ACCEPT
    reason: "Duplicate of annotation from PMID:15817158 but from different reference. Both support NPHP-1 localization to non-motile sensory cilia. Valid annotation.\n"
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: C. elegans nphp-1 and nphp-4 orthologues are expressed in the ciliated sensory nervous system
- term:
    id: GO:1905515
    label: non-motile cilium assembly
  evidence_type: IMP
  original_reference_id: PMID:18316409
  review:
    summary: "IMP annotation based on ciliary assembly defects observed in nephrocystin mutants. The study shows NPHP-1 and NPHP-4 are important for proper cilium assembly and structure.\n"
    action: ACCEPT
    reason: "UniProt states NPHP-1 may be necessary for initial assembly of the cilium. The Jauregui 2008 study demonstrates that NPHP-1 and NPHP-4 act at the TZ to regulate ciliary components, and double mutants have ciliary structure defects. NPHP-1 contributes to cilium assembly through its role at the TZ.\n"
    supported_by:
    - reference_id: PMID:18316409
      supporting_text: nphp-1 and nphp-4 are important modulators of ciliary ultrastructure, with defects resulting in a broad phenotypic spectrum
    - reference_id: PMID:21422230
      supporting_text: MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension
references:
- id: GO_REF:0000015
  title: Use of the ND evidence code for Gene Ontology (GO) terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  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 localizes to ciliated sensory endings of dendrites
    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.
  - statement: NPHP-1 and NPHP-4 colocalize with PKD-2 in male-specific sensory cilia
    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.
  - statement: nphp-1;nphp-4 double mutant males are response defective
    supporting_text: nphp-1; nphp-4 double, but not single, mutant males are response defective.
  - statement: NPHP-1 and NPHP-4 play redundant roles in ciliary sensory signal transduction
    supporting_text: We propose that NPHP-1 and NPHP-4 proteins play important and redundant roles in facilitating ciliary sensory signal transduction.
- 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: GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization
  - statement: NPHP-1 requires NPHP-4 for TZ localization
    supporting_text: GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization
  - statement: NPHP-1 and NPHP-4 regulate ciliary access of IFT machinery and signaling molecules
    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
  - statement: Loss of NPHP-1 and NPHP-4 causes changes in localization of specific ciliary components
    supporting_text: In conclusion, 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.
  - statement: nphp-1 mutants have stunted or misshaped CEM cilia
    supporting_text: In nphp-1 mutants, CEM cilia are stunted or misshaped
- 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/MKSR proteins localize to transition zones/basal bodies of sensory cilia
    supporting_text: MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia
  - statement: Genetic interactions between mks/mksr mutants manifest as increased lifespan due to abnormal insulin-IGF-I signaling
    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
- 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-1 and NPHP-4 localize to the transition zone
    supporting_text: Using fluorescently tagged proteins, we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB).
  - statement: NPHP-1 and NPHP-4 are part of the NPHP module
    supporting_text: we group MKS-1, MKSR-1, MKSR-2, MKS-3, and MKS-6 into an MKS/MKSR module and NPHP-1 and NPHP-4 into an NPHP module
  - statement: NPHP and MKS modules cooperate for BB/TZ membrane associations
    supporting_text: MKS/MKSR/NPHP proteins establish basal body/TZ membrane attachments before or coinciding with intraflagellar transport-dependent axoneme extension
  - statement: TZ proteins establish a ciliary gate that restricts protein accumulation in cilia
    supporting_text: the two modules restrict inappropriate accumulation of membrane-associated proteins inside cilia
- id: PMID:25335890
  title: Ciliopathy proteins establish a bipartite signaling compartment in a C. elegans thermosensory neuron.
  findings:
  - statement: Ciliopathy proteins including nephronophthisis proteins localize to the ciliary base
    supporting_text: proteins associated with Bardet-Biedl syndrome (BBS), Meckel syndrome and nephronophthisis at its base
- 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 to regulate cilium integrity
    supporting_text: nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins
  - statement: TZ proteins organize recruitment of ciliopathy proteins
    supporting_text: nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins
- id: PMID:27623382
  title: A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis.
  findings: []
- id: PMID:15659564
  title: Expression and phenotype analysis of the nephrocystin-1 and nephrocystin-4 homologs in Caenorhabditis elegans.
  findings: []
- id: file:worm/nphp-1/nphp-1-deep-research-falcon.md
  title: Deep research report on nphp-1
  findings: []
core_functions:
- description: "NPHP-1 is a transition zone scaffold protein that functions as part of the NPHP module. It localizes specifically to the ciliary transition zone where it contributes to establishing the ciliary gate and regulating cilium assembly. The protein works redundantly with NPHP-4 and cooperates with the MKS module to anchor the basal body/TZ to the membrane.\n"
  directly_involved_in:
  - id: GO:1905515
    label: non-motile cilium assembly
  - id: GO:0023041
    label: neuronal signal transduction
  locations:
  - id: GO:0035869
    label: ciliary transition zone
  supported_by:
  - reference_id: PMID:21422230
    supporting_text: Using fluorescently tagged proteins, we detect MKS/MKSR/NPHP proteins in a region corresponding to the TZ (adjacent to where IFT proteins concentrate at the TFs/BB).
  - reference_id: PMID:18316409
    supporting_text: GFP-tagged NPHP-1 and NPHP-4 proteins localize to the ciliary TZ, with NPHP-1 requiring the presence of NPHP-4 for TZ localization
proposed_new_terms: []
suggested_questions:
- question: What is the precise molecular function of the SH3 domain in NPHP-1?
- question: Does NPHP-1 directly participate in Y-link formation at the transition zone?
- question: Are there specific protein-protein interactions mediated by NPHP-1 that are essential for ciliary gate function?
suggested_experiments:
- description: Identify direct binding partners of NPHP-1 using immunoprecipitation or proximity labeling approaches
  hypothesis: NPHP-1 interacts with specific TZ proteins through its SH3 domain
- description: Determine if the SH3 domain is required for TZ localization using domain deletion constructs
  hypothesis: The SH3 domain mediates protein-protein interactions required for TZ anchoring
- description: Examine whether NPHP-1 is a structural component of Y-links using immuno-EM
  hypothesis: NPHP-1 may be a direct structural component of Y-link connectors
tags: [caeel-ciliopathy]