Affinage

EFHC1

EF-hand domain-containing protein 1 · UniProt Q5JVL4

Length
640 aa
Mass
74.0 kDa
Annotated
2026-04-28
38 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EFHC1 (myoclonin1) is a microtubule-associated, EF-hand-containing axonemal protein predominantly expressed in motile-cilia-bearing cells—choroid plexus, ependymal cells, trachea, and sperm flagella—where it regulates ciliary beat frequency, axoneme assembly, and calcium homeostasis (PMID:15670853, PMID:18164683, PMID:33328576, PMID:26783883). EFHC1 modulates neuronal excitability through physical interactions with the R-type voltage-gated calcium channel Cav2.3 and the TRPM2 channel, enhancing their Ca²⁺ currents, and through regulation of ER-Ca²⁺ release via IP3 receptors; JME-causing mutations reverse these functional effects (PMID:15258581, PMID:22226147). In invertebrate models, EFHC1 orthologs bind microtubules directly, restrain synaptic overgrowth and spontaneous neurotransmitter release, and regulate mechanosensory cilium and synapse function in cooperation with R-type calcium channels (PMID:21835885, PMID:30810526). Loss of EFHC1 specifically in motile-ciliated cells produces increased seizure susceptibility and ventriculomegaly, establishing that its ciliary function contributes directly to the epileptic phenotype of juvenile myoclonic epilepsy (PMID:19147686, PMID:42000019).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 High

    Establishing that EFHC1 is a functional modulator of a specific ion channel answered how a newly identified epilepsy gene could alter neuronal excitability: EFHC1 physically interacts with Cav2.3 and increases R-type Ca²⁺ currents, with JME mutations abolishing this effect and suppressing pro-apoptotic activity.

    Evidence Co-immunoprecipitation, patch-clamp electrophysiology, and apoptosis assays with pharmacological validation in hippocampal neurons

    PMID:15258581

    Open questions at the time
    • Mechanism by which EFHC1 potentiates Cav2.3 currents not resolved
    • In vivo relevance of EFHC1-induced apoptosis unclear
    • Whether the interaction is direct or mediated by a complex not determined
  2. 2005 Medium

    Resolving where endogenous EFHC1 protein resides answered a critical cell-biological question: EFHC1 is a motile-cilia/flagella protein homologous to Chlamydomonas axonemal Rib72, abundantly present in sperm and trachea but scarce in brain and absent from primary cilia.

    Evidence Western blot and immunofluorescence in mouse tissues

    PMID:15670853

    Open questions at the time
    • Functional role in motile cilia not yet tested
    • Brain expression level low—functional significance in neurons ambiguous
    • Antibody specificity not validated against KO at this time
  3. 2006 High

    Demonstrating centrosome and mitotic spindle localization raised the possibility that EFHC1 has a cell-division role beyond cilia, with N-terminal domain mapping showing requirements for spindle and midbody association.

    Evidence EGFP-fusion live imaging and immunofluorescence with deletion constructs in mammalian cell lines

    PMID:16824517

    Open questions at the time
    • Whether endogenous EFHC1 at spindle is functionally required not tested
    • Spindle localization later contested by KO-validated antibody study (PMID:33328576)
    • Relevance to in vivo cell division unknown
  4. 2007 Medium

    Mapping developmental expression dynamics in choroid plexus and ependyma clarified that EFHC1 is sequentially deployed in specific motile-ciliated cell populations across brain development.

    Evidence Immunohistochemistry and in situ hybridization across mouse developmental stages, validated in Efhc1-KO tissue

    PMID:18164683

    Open questions at the time
    • Functional consequence of developmental switch in expression not tested
    • Whether brain expression extends to neurons still debated
  5. 2008 High

    Biochemical characterization of the C-terminal EF-hand domain established that EFHC1 is a redox-sensitive calcium sensor: it binds Ca²⁺/Mg²⁺ at 1:1 stoichiometry under reducing conditions but dimerizes via Cys575 disulfide under oxidizing conditions, which blocks divalent cation binding.

    Evidence Size exclusion chromatography, mass spectrometry, thiol assay, and isothermal titration calorimetry on purified C-terminal fragment

    PMID:18593566

    Open questions at the time
    • Physiological relevance of redox-regulated dimerization untested in cells
    • Whether full-length protein behaves similarly unknown
    • No structural model available
  6. 2009 High

    Two landmark studies established that EFHC1 loss of function has both ciliary and neurodevelopmental consequences: knockout mice show reduced ependymal ciliary beat frequency, ventriculomegaly, myoclonus, and lowered seizure threshold, while in developing rat cortex, EFHC1 knockdown disrupts mitotic spindle organization and radial neuronal migration.

    Evidence Efhc1-KO mice with ciliary beat frequency, behavioral and PTZ seizure phenotyping; in utero electroporation and spindle imaging in rat neocortex

    PMID:19147686 PMID:19734894

    Open questions at the time
    • Relative contribution of ciliary vs. neuronal migration defects to seizure phenotype unclear
    • Whether spindle phenotype reflects endogenous neuronal EFHC1 later challenged
    • Mechanism linking reduced ciliary beat frequency to seizures not established
  7. 2011 High

    Drosophila ortholog studies answered whether EFHC1 directly binds microtubules and regulates synaptic architecture: Defhc1.1 binds microtubules in vitro, and its loss increases synaptic boutons and spontaneous neurotransmitter release—phenotypes suppressed by the microtubule-stabilizing drug vinblastine—establishing EFHC1 as a negative regulator of microtubule dynamics at synapses.

    Evidence Drosophila KO, in vitro microtubule binding assay, electrophysiology, vinblastine rescue, dendritic morphometry

    PMID:21835885

    Open questions at the time
    • Mammalian synaptic function of EFHC1 not confirmed
    • Direct microtubule binding not demonstrated for mammalian protein
    • Whether synaptic phenotype is cell-autonomous not resolved
  8. 2012 High

    Two studies extended the ion channel and neurodevelopmental story: EFHC1 physically interacts with TRPM2 to potentiate oxidative stress-induced Ca²⁺ entry (reversed by JME mutations), and JME mutations act dominant-negatively to disrupt mitotic spindle organization and both radial and tangential neuronal migration.

    Evidence Co-IP, patch-clamp, and cell death assays in HEK293 for TRPM2; ex vivo electroporation with mutant constructs and migration/spindle assays for neuronal migration

    PMID:22226147 PMID:22926142

    Open questions at the time
    • In vivo relevance of TRPM2 interaction to epilepsy not tested
    • Dominant-negative mechanism at molecular level unresolved
    • Whether neuronal migration defects are primary or secondary to spindle disruption unclear
  9. 2016 High

    Xenopus studies revealed EFHC1 is required for axoneme assembly in multiciliated cells and identified a separable role in restraining Wnt/β-catenin signaling, linking EFHC1 to a major developmental signaling pathway.

    Evidence Morpholino knockdown in Xenopus with GFP-fusion localization, TOPFLASH reporter, and domain-deletion rescue

    PMID:26783883

    Open questions at the time
    • Mechanism of Wnt pathway modulation unknown
    • Whether Wnt regulation occurs in mammalian ciliated cells not tested
    • Relationship between Wnt modulation and epilepsy unexplored
  10. 2019 High

    C. elegans studies demonstrated that EFHC-1 functions in both non-motile mechanosensory cilia and at synapses to regulate neuronal excitability, cooperating with the R-type VGCC ortholog—extending the Cav2.3 interaction to an in vivo dual-site regulatory model.

    Evidence C. elegans genetics, live imaging, behavioral assays, epistasis with R-type VGCC ortholog

    PMID:30810526

    Open questions at the time
    • Whether dual ciliary-synaptic regulation applies in mammalian neurons not confirmed
    • Molecular mechanism of cooperation with R-type VGCC at synapse unresolved
  11. 2020 High

    A rigorous antibody validation study using Efhc1-KO controls challenged earlier neuronal and spindle localizations: KO-validated monoclonal antibody detected myoclonin1 only in motile-ciliated cells, not in neurons or at the mitotic spindle, and complete Efhc1 elimination did not affect cell division or cortical neuronal migration.

    Evidence Immunohistochemistry and western blot with KO-validated monoclonal antibody (6A3-mAb), immunocytochemistry in dividing cells

    PMID:33328576

    Open questions at the time
    • Discrepancy with earlier spindle/neuron findings not fully reconciled—may reflect overexpression artifacts vs. endogenous protein
    • Does not rule out low-level neuronal expression below detection
    • Functional role that produces seizure phenotype if protein is absent from neurons needs alternative explanation
  12. 2024 Medium

    Identification of IP3R1 as a physical binding partner in choroid plexus/ependymal cells, with loss of EFHC1 causing elevated ER Ca²⁺ stores and enhanced IP3-induced Ca²⁺ release, provided a molecular mechanism for EFHC1's role in calcium homeostasis within its primary expression domain.

    Evidence (preprint) Co-immunoprecipitation, Ca²⁺ imaging in Efhc1-KO vs. WT choroid plexus/ependymal cells

    PMID:bio_10.1101_2024.07.01.601633

    Open questions at the time
    • Preprint awaiting peer review
    • Whether ER-Ca²⁺ dysregulation is causally linked to seizure susceptibility not tested
    • Stoichiometry and structural basis of IP3R interaction unknown
  13. 2026 High

    Cell-type-specific conditional deletion established that loss of myoclonin1 specifically in motile-ciliated (FoxJ1+) cells is sufficient to increase seizure susceptibility, directly linking ciliary dysfunction to the epileptic phenotype and resolving a long-standing question about the relevant cell type.

    Evidence Conditional KO mouse (FoxJ1-Cre × floxed-Efhc1), PTZ seizure threshold testing, ventricle morphometry

    PMID:42000019

    Open questions at the time
    • Heterozygote seizure phenotype suggests haploinsufficiency but mechanism not resolved
    • How ciliary dysfunction in ependyma/choroid plexus lowers seizure threshold remains unknown
    • Whether additional non-ciliated cell contributions exist cannot be excluded

Open questions

Synthesis pass · forward-looking unresolved questions
  • The central unresolved question is the mechanism by which EFHC1 loss in motile-ciliated ependymal/choroid plexus cells leads to altered neuronal excitability and seizure susceptibility—whether through CSF composition changes, Wnt signaling, Ca²⁺ homeostasis perturbation, or another pathway.
  • No direct link established between ciliary beat/ER-Ca²⁺ defect and circuit-level hyperexcitability
  • Mammalian synaptic function of EFHC1 not demonstrated with endogenous protein
  • No high-resolution structure of EFHC1 or its complexes available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005929 cilium 6 GO:0005856 cytoskeleton 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1852241 Organelle biogenesis and maintenance 3
Partners
CACNA1EITPR1PRKCSHTRPM2

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 EFHC1 coimmunoprecipitates with the C terminus of the R-type voltage-dependent Ca2+ channel (Cav2.3), and overexpression of EFHC1 specifically increases R-type Ca2+ currents in patch-clamp analysis; JME-associated mutations reverse this current increase and suppress EFHC1-induced apoptosis in hippocampal neurons Co-immunoprecipitation, patch-clamp electrophysiology, neuronal apoptosis assay with pharmacological rescue (SNX-482) Nature genetics High 15258581
2006 EFHC1 localizes to the centrosome during interphase and co-localizes with the mitotic spindle (especially spindle poles) and midbody during mitosis/cytokinesis; deletion analysis shows the N-terminal region is required for spindle and midbody association EGFP-fusion live imaging, immunofluorescence with endogenous antibody, deletion constructs in multiple cell lines Experimental cell research High 16824517
2009 EFHC1 is a microtubule-associated protein (MAP); loss of function disrupts mitotic spindle organization, impairs M-phase progression, induces microtubule bundling, increases apoptosis, and causes radial migration defects in the developing neocortex by impairing cell-cycle exit of cortical progenitors and radial glia scaffold organization In vitro EFHC1 loss-of-function, ex vivo and in utero electroporation in rat neocortex, mitotic spindle imaging Nature neuroscience High 19734894
2009 Efhc1-deficient mice show reduced ciliary beating frequency in ependymal cilia (despite intact ciliary structure), enlarged brain ventricles, spontaneous myoclonus, and reduced pentylenetetrazol seizure threshold, establishing a loss-of-function epileptic phenotype Knockout mouse generation, ciliary beat frequency measurement, behavioral seizure monitoring, PTZ threshold testing Human molecular genetics High 19147686
2005 The mouse ortholog mRib72-1/Efhc1 is a homolog of the Chlamydomonas axonemal protein Rib72 and is abundantly present in sperm flagella and tracheal cilia (motile cilia) but only in small amounts in the brain; it is absent from immotile primary cilia Western blot analysis and immunofluorescence localization in mouse tissues FEBS letters Medium 15670853
2012 EFHC1 physically interacts with both the N- and C-terminal cytoplasmic regions of the TRPM2 channel (demonstrated by immunoprecipitation); co-expression of EFHC1 potentiates H2O2- and ADPR-induced Ca2+ responses and cationic currents via TRPM2, and enhances TRPM2-mediated cell death susceptibility; JME mutations reverse these effects Co-immunoprecipitation, Ca2+ imaging, whole-cell patch-clamp in HEK293 cells, cell death assay with JME mutants Cell calcium High 22226147
2012 JME mutations in EFHC1 (including F229L) act in a dominant-negative manner to impair mitotic spindle organization; mutant EFHC1 expression disrupts radial and tangential neuronal migration by affecting radial glia morphology and migrating neuron morphology, while not altering centrosome/spindle colocalization Ex vivo electroporation with mutant constructs, immunofluorescence of mitotic spindles and radial glia, neuronal migration assay Human molecular genetics High 22926142
2008 The C-terminal half of EFHC1 (residues 403–640), which contains the EF-hand motif, can dimerize via disulfide bond through Cys575; dimerization under oxidizing conditions blocks Ca2+ and Mg2+ binding to the EF-hand (1:1 binding stoichiometry under reducing but not oxidizing conditions) Size exclusion chromatography, mass spectrometry, tandem MS/MS, DTNB thiol assay, isothermal titration calorimetry Archives of biochemistry and biophysics High 18593566
2011 Drosophila Defhc1.1 (EFHC1 ortholog) binds to microtubules in vitro and co-localizes with axonal and synaptic microtubules in vivo; its loss reduces microtubule loops at synaptic terminals, increases satellite boutons and spontaneous neurotransmitter release, and expands the dendritic arbor; pharmacological inhibition of microtubule dynamics (vinblastine) suppresses the satellite bouton phenotype, establishing EFHC1 as a negative regulator of microtubule dynamics at synapses Drosophila KO, in vitro microtubule binding, immunofluorescence, electrophysiology (mEPSPs), vinblastine pharmacological rescue, dendritic morphometry Human molecular genetics High 21835885
2016 In Xenopus laevis, EFHC1b morpholino knockdown inhibits multiciliated cell formation and specifically blocks axoneme (but not basal body) formation; EFHC1b-GFP localizes to ciliary axonemes; knockdown increases Wnt8a RNA levels and activates β-catenin/TOPFLASH reporter; the Wnt-related phenotypes are rescued by a truncated EFHC1b lacking full ciliary-localization sequences, while axonemal phenotypes require the full-length protein Xenopus morpholino knockdown, GFP-fusion localization, TOPFLASH reporter assay, domain-deletion rescue experiments, in situ hybridization Developmental biology High 26783883
2019 C. elegans EFHC-1 functions within non-motile mechanosensory cilia to regulate neuronal activation; it also localizes at the synapse where it modulates dopamine signaling in cooperation with the R-type voltage-gated calcium channel ortholog, revealing a dual regulation of neuronal excitability at cilium and synapse C. elegans genetics, live imaging, behavioral assays, dopamine signaling readouts, epistasis with R-type VGCC ortholog eLife High 30810526
2020 Using a validated monoclonal antibody (6A3-mAb) and Efhc1-/- mice as negative controls, myoclonin1 is detected only in cells with motile cilia (ependymal cells, choroid plexus, trachea, sperm) but not in neurons or at the mitotic spindle/midbody; complete elimination of myoclonin1 does not affect cell division or neuronal migration in the cerebral cortex Immunohistochemistry and western blot with monoclonal antibody validated in Efhc1-/- mice, immunocytochemistry in dividing cells Scientific reports High 33328576
2007 Myoclonin1/EFHC1 is sequentially expressed in choroid plexus epithelial cells (embryonic), then ependymal cell cilia lining ventricle walls (postnatal to adult), as well as tracheal cilia and sperm flagella; it is absent from choroid plexus in adults; localization verified using Efhc1-deficient mice as negative controls Immunohistochemistry and in situ hybridization in mouse across developmental stages, validated in Efhc1-KO Biochemical and biophysical research communications Medium 18164683
2026 Selective deletion of myoclonin1 in choroid plexus and ependymal cells (FoxJ1-Cre × floxed-Efhc1) produces increased PTZ seizure susceptibility in adult heterozygotes and enlarged brain ventricles in homozygotes, partially recapitulating the systemic Efhc1-KO phenotype and establishing that loss of myoclonin1 specifically in motile-ciliated cells contributes to epileptic pathophysiology Conditional KO mouse (FoxJ1-Cre driver), PTZ seizure threshold testing, brain ventricle morphometry Molecular and cellular neurosciences High 42000019
2024 Myoclonin1 co-localizes with and physically binds to IP3 receptor type 1 (IP3R1) in choroid plexus and ependymal cells; Efhc1-/- cells show elevated ER Ca2+ stores and enhanced IP3-induced Ca2+ release; myoclonin1 also interacts with PRKCSH (80K-H), a known IP3R1-interacting protein, and binds IP3R2 and IP3R3, indicating that myoclonin1 modulates ER-Ca2+ homeostasis through IP3R interactions Co-immunoprecipitation, Ca2+ imaging in Efhc1-/- vs WT cells, co-localization imaging bioRxivpreprint Medium bio_10.1101_2024.07.01.601633

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nature genetics 239 15258581
1997 Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6. Neurology 79 9305351
2009 EFHC1 interacts with microtubules to regulate cell division and cortical development. Nature neuroscience 57 19734894
2002 Rib72, a conserved protein associated with the ribbon compartment of flagellar A-microtubules and potentially involved in the linkage between outer doublet microtubules. The Journal of biological chemistry 57 12435737
2009 Efhc1 deficiency causes spontaneous myoclonus and increased seizure susceptibility. Human molecular genetics 56 19147686
2006 Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations. Neurology 53 17159113
2005 The mouse ortholog of EFHC1 implicated in juvenile myoclonic epilepsy is an axonemal protein widely conserved among organisms with motile cilia and flagella. FEBS letters 53 15670853
2008 Novel mutations in Myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy. Neurology 48 18505993
2006 Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy. Epilepsy research 38 16839746
1995 The phenotypic spectrum related to the human epilepsy susceptibility gene "EJM1". Annals of neurology 38 7654068
2012 The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death. Cell calcium 37 22226147
2007 Mutational analysis of EFHC1 gene in Italian families with juvenile myoclonic epilepsy. Epilepsia 37 17634063
1990 Characterization of new IgG lambda myeloma plasma cell line (EJM): a further tool in the investigation of the biology of multiple myeloma. British journal of haematology 35 2117464
2012 Mutations of EFHC1, linked to juvenile myoclonic epilepsy, disrupt radial and tangential migrations during brain development. Human molecular genetics 29 22926142
2006 EFHC1, a protein mutated in juvenile myoclonic epilepsy, associates with the mitotic spindle through its N-terminus. Experimental cell research 29 16824517
2007 Sequential expression of Efhc1/myoclonin1 in choroid plexus and ependymal cell cilia. Biochemical and biophysical research communications 22 18164683
2016 EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality. Genetics in medicine : official journal of the American College of Medical Genetics 21 27467453
2014 Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry. Epilepsia 21 25489633
2012 Novel Myoclonin1/EFHC1 mutations in Mexican patients with juvenile myoclonic epilepsy. Seizure 19 22727576
2013 Juvenile myoclonic epilepsy as a possible neurodevelopmental disease: role of EFHC1 or Myoclonin1. Epilepsy & behavior : E&B 17 23756481
2021 Proteomic analysis of microtubule inner proteins (MIPs) in Rib72 null Tetrahymena cells reveals functional MIPs. Molecular biology of the cell 15 34406789
2019 EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling. eLife 15 30810526
2012 Intractable epilepsy of infancy due to homozygous mutation in the EFHC1 gene. Epilepsia 15 22690745
2011 Defhc1.1, a homologue of the juvenile myoclonic gene EFHC1, modulates architecture and basal activity of the neuromuscular junction in Drosophila. Human molecular genetics 15 21835885
2006 Heterogeneity at the JME 6p11-12 locus: absence of mutations in the EFHC1 gene in linked Dutch families. Epilepsia 15 17054699
2016 Identifying domains of EFHC1 involved in ciliary localization, ciliogenesis, and the regulation of Wnt signaling. Developmental biology 14 26783883
2021 Biostimulation of sulfate-reducing bacteria used for treatment of hydrometallurgical waste by secondary metabolites of urea decomposition by Ochrobactrum sp. POC9: From genome to microbiome analysis. Chemosphere 13 34118631
2009 DNA variants in coding region of EFHC1: SNPs do not associate with juvenile myoclonic epilepsy. Epilepsia 13 18823326
2009 Distribution of EFHC1 or Myoclonin 1 in mouse neural structures. Epilepsy research 13 20015616
2017 EFHC1 mutation in Indian juvenile myoclonic epilepsy patient. Epilepsia open 9 29750216
2020 Epilepsy protein Efhc1/myoclonin1 is expressed in cells with motile cilia but not in neurons or mitotic apparatuses in brain. Scientific reports 8 33328576
2017 Microtubule-associated defects caused by EFHC1 mutations in juvenile myoclonic epilepsy. Human mutation 7 28370826
2015 Predictive value of EFHC1 variants for the long-term seizure outcome in juvenile myoclonic epilepsy. Epilepsy & behavior : E&B 7 25625532
2008 Characterization of the C-terminal half of human juvenile myoclonic epilepsy protein EFHC1: dimer formation blocks Ca2+ and Mg2+ binding to its functional EF-hand. Archives of biochemistry and biophysics 6 18593566
2005 Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG. Neuroscience letters 5 16378686
2020 Revisiting the clinical impact of variants in EFHC1 in patients with different phenotypes of genetic generalized epilepsy. Epilepsy & behavior : E&B 4 33181902
2023 EFHC1 gene mutation profile of Turkish JME patients and its association with disease risk. Seizure 1 38088014
2026 Myoclonin1 haploinsufficiency in motile ciliated cells partially recapitulates epileptic features of Efhc1-deficient mice in adult age. Molecular and cellular neurosciences 0 42000019