EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling
Open accessAbstract
Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy.
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EFHC1 is associated with ciliary signalling in both human cells and C. elegans, but its disruption in humans results in juvenile myoclonic epilepsy.
“EFHC1 is associated with ciliary signalling in both human cells and C. elegans, but its disruption in humans results in juvenile myoclonic epilepsy, whose aetiology could potentially result from non-motile cilia dysfunction84,85.”
From The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision (2022) · cites this paper as [85]
The Introduction (page unavailable) reports that EFHC1 disruption has been linked to juvenile myoclonic epilepsy, and the Discussion (page unavailable) reports a role for EFHC-1 in ciliary mechanosensation and dopamine signaling in C. elegans. The paper associates EFHC1 with motile cilia in humans but says its signaling role in human neuronal non-motile cilia remains unexplored; it does not establish ciliary signaling in human cells. (LLM, conf=0.85)
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Cites
The structure of the nervous system of the nematode <i>Caenorhabditis elegans</i>
White, J. G., Southgate, E., Thomson, J. N., & Brenner, S. (1986) · Philosophical Transactions of the Royal Society of London. B, Biological Sciences · doi:10.1098/rstb.1986.0056 · Cited by 5,589 · cited 2× · see citing works
“Both classes of neurons terminate in cilia embedded in the cuticle, ideally positioned to mediate mechanosensation at various locations along the body: four CEP neurons paired with four OLQ neurons project cilia in the nose, two ADE neurons position cilia in the anterior body, and two PDE neurons localize cilia to the…”
BackgroundLogistic Regression: A Brief Primer
Stoltzfus, J. C. (2011) · Academic Emergency Medicine · doi:10.1111/j.1553-2712.2011.01185.x · Cited by 1,290 · see citing works
Sawin, E. R., Ranganathan, R., & Horvitz, H. R. (2000) · Neuron · doi:10.1016/s0896-6273(00)81199-x · Cited by 1,076 · see citing works
Heritable genome editing in C. elegans via a CRISPR-Cas9 system
Friedland, A. E., Tzur, Y. B., Esvelt, K. M., Colaiácovo, M. P., Church, G. M., & Calarco, J. A. (2013) · Nature Methods · doi:10.1038/nmeth.2532 · Cited by 899 · see citing works
Streamlined Genome Engineering with a Self-Excising Drug Selection Cassette
Dickinson, D. J., Pani, A. M., Heppert, J. K., Higgins, C. D., & Goldstein, B. (2015) · Genetics · doi:10.1534/genetics.115.178335 · Cited by 546 · see citing works
A dual mechanosensory and chemosensory neuron in Caenorhabditis elegans.
Kaplan, J. M., & Horvitz, H. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.6.2227 · Cited by 487 · see citing works
Dopaminergic neurons in the nematode Caenorhabditis elegans
Sulston, J., Dew, M., & Brenner, S. (1975) · The Journal of Comparative Neurology · doi:10.1002/cne.901630207 · Cited by 477 · see citing works
High-throughput behavioral analysis in C. elegans
Swierczek, N. A., Giles, A. C., Rankin, C. H., & Kerr, R. A. (2011) · Nature Methods · doi:10.1038/nmeth.1625 · Cited by 460 · see citing works
Self-citationAn open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming
Richmond, J. E., Weimer, R. M., & Jorgensen, E. M. (2001) · Nature · doi:10.1038/35085583 · Cited by 437 · see citing works
Synaptic code for sensory modalities revealed by C. elegans GLR-1 glutamate receptor
Hart, A. C., Sims, S., & Kaplan, J. M. (1995) · Nature · doi:10.1038/378082a0 · Cited by 426 · see citing works
Epilepsy with impulsive petit mal (Juvenile Myoclonic Epilepsy)
Janz, D. (2009) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1985.tb00900.x · Cited by 393 · see citing works
Mutations in EFHC1 cause juvenile myoclonic epilepsy
Suzuki, T., Delgado‐Escueta, A. V., Aguan, K., Alonso, M. E., Shi, J., Hara, Y., Nishida, M., Numata, T., Medina, M. T., Takeuchi, T., et al. (2004) · Nature Genetics · doi:10.1038/ng1393 · Cited by 371 · see citing works
Nonet, M. L., Staunton, J. E., Kilgard, M. P., Fergestad, T., Hartwieg, E. A., Horvitz, H. R., Jørgensen, E. M., & Meyer, B. J. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-21-08061.1997 · Cited by 354 · see citing works
Schafer, W. R., & Kenyon, C. J. (1995) · Nature · doi:10.1038/375073a0 · Cited by 317 · see citing works
Self-citationType III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain
Bishop, G. A., Berbari, N. F., Lewis, J., & Mykytyn, K. (2007) · Journal of Comparative Neurology · doi:10.1002/cne.21510 · Cited by 317 · see citing works
A database of Caenorhabditis elegans behavioral phenotypes
Yemini, E., Jucikas, T., Grundy, L. J., Brown, A. E., & Schafer, W. R. (2013) · Nature Methods · doi:10.1038/nmeth.2560 · Cited by 309 · see citing works
Self-citationMechanism of extrasynaptic dopamine signaling in Caenorhabditis elegans
Chase, D. L., Pepper, J. S., & Koelle, M. R. (2004) · Nature Neuroscience · doi:10.1038/nn1316 · Cited by 296 · see citing works
Bailet, L. L., & Turk, W. R. (2000) · Epilepsia · doi:10.1111/j.1528-1157.2000.tb00184.x · Cited by 282 · see citing works
Caenorhabditis elegans: A new model system for the study of learning and memory
Rankin, C. H., Beck, C., & Chiba, C. M. (1990) · Behavioural Brain Research · doi:10.1016/0166-4328(90)90074-o · Cited by 278 · see citing works
Self-citationKang, L., Gao, J., Schafer, W. R., Xie, Z., & Xu, X. Z. S. (2010) · Neuron · doi:10.1016/j.neuron.2010.06.032 · Cited by 238 · see citing works
Self-citationCaenorhabditis elegans TRPA-1 functions in mechanosensation
Kindt, K. S., Viswanath, V., Macpherson, L. J., Quast, K. B., Hu, H., Patapoutian, A., & Schafer, W. R. (2007) · Nature Neuroscience · doi:10.1038/nn1886 · Cited by 238 · see citing works
Self-citationDopamine modulates the plasticity of mechanosensory responses in Caenorhabditis elegans
Sanyal, S., Wintle, R. F., Kindt, K. S., Nuttley, W. M., Arvan, R., Fitzmaurice, P. S., Bigras, E., Merz, D. C., Hébert, T. E., van der Kooy, D., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600057 · Cited by 236 · see citing works
Self-citationThe primary cilium as a cellular receiver: organizing ciliary GPCR signaling
Hilgendorf, K. I., Johnson, C. T., & Jackson, P. K. (2016) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2016.02.008 · Cited by 224 · see citing works
Dopamine Mediates Context-Dependent Modulation of Sensory Plasticity in C. elegans
Kindt, K. S., Quast, K. B., Giles, A. C., De, S., Hendrey, D., Nicastro, I. A., Rankin, C. H., & Schafer, W. R. (2007) · Neuron · doi:10.1016/j.neuron.2007.07.023 · Cited by 210 · see citing works
Self-citationThe sensory cilia of Caenorhabditis elegans_Revised
Scholey, J. M. (2007) · WormBook · doi:10.1895/wormbook.1.126.2 · Cited by 209 · see citing works
The role of dopamine signaling in epileptogenesis
Bozzi, Y., & Borrelli, E. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00157 · Cited by 199 · see citing works
Pascalicchio, T. F., Filho, G. M. D. A., Noffs, M. H. D. S., et al. (2007) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2006.11.012 · Cited by 173 · see citing works
Frontal functions in juvenile myoclonic epilepsy.
Devinsky, O., Gershengorn, J., Brown, E., et al. (1997) · PubMed · Cited by 171 · see citing works
Dwyer, N. D., Adler, C. E., Crump, J. G., L’Étoile, N. D., & Bargmann, C. I. (2001) · Neuron · doi:10.1016/s0896-6273(01)00361-0 · Cited by 160 · see citing works
The sensory cilia of Caenorhabditis elegans
Inglis, P. N. (2006) · WormBook · doi:10.1895/wormbook.1.126.1 · Cited by 151 · see citing works
Food sensitizes C. elegans avoidance behaviours through acute dopamine signalling
Ezcurra, M., Tanizawa, Y., Swoboda, P., & Schafer, W. R. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.22 · Cited by 143 · see citing works
Self-citationMcDonald, P., Hardie, S. L., Jessen, T. N., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2992-07.2007 · Cited by 140 · see citing works
Visual working memory in primary generalized epilepsy
Swartz, B. E., Simpkins, F. A., Halgren, E., et al. (1996) · Neurology · doi:10.1212/wnl.47.5.1203 · Cited by 130 · see citing works
Cevik, S., Sanders, A. A. W. M., van Wijk, E., Boldt, K., Clarke, L., van Reeuwijk, J., Hori, Y., Horn, N., Hetterschijt, L., Wdowicz, A., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003977 · Cited by 97 · see citing works
Self-citationPresynaptic CaV2 calcium channel traffic requires CALF-1 and the α2δ subunit UNC-36
Saheki, Y., & Bargmann, C. I. (2009) · Nature Neuroscience · doi:10.1038/nn.2383 · Cited by 82 · see citing works
EFHC1 interacts with microtubules to regulate cell division and cortical development
de Nijs, L., Léon, C., Nguyen, L., LoTurco, J. J., Delgado‐Escueta, A. V., Grisar, T. M., & Lakaye, B. (2009) · Nature Neuroscience · doi:10.1038/nn.2390 · Cited by 82 · see citing works
New wave of research in the epilepsies.
Delgado‐Escueta, A. V., Ward, A. A., Dm, W., et al. (1986) · PubMed · Cited by 82 · see citing works
Insights into the Structure and Function of Ciliary and Flagellar Doublet Microtubules
Linck, R. W., Fu, X., Lin, J., Ouch, C., Schefter, A. M., Steffen, W., Warren, P. G., & Nicastro, D. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.568949 · Cited by 81 · see citing works
Efhc1 deficiency causes spontaneous myoclonus and increased seizure susceptibility
Suzuki, T., Miyamoto, H., Nakahari, T., Inoue, I., Suemoto, T., Jiang, B., Hirota, Y., Itohara, S., Saido, T. C., Tsumoto, T., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp006 · Cited by 76 · see citing works
Ikeda, K., Brown, J. A., Yagi, T., Norrander, J. M., Hirono, M., Eccleston, E., Kamiya, R., & Linck, R. W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210751200 · Cited by 75 · see citing works
Mathews, E., Garcı́a, E., Santi, C. M., Mullen, G. P., Thacker, C. M., Moerman, D. G., & Snutch, T. P. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-16-06537.2003 · Cited by 75 · see citing works
Redundant Localization Mechanisms of RIM and ELKS in<i>Caenorhabditis elegans</i>
Deken, S. L., Vincent, R., Hadwiger, G., Liu, Q., Wang, Z.-W., & Nonet, M. L. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.0804-05.2005 · Cited by 72 · see citing works
Reduced dopamine transporter binding in patients with juvenile myoclonic epilepsy
Ciumas, C., Wahlin, T.-B. R., Jučaitė, A., Lindström, P., Halldin, C., & Savić, I. (2008) · Neurology · doi:10.1212/01.wnl.0000316120.70504.d5 · Cited by 67 · see citing works
Ikeda, T., Ikeda, K., Enomoto, M., et al. (2005) · FEBS Letters · doi:10.1016/j.febslet.2004.12.070 · Cited by 62 · see citing works
Katano, M., Numata, T., Aguan, K., Hara, Y., Kiyonaka, S., Yamamoto, S., Miki, T., Sawamura, S., Suzuki, T., Yamakawa, K., et al. (2012) · Cell Calcium · doi:10.1016/j.ceca.2011.12.011 · Cited by 58 · see citing works
Advances in Genetics of Juvenile Myoclonic Epilepsies
Delgado‐Escueta, A. V. (2007) · Epiliepsy currents/Epilepsy currents · doi:10.1111/j.1535-7511.2007.00171.x · Cited by 58 · see citing works
The dopamine system in idiopathic generalized epilepsies: Identification of syndrome-related changes
Ciumas, C., Wahlin, T. R., Espino, C., & Savić, I. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.02.051 · Cited by 53 · see citing works
A Gap Junction Circuit Enhances Processing of Coincident Mechanosensory Inputs
Rabinowitch, I., Chatzigeorgiou, M., & Schafer, W. R. (2013) · Current Biology · doi:10.1016/j.cub.2013.04.030 · Cited by 50 · see citing works
Self-citationde Nijs, L., Lakaye, B., Coumans, B., et al. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.05.011 · Cited by 39 · see citing works
de Nijs, L., Wolkoff, N., Coumans, B., Delgado‐Escueta, A. V., Grisar, T. M., & Lakaye, B. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds356 · Cited by 39 · see citing works
Sequential expression of Efhc1/myoclonin1 in choroid plexus and ependymal cell cilia
Suzuki, T., Inoue, I., Yamagata, T., et al. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.12.126 · Cited by 36 · see citing works
Odano, I., Varrone, A., Savić, I., Ciumas, C., Karlsson, P., Jučaitė, A., Halldin, C., & Farde, L. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.10.067 · Cited by 36 · see citing works
Sanders, A. A. W. M., Kennedy, J. E., & Blacque, O. E. (2015) · Methods in cell biology · doi:10.1016/bs.mcb.2015.01.010 · Cited by 29 · see citing works
Self-citationCorrea, P. A., LeBoeuf, B., & Garcia, L. R. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1003015 · Cited by 29 · see citing works
Torres, V. I., & Inestrosa, N. C. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0661-9 · Cited by 27 · see citing works
PACRG, a protein linked to ciliary motility, mediates cellular signaling
Loucks, C. M., Bialas, N. J., Dekkers, M. P. J., Walker, D. S., Grundy, L. J., Li, C., Inglis, P. N., Kida, K., Schafer, W. R., Blacque, O. E., et al. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-07-0490 · Cited by 23 · see citing works
Self-citationSummation of the workshops and discussion: The new wave of research in the epilepsies
Delgado‐Escueta, A. V. (1984) · Annals of Neurology · doi:10.1002/ana.410160721 · Cited by 18 · see citing works
Rossetto, M. G., Zanarella, E., Orso, G., Scorzeto, M., Megighian, A., Kumar, V., Delgado‐Escueta, A. V., & Daga, A. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr352 · Cited by 18 · see citing works
Zhao, Y., Shi, J., Winey, M., & Klymkowsky, M. W. (2016) · Developmental Biology · doi:10.1016/j.ydbio.2016.01.004 · Cited by 17 · see citing works
Chapter 21 Electron Microscopy of Lamin and the Nuclear Lamina in Caenorhabditis elegans
Cohen, M., Santarella, R. A., Wiesel, N., et al. (2008) · Methods in cell biology · doi:10.1016/s0091-679x(08)00421-4 · Cited by 11 · see citing works
Expression Profile and Distribution of Efhc1 Gene Transcript During Rodent Brain Development
Conte, F. F., Ribeiro, P. A. O., Marchesini, R. B., et al. (2009) · Journal of Molecular Neuroscience · doi:10.1007/s12031-009-9179-6 · Cited by 10 · see citing works
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Self-citationThe primary cilia are associated with the axon initial segment in neurons
Wang, H., Li, Y., Li, X., Sun, Z., Yu, F., Pashang, A., Kulasiri, D., Li, H. W., Chen, H., Hou, H., et al. (2025) · Advanced Science · doi:10.1002/advs.202407405 · Cited by 13 · see citing works
- Authors
- Loucks, C. M., Park, K., Walker, D. S., McEwan, A. H., Timbers, T. A., Ardiel, E. L., Grundy, L. J., Li, C., Johnson, J.-L., Kennedy, J., Blacque, O. E., Schafer, W., Rankin, C. H., & Leroux, M. R.
- Affiliations
- Simon Fraser University (CA)
- MRC Laboratory of Molecular Biology (GB)
- University of British Columbia (CA)
- University College Dublin (IE)
- Corresponding author
- Leroux, Michel R
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-02-27
- Volume
- 8
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6392500
- OpenAlex
- W2917903841
- Cited by
- 18
- References
- 61
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 1
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Summit (Simon Fraser University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Summit (Simon Fraser University) (submittedVersion, cc-by)
- Funders
- Canadian Institutes of Health Research (MOP82870, MOP130287, Frederick Banting and Charles Best Canada Graduate Scholarship)
- Michael Smith Foundation for Health Research (Senior Scholar Award)
- Natural Sciences and Engineering Research Council of Canada (Discover Grant 122216-2013, Vanier Canada Graduate Scholarship)
- Science Foundation Ireland (11/PI/1037)
- Medical Research Council (MC_A023_5PB91)
- Wellcome (WT103784MA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- EFHC1, juvenile myoclonic epilepsy, dopamine signaling, synapses, neuronal excitability, Caenorhabditis elegans, genetic epilepsy
- MeSH terms
- Animals, Cilia, Synaptic Transmission, Synapses, Caenorhabditis elegans, Dopaminergic Neurons
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