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Molecular Neurobiology

, Volume 44, Issue 1, pp 111–121 | Cite as

Progressive Myoclonic Epilepsy-Associated Gene KCTD7 is a Regulator of Potassium Conductance in Neurons

  • Régis AziziehEmail author
  • David Orduz
  • Patrick Van Bogaert
  • Tristan Bouschet
  • Wendy Rodriguez
  • Serge N. Schiffmann
  • Isabelle Pirson
  • Marc J. Abramowicz
Article

Abstract

The potassium channel tetramerization domain-containing protein 7 (KCTD7) was named after the structural homology of its predicted N-terminal broad complex, tramtrack and bric à brac/poxvirus and zinc finger domain with the T1 domain of the Kv potassium channel, but its expression profile and cellular function are still largely unknown. We have recently reported a homozygous nonsense mutation of KCTD7 in patients with a novel form of autosomal recessive progressive myoclonic epilepsy. Here, we show that KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments. We found the expression of KCTD7 in the hippocampal and Purkinje cells of the murine brain, an expression profile consistent with our patients’ phenotype. The effect on the plasma membrane resting potential is possibly mediated by Cullin-3, as we demonstrated direct molecular interaction of KCTD7 with Cullin-3 in co-immunoprecipitation assays. Our data link progressive myoclonic epilepsy to an inherited defect of the neuron plasma membrane’s resting potential in the brain.

Keywords

KCTD7 Cullin-3 Potassium channel Progressive myoclonic epilepsy EPM3 

Notes

Acknowledgments

Regis Azizieh is a PhD student supported by the FRIA (Fonds pour la formation à la Recherche dans l’Industrie et dans l’Agriculture) and Van Buuren grants. Marc J. Abramowicz and Serge N. Schiffmann are supported by FRSM (Fonds de la Recherche scientifique médicale) grants of the Belgian FNRS (Fonds national de la Recherche Scientifique), Marc J. Abramowicz is supported by the Fonds Erasme and Serge N. Schiffmann by grant from the Queen Elisabeth Medical foundation (FMRE, Belgium). We thank Pierre Vanderhaeghen and Alban de Kerchove d’Exaerde for discussion and Sandra Strollo, Chantal Degraef, Patrick Massoma and Sandra Pietri for expert technical help.

References

  1. 1.
    Stogios PJ, Downs GS, Jauhal JJ, Nandra SK, Prive GG (2005) Sequence and structural analysis of BTB domain proteins. Genome Biol 6:R82PubMedCrossRefGoogle Scholar
  2. 2.
    Azizieh R, Van Bogaert P, Désir J, Aeby A, De Meirleir L, Laes JF, Christiaens F, Abramowicz MJ (2007) Mutation of a potassium channel-related gene in progressive myoclonic epilepsy. Ann Neurol 61(6):579–586PubMedCrossRefGoogle Scholar
  3. 3.
    Niedermeyer E, Lopes Da Silva F (2005) Electroencephalography: basic principles, clinical applications, and related fields. Lippicott Williams & Wilkins, Philadelphia, p 389Google Scholar
  4. 4.
    Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV, McHarg ML, Gagnon D, Rosales TO, Peiffer A, Anderson VE, Leppert M (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 18(1):25–29PubMedCrossRefGoogle Scholar
  5. 5.
    Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, Leppert M (1998) A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 18(1):53–55PubMedCrossRefGoogle Scholar
  6. 6.
    Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S (2004) Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet 36(1):40–45PubMedCrossRefGoogle Scholar
  7. 7.
    NCBI Reference Sequence: NC_000007.13Google Scholar
  8. 8.
    Dutta S, Dawid IB (2010) Kctd15 inhibits neural crest formation by attenuating Wnt/beta-catenin signaling output. Development 137(18):3013–3018, Epub 2010 Aug 4PubMedCrossRefGoogle Scholar
  9. 9.
    Canettieri G, Di Marcotullio L, Greco A, Coni S, Antonucci L, Infante P, Pietrosanti L, De Smaele E, Ferretti E, Miele E, Pelloni M, De Simone G, Pedone EM, Gallinari P, Giorgi A, Steinkühler C, Vitagliano L, Pedone C, Schinin ME, Screpanti I, Gulino A (2010) Histone deacetylase and Cullin-3-REN (KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol 12(2):132–142, Epub 2010 Jan 17PubMedCrossRefGoogle Scholar
  10. 10.
    D’Angelo E, De Filippi G, Rossi P, Taglietti V (1995) Synaptic excitation of individual rat cerebellar granule cells in situ: evidence for the role of NMDA receptors. J Physiol 484(Pt 2):397–413PubMedGoogle Scholar
  11. 11.
    Joensuu T, Kuronen M, Alakurtti K, Tegelberg S, Hakala P, Aalto A, Huopaniemi L, Aula N, Michellucci R, Eriksson K, Lehesjoki A-E (2007) Cystatin B: mutation detection, alternative splicing and expression in progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) patients. Eur J Hum Genet 15:185–193PubMedCrossRefGoogle Scholar
  12. 12.
    Pennacchio LA, Bouley DM, Higgins KM, Scott MP, Noebels JL, Myers RM (1998) Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet 20(3):251–258PubMedCrossRefGoogle Scholar
  13. 13.
    Fujiwara T (2006) Clinical spectrum of mutations in SCN1A gene: severe myoclonic epilepsy in infancy and related epilepsies. Epilepsy Res 70(Suppl 1):S223–S230, Epub 2006 Jun 27PubMedCrossRefGoogle Scholar
  14. 14.
    Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E, Capovilla G, Chiron C, Cristofori G, Elia M, Fontana E, Gaggero R, Granata T, Guerrini R, Loi M, La Selva L, Lispi ML, Matricardi A, Romeo A, Tzolas V, Valseriati D, Veggiotti P, Vigevano F, Vallée L, Dagna Bricarelli F, Bianchi A, Zara F (2003) Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 60(12):1961–1967PubMedGoogle Scholar
  15. 15.
    Escayg, Goldin (2010) Epilepsia 51:1650–1658PubMedCrossRefGoogle Scholar
  16. 16.
    Benatar M (2000) Neurological potassium channelopathies. QJM 93(12):787–797PubMedCrossRefGoogle Scholar
  17. 17.
    Schwenk J, Metz M, Zolles G, Turecek R, Fritzius T, Bildl W, Tarusawa E, Kulik A, Unger A, Ivankova K, Seddik R, Tiao JY, Rajalu M, Trojanova J, Rohde V, Gassmann M, Schulte U, Fakler B, Bettler B (2010) Native GABAb receptors are heteromultimers with a family of auxiliary subunits. Nature 465(7295):231–235. doi: 10.1038/nature08964 PubMedCrossRefGoogle Scholar
  18. 18.
    Yi BA, Minor DL Jr, Lin YF, Jan YN, Jan LY (2001) Controlling potassium channel activities: interplay between the membrane and intracellular factors. Proc Natl Acad Sci USA 98(20):11016–11023PubMedCrossRefGoogle Scholar
  19. 19.
    Bayón Y, Trinidad AG, de la Puerta ML, Del Carmen Rodríguez M, Bogetz J, Rojas A, De Pereda JM, Rahmouni S, Williams S, Matsuzawa S, Reed JC, Crespo MS, Mustelin T, Alonso A (2008) KCTD5, a putative substrate adaptor for Cullin-3 ubiquitin ligases. FEBS J 275(15):3900–3910, EpubJun 28PubMedCrossRefGoogle Scholar
  20. 20.
    Ekberg J, Schuetz F, Boase NA, Conroy SJ, Manning J, Kumar S, Poronnik P, Adams DJ (2007) Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by ubiquitination. Novel role for Nedd4-2. J Biol Chem 282(16):12135–12142PubMedCrossRefGoogle Scholar
  21. 21.
    Henke G et al (2004) Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol 199(2):194–199Google Scholar
  22. 22.
    Boehmer C et al (2008) Modulation of the Voltage-Gated Potassium Channel Kv1.5 by the SGK1 Protein Kinase Involves Inhibition of Channel Ubiquitination. Cell Physiol Biochem 22(5–6):591–600Google Scholar
  23. 23.
    Chapman H et al (2005) Downregulation of the HERG (KCNH2) K+ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation. J Cell Sci 118(22):5325–34PubMedCrossRefGoogle Scholar
  24. 24.
    Fotia AB et al (2004) Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4–2. J Biol Chem 279(28):28930–5PubMedCrossRefGoogle Scholar
  25. 25.
    Hryciw DH et al (2004) Nedd4–2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem 279(53):54996–5007PubMedCrossRefGoogle Scholar
  26. 26.
    He Y et al (2008) The ubiquitin-protein ligase Nedd4–2 differentially interacts with and regulates members of the Tweety family of chloride ion channels. J Biol Chem 283(35):24000–10PubMedCrossRefGoogle Scholar
  27. 27.
    Salinas GD, Blair LA, Needleman LA, Gonzales JD, Chen Y, Li M, Singer JD, Marshall J (2006) Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway. J Biol Chem 281(52):40164–40173PubMedCrossRefGoogle Scholar
  28. 28.
    Nadler JV (1981) Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 29(20):2031–2042PubMedCrossRefGoogle Scholar
  29. 29.
    Fisahn A, Heinemann SF, McBain CJ (2005) The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurones. J Physiol 562(1):199–203PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Régis Azizieh
    • 1
    Email author
  • David Orduz
    • 3
  • Patrick Van Bogaert
    • 4
  • Tristan Bouschet
    • 1
  • Wendy Rodriguez
    • 1
  • Serge N. Schiffmann
    • 3
  • Isabelle Pirson
    • 1
    • 5
  • Marc J. Abramowicz
    • 1
    • 2
  1. 1.Institute of Interdisciplinary Research (IRIBHM)-ULBBrusselsBelgium
  2. 2.Department of Medical GeneticsHôpital Erasme–ULBBrusselsBelgium
  3. 3.Laboratory of Neurophysiology-ULBBrusselsBelgium
  4. 4.Department of Pediatric NeurologyHôpital Erasme–ULBBrusselsBelgium
  5. 5.Institute of Interdisciplinary Research, IRIBHM, School of MedicineFree University of Brussels (ULB)BrusselsBelgium

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