Neurogenetics

, Volume 6, Issue 4, pp 185–193 | Cite as

Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC)

  • Maria T. Bassi
  • Umberto Balottin
  • Chris Panzeri
  • Paolo Piccinelli
  • Pasqualina Castaldo
  • Vincenzo Barrese
  • Maria V. Soldovieri
  • Francesco Miceli
  • Maria Colombo
  • Nereo Bresolin
  • Renato Borgatti
  • Maurizio Taglialatela
Original Article

Abstract

Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in KCNQ2 and KCNQ3, two genes encoding for potassium channel subunits. A large family with nine members affected by BFNC is described in the present study. All affected members of this family carry a novel deletion/insertion mutation in the KCNQ2 gene (c.761_770del10insA), which determines a premature truncation of the protein. In addition, in the family of the proposita's father, a novel sequence variant (c.2687A>G) in KCNQ3 leading to the p.N821S amino acid change was detected. When heterologously expressed in Chinese hamster ovary cells, KCNQ2 subunits carrying the mutation failed to form functional potassium channels in homomeric configuration and did not affect channels formed by KCNQ2 and/or KCNQ3 subunits. On the other hand, homomeric and heteromeric potassium channels formed by KCNQ3 subunits carrying the p.N821S variant were indistinguishable from those formed by wild-type KCNQ3 subunits. Finally, the current density of the cells mimicking the double heterozygotic condition for both KCNQ2 and KCNQ3 alleles of the proband was decreased by approximately 25% when compared to cells expressing only wild-type alleles. Collectively, these results suggest that, in the family investigated, the KCNQ2 mutation is responsible for the BFNC phenotype, possibly because of haplo-insufficiency, whereas the KCNQ3 variant is functionally silent, a result compatible with its lack of segregation with the BFNC phenotype.

Keywords

Epilepsy Benign familial neonatal convulsion KCNQ2 KCNQ3 Gene variant 

References

  1. 1.
    Plouin P (1994) Benign familial neonatal convulsions. In: Malafosse A, Genton P, Hirsch E, Marescaux C, Broglin D, Bernasconi R (eds). Idiopathic generalized epilepsies: clinical, experimental and genetic aspects. John Libbey, London, pp 39–44Google Scholar
  2. 2.
    Ronen GM, Rosales TO, Connolly M, Anderson VE, Leppert M (1993) Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology 43:1355–1360PubMedGoogle Scholar
  3. 3.
    Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK (1998) A potassium channel mutation in neonatal human epilepsy. Science 279:403–406CrossRefPubMedGoogle 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 18:25–29CrossRefPubMedGoogle 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 18:53–55CrossRefPubMedGoogle Scholar
  6. 6.
    Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, Anderson VE, Sanguinetti MC, Leppert MF, BFNC Physician Consortium (2003) KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 126:2726–2737CrossRefPubMedGoogle Scholar
  7. 7.
    Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282:1890–1893PubMedCrossRefGoogle Scholar
  8. 8.
    Rogawski MA (2000) KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. Trends Neurosci 23:393–398CrossRefPubMedGoogle Scholar
  9. 9.
    Schroeder BC, Kubisch C, Stein V, Jentsch TJ (1998) Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature 396:687–690CrossRefPubMedGoogle Scholar
  10. 10.
    Lerche H, Biervert C, Alekov AK, Schleithoff L, Lindner M, Klinger W, Bretschneider F, Mitrovic N, Jurkat-Rott K, Bode H, Lehmann-Horn F, Steinlein OK (1999) A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsion. Ann Neurol 46:305–312CrossRefPubMedGoogle Scholar
  11. 11.
    Schwake M, Pusch M, Kharkovets T, Jentsch TJ (2000) Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. J Biol Chem 275:13343–13348CrossRefPubMedGoogle Scholar
  12. 12.
    Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ, Steinlein OK (2001) Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci U S A 98:12272–12277CrossRefPubMedGoogle Scholar
  13. 13.
    Den Dunnen JT, Paalman MH (2003) Standardizing mutation nomenclature: why bother? Hum Mutat 22:181–182CrossRefPubMedGoogle Scholar
  14. 14.
    Castaldo P, Miraglia del Giudice E, Coppola G, Pascotto A, Annunziato L, Taglialatela M (2002) Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. J Neurosci 22:RC199:1–6Google Scholar
  15. 15.
    Cooper EC, Aldape KD, Abosch A, Barbaro NM, Berger MS, Peacock WS, Jan YN, Jan LY (2000) Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. Proc Natl Acad Sci U S A 97:4914–4919CrossRefPubMedGoogle Scholar
  16. 16.
    Borgatti R, Zucca C, Cavallini A, Ferrario M, Panzeri C, Castaldo P, Sodovieri MV, Baschirotto C, Bresolin N, Dalla Bernardina B, Taglialatela M, Bassi MT (2004) A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology 63:57–65PubMedGoogle Scholar
  17. 17.
    Dedek K, Fusco L, Teloy N, Steinlein OK (2003) Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res 54:21–27CrossRefPubMedGoogle Scholar
  18. 18.
    Bezanilla F (2000) The voltage-sensor in voltage-dependent ion channels. Physiol Rev 80:555–592PubMedGoogle Scholar
  19. 19.
    Shieh C-C, Coghlan M, Sullivan JP, Gopalakrishnan M (2000) Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 52:557–593PubMedGoogle Scholar
  20. 20.
    Hoshi N, Zhang JS, Omaki M, Takeuchi T, Yokoyama S, Wanaverbecq N, Langeberg LK, Yoneda Y, Scott JD, Brown DA, Higashida H (2003) AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. Nat Neurosci 6:564–571CrossRefPubMedGoogle Scholar
  21. 21.
    Yus-Najera E, Santana-Castro I, Villarroel A (2002) The identification and characterization of a noncontinuous calmodulin-binding site in noninactivating voltage-dependent KCNQ potassium channels. J Biol Chem 277:28545–28553CrossRefPubMedGoogle Scholar
  22. 22.
    Wen H, Levitan IB (2002) Calmodulin is an auxiliary subunit of KCNQ2/3 potassium channels. J Neurosci 22:7991–8001PubMedGoogle Scholar
  23. 23.
    Saldana C, Naranjo D, Coria R, Pena A, Vaca L (2002) Splitting the two pore domains from TOK1 results in two cationic channels with novel functional properties. J Biol Chem 15:4797–4805CrossRefGoogle Scholar
  24. 24.
    Schwake M, Jentsch TJ, Friedrich T (2003) A carboxy-terminal domain determines the subunit specificity of KCNQ K+ channel assembly. EMBO Rep 4:76–81CrossRefPubMedGoogle Scholar
  25. 25.
    Maljevic S, Lerche C, Seebohm G, Alekov AK, Busch AE, Lerche H (2003) C-terminal interaction of KCNQ2 and KCNQ3 K+ channels. J Physiol 548(Pt 2):353–360PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Maria T. Bassi
    • 1
  • Umberto Balottin
    • 2
    • 3
  • Chris Panzeri
    • 1
  • Paolo Piccinelli
    • 2
  • Pasqualina Castaldo
    • 4
  • Vincenzo Barrese
    • 4
  • Maria V. Soldovieri
    • 4
  • Francesco Miceli
    • 4
  • Maria Colombo
    • 2
  • Nereo Bresolin
    • 1
    • 5
    • 6
  • Renato Borgatti
    • 1
  • Maurizio Taglialatela
    • 4
    • 7
  1. 1.IRCCS E. MedeaBosisio Parini LeccoItaly
  2. 2.Child Neuropsychiatry UnitUniversity of Insubria, Macchi Foundation HospitalVareseItaly
  3. 3.Department of Child NeuropsychiatryIRCCS Fondazione C. MondinoPaviaItaly
  4. 4.Division of Pharmacology, Department of Neuroscience, School of MedicineUniversity of Naples Federico IINaplesItaly
  5. 5.IRCCS Ospedale Maggiore PoliclinicoMilanItaly
  6. 6.Centro Dino Ferrari, Department of NeurologyUniversity of MilanMilanItaly
  7. 7.Department of Health SciencesUniversity of MoliseCampobassoItaly

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