First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy

Katrien Smets, Anna Duarri, Tine Deconinck, Berten Ceulemans, Bart P. van de Warrenburg, Stephan Züchner, Michael Anthony Gonzalez, Rebecca Schüle, Matthis Synofzik, Nathalie Van der Aa, Peter De Jonghe, Dineke S. Verbeek, Jonathan Baets

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Background: Identification of the first de novo mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) in a patient with complex early onset cerebellar ataxia in order to expand the genetic and phenotypic spectrum. Methods: Whole exome sequencing in a cerebellar ataxia patient and subsequent immunocytochemistry, immunoblotting and patch clamp assays of the channel were performed. Results: A de novo KCND3 mutation (c.877_885dupCGCGTCTTC; p.Arg293_Phe295dup) was found duplicating the RVF motif and thereby adding an extra positive charge to voltage-gated potassium 4.3 (Kv4.3) in the voltage-sensor domain causing a severe shift of the voltage-dependence gating to more depolarized voltages. The patient displayed a severe phenotype with early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Conclusions: We identified a de novo KCND3 mutation causing the most marked change in Kv4.3's channel properties reported so far, which correlated with a severe and unique spinocerebellar ataxia (SCA) type 19/22 disease phenotype.

Original languageEnglish (US)
Article number51
JournalBMC medical genetics
Volume16
Issue number1
DOIs
StatePublished - Jul 21 2015

Keywords

  • Channelopathy
  • Early onset cerebellar ataxia
  • Epilepsy
  • Immunoblotting
  • Immunocytochemistry
  • Intellectual disability
  • KCND3
  • Patch clamp study
  • SCA19/22
  • Whole exome sequencing/WES

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Smets, K., Duarri, A., Deconinck, T., Ceulemans, B., van de Warrenburg, B. P., Züchner, S., Gonzalez, M. A., Schüle, R., Synofzik, M., Van der Aa, N., De Jonghe, P., Verbeek, D. S., & Baets, J. (2015). First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy. BMC medical genetics, 16(1), [51]. https://doi.org/10.1186/s12881-015-0200-3