title: First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy.
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.
authors.affiliation: Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610, Antwerp, Belgium. katrien.smets@uza.be.|Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. katrien.smets@uza.be.|Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. katrien.smets@uza.be.
authors.forename: Katrien
authors.initials: K
authors.lastname: Smets
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. a.duarri@umcg.nl.
authors.forename: Anna
authors.initials: A
authors.lastname: Duarri
authors.affiliation: Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610, Antwerp, Belgium. tine.deconinck@molgen.vib-ua.be.|Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. tine.deconinck@molgen.vib-ua.be.
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.affiliation: Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. berten.ceulemans@uza.be.
authors.forename: Berten
authors.initials: B
authors.lastname: Ceulemans
authors.affiliation: Department of Neurology, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Bart.vandeWarrenburg@radboudumc.nl.
authors.forename: Bart P
authors.initials: BP
authors.lastname: van de Warrenburg
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, USA. SZuchner@med.miami.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, USA. MGonzalez15@med.miami.edu.
authors.forename: Michael Anthony
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, USA. rebecca.schuele-freyer@uni-tuebingen.de.|Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany. rebecca.schuele-freyer@uni-tuebingen.de.|German Research Center for Neurodegenerative Diseases, Tübingen, Germany. rebecca.schuele-freyer@uni-tuebingen.de.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany. matthis.synofzik@uni-tuebingen.de.|German Research Center for Neurodegenerative Diseases, Tübingen, Germany. matthis.synofzik@uni-tuebingen.de.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Pediatrics Outpatient Clinic, Edegem, Antwerp, Belgium. nathalie.van.der.aa1@telenet.be.|University of Antwerp, Antwerp, Belgium. nathalie.van.der.aa1@telenet.be.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van der Aa
authors.affiliation: Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610, Antwerp, Belgium. peter.dejonghe@molgen.vib-ua.be.|Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. peter.dejonghe@molgen.vib-ua.be.|Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. peter.dejonghe@molgen.vib-ua.be.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. d.s.verbeek@umcg.nl.
authors.forename: Dineke S
authors.initials: DS
authors.lastname: Verbeek
authors.affiliation: Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610, Antwerp, Belgium. jonathan.baets@molgen.vib-ua.be.|Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. jonathan.baets@molgen.vib-ua.be.|Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. jonathan.baets@molgen.vib-ua.be.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
mesh_terms: D001072:Apraxias / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D004827:Epilepsy / Q000235:genetics; D005819:Genetic Markers; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D018408:Patch-Clamp Techniques; D017422:Sequence Analysis, DNA; D051672:Shal Potassium Channels / Q000235:genetics*; D013132:Spinocerebellar Degenerations / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C497021:KCND3 protein, human; D051672:Shal Potassium Channels