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

doi:10.1186/s12881-015-0200-3

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

Journal article

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Peer reviewed

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, …

BMC medical genetics, Vol.16(1), pp.51-51

2015-07-21

DOI: https://doi.org/10.1186/s12881-015-0200-3

PMCID: PMC4557545

PMID: 26189493

Abstract

Humans

Male

Genetic Markers

Spinocerebellar Degenerations - genetics

Sequence Analysis, DNA

Intellectual Disability - genetics

Patch-Clamp Techniques

Shal Potassium Channels - genetics

Apraxias - genetics

Base Sequence

Cell Line, Tumor

Epilepsy - genetics

HeLa Cells

Child

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. Whole exome sequencing in a cerebellar ataxia patient and subsequent immunocytochemistry, immunoblotting and patch clamp assays of the channel were performed. 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. 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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.951 Huntington's Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy
Creators: Katrien Smets - Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. katrien.smets@uza.be
Anna Duarri - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. a.duarri@umcg.nl
Tine Deconinck - Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. tine.deconinck@molgen.vib-ua.be
Berten Ceulemans - Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. berten.ceulemans@uza.be
Bart P van de Warrenburg - Department of Neurology, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Bart.vandeWarrenburg@radboudumc.nl
Stephan Züchner - Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, USA. SZuchner@med.miami.edu
Michael Anthony Gonzalez - Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, USA. MGonzalez15@med.miami.edu
Rebecca Schüle - German Research Center for Neurodegenerative Diseases, Tübingen, Germany. rebecca.schuele-freyer@uni-tuebingen.de
Matthis Synofzik - German Research Center for Neurodegenerative Diseases, Tübingen, Germany. matthis.synofzik@uni-tuebingen.de
Nathalie Van der Aa - University of Antwerp, Antwerp, Belgium. nathalie.van.der.aa1@telenet.be
Peter De Jonghe - Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. peter.dejonghe@molgen.vib-ua.be
Dineke S Verbeek - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. d.s.verbeek@umcg.nl
Jonathan Baets - Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. jonathan.baets@molgen.vib-ua.be
Publication Details: BMC medical genetics, Vol.16(1), pp.51-51
Publisher: England
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 26189493
PMCID: PMC4557545
Record Identifier: 991031578614602976