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

Jonathan Baets⁶  Dineke S. Verbeek¹  Peter De Jonghe⁶  Nathalie Van der Aa⁴  Matthis Synofzik⁷  Rebecca Schüle⁷  Michael Anthony Gonzalez³  Stephan Züchner³  Bart P. van de Warrenburg²  Berten Ceulemans⁵  Tine Deconinck⁶  Anna Duarri¹  Katrien Smets⁶ 

[1] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;Department of Neurology, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands;Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, USA;Pediatrics Outpatient Clinic, Edegem, Antwerp, Belgium;Department of Neurology, Antwerp University Hospital, Antwerp, Belgium;Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium;German Research Center for Neurodegenerative Diseases, Tübingen, Germany

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

Others  :  1220328
DOI  :  10.1186/s12881-015-0200-3

 received in 2015-01-26, accepted in 2015-07-10,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Smets et al.

【 图 表 】

Fig. 1.

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