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 Zuechner, Michael Anthony Gonzalez, Rebecca Schuele, Matthis Synofzik, Nathalie Van der Aa, Peter De Jonghe*, Dineke S. Verbeek, Jonathan Baets

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

34 Citaten (Scopus)
197 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Artikelnummer51
Aantal pagina's7
TijdschriftBMC MEDICAL GENETICS
Volume16
DOI's
StatusPublished - 21-jul-2015

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