Referenced in: none

Automatically associated channels: Kv1.4 , Kv3.1 , Kv4.1 , Kv4.3

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

Authors: 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

Journal, date & volume: BMC Med. Genet., 2015 , 16, 51

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26189493

Abstract
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.