title: Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner.
abstract: The dominantly inherited cerebellar ataxias are a heterogeneous group of neurodegenerative disorders caused by Purkinje cell loss in the cerebellum. Recently, we identified loss-of-function mutations in the KCND3 gene as the cause of spinocerebellar ataxia type 19/22 (SCA19/22), revealing a previously unknown role for the voltage-gated potassium channel, Kv4.3, in Purkinje cell survival. However, how mutant Kv4.3 affects wild-type Kv4.3 channel functioning remains unknown. We provide evidence that SCA19/22-mutant Kv4.3 exerts a dominant negative effect on the trafficking and surface expression of wild-type Kv4.3 in the absence of its regulatory subunit, KChIP2. Notably, this dominant negative effect can be rescued by the presence of KChIP2. We also found that all SCA19/22-mutant subunits either suppress wild-type Kv4.3 current amplitude or alter channel gating in a dominant manner. Our findings suggest that altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia.
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands.
authors: Anna
authors: A
authors: Duarri
authors: Meng-Chin A
authors: MC
authors: Lin
authors: Michiel R
authors: MR
authors: Fokkens
authors: Michel
authors: M
authors: Meijer
authors: Cleo J L M
authors: CJ
authors: Smeets
authors: Esther A R
authors: EA
authors: Nibbeling
authors: Erik
authors: E
authors: Boddeke
authors: Richard J
authors: RJ
authors: Sinke
authors: Harm H
authors: HH
authors: Kampinga
authors: Diane M
authors: DM
authors: Papazian
authors: Dineke S
authors: DS
authors: Verbeek
mesh_terms: D000704:Analysis of Variance; D003513:Cycloheximide; D017931:DNA Primers / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism*; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013132:Spinocerebellar Degenerations / Q000235:genetics*
chemical_list: D017931:DNA Primers; C497021:KCND3 protein, human; D051672:Shal Potassium Channels; D003513:Cycloheximide