Author(s):
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Smets, K.; Duarri, A.; Deconinck, T.; Ceulemans, B.;
Warrenburg, B.P.C. van de
; Zuchner, S.; Gonzalez, M.A.; Schule, R.; Synofzik, M.; Aa, N. van der; Jonghe, P. De; Verbeek, D.S.; Baets, J.
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Subject:
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Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience |
Abstract:
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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.
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