Mutations in the potassium channel gene KCNC3 (Kv3.3) cause the autosomal dominant neurological disease, spinocerebellar ataxia 13 (SCA13). In this study, we expand the genotype-phenotype repertoire of SCA13 by describing the novel KCNC3 deletion p.Pro583_Pro585del highlighting the allelic heterogeneity observed in SCA13 patients. We characterize adult-onset, progressive clinical symptoms of two afflicted kindred and introduce the symptom of profound spasticity not previously associated with the SCA13 phenotype. We also present molecular and electrophysiological characterizations of the mutant protein in mammalian cell culture. Mechanistically, the p.Pro583_Pro585del protein showed normal membrane trafficking with an altered electrophysiological profile, including slower inactivation and decreased sensitivity to the inactivation-accelerating effects of the actin depolymerizer latrunculin B. Taken together, our results highlight the clinical importance of the intracellular C-terminal portion of Kv3.3 and its association with ion channel function.
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We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.
Financial support was provided by NIH grants NINDS K23 NS054715 (M.F.W.), NIDCD01919 (L.K.K.), and the McKnight Brain Institute at the University of Florida.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Conflict of Interest
The authors declare that they have no conflict of interest.
Written informed consent was obtained from the patients for the publication of this study with approval from the Institutional Review Board (University of Florida and Columbia University). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Khare, S., Galeano, K., Zhang, Y. et al. C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity. Cerebellum 17, 692–697 (2018). https://doi.org/10.1007/s12311-018-0950-5
- Spinocerebellar ataxia 13
- C-terminal deletion
- Allelic heterogeneity