A novel KCNC3 gene variant in the voltage-dependent Kv3.3 channel in an atypical form of SCA13 with dominant central vertigo
Potassium channel mutations play an important role in neurological diseases, such as spinocerebellar ataxia (SCA). SCA is a heterogeneous autosomal-dominant neurodegenerative disorder with multiple sub-entities, such as SCA13, which is characterized by mutations in the voltage-gated potassium cha...
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Main Authors: | , , , , , |
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Format: | Article |
Language: | English |
Published: |
Philipps-Universität Marburg
2024
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Online Access: | PDF Full Text |
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Summary: | Potassium channel mutations play an important role in neurological diseases, such
as spinocerebellar ataxia (SCA). SCA is a heterogeneous autosomal-dominant
neurodegenerative disorder with multiple sub-entities, such as SCA13, which is
characterized by mutations in the voltage-gated potassium channel Kv3.3 (KCNC3). In
this study, we present a rare and atypical case of SCA13 with a predominant episodic
central rotational vertigo, while the patient suffered only from mild progressive
cerebellar symptoms, such as dysarthria, ataxia of gait and stand, and recently a
cognitive impairment. In this patient, we identified a heterozygous variant in KCNC3
(c.2023G> A, p.Glu675Lys) by next-generation sequencing. This Kv3.3E675K variant
was studied using voltage-clamp recordings in Xenopus oocytes. While typical
SCA13 variants are dominant-negative, show shifts in the voltage-dependence of
activation or an altered TBK1 regulation, the Kv3.3E675K variant caused only a reduction
in current amplitude and a more pronounced cumulative inactivation. Thus, the
differences to phenotypes observed in patients with classical SCA13 mutations may
be related to the mechanism of the observed Kv3.3 loss-of-function. Treatment of
our patient with riluzole, a drug that is known to also activate potassium channels,
turned out to be partly beneficial. Strikingly, we found that the Kv3.3 and Kv3.3E675K
inactivation and the frequency-dependent cumulative inactivation was antagonized
by increased extracellular potassium levels. Thus, and most importantly, carefully
elevated plasma potassium levels in the physiological range, or novel drugs attenuating
Kv3.3 inactivation might provide novel therapeutic approaches to rescue potassium
currents of SCA13 variants per se. In addition, our findings broaden the phenotypic
spectrum of Kv3.3 variants, expanding it to atypical phenotypes of Kv3.3-associated
neurological disorders. |
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Item Description: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
DOI: | 10.3389/fncel.2024.1441257 |