An E280K Missense Variant in KCND3/Kv4.3—Case Report and Functional Characterization
Abstract
:1. Introduction
2. Results
2.1. Clinical Findings
2.2. Genetic Analyses
2.3. Electrophysiology Investigations of KCND3 E280K
3. Discussion
4. Materials and Methods
4.1. Ethical Statement
4.2. Clinical Evaluation and Genetic Analysis
4.3. Molecular Biology
4.4. Oocyte Preparation
4.5. Parallel Oocyte Voltage-Clamp Recordings
4.6. Data Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Serôdio, P.; Rudy, B. Differential expression of Kv4 K+ channel subunits mediating subthreshold transient K+ (A-type) currents in rat brain. J. Neurophysiol. 1998, 79, 1081–1091. [Google Scholar] [CrossRef] [Green Version]
- Dixon, J.E.; Shi, W.; Wang, H.S.; McDonald, C.; Yu, H.; Wymore, R.S.; Cohen, I.S.; McKinnon, D. Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circ. Res. 1996, 79, 659–668. [Google Scholar] [CrossRef] [PubMed]
- Lee, Y.-C.; Durr, A.; Majczenko, K.; Huang, Y.-H.; Liu, Y.-C.; Lien, C.-C.; Tsai, P.-C.; Ichikawa, Y.; Goto, J.; Monin, M.-L.; et al. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann. Neurol. 2012, 72, 859–869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Duarri, A.; Jezierska, J.; Fokkens, M.; Meijer, M.; Schelhaas, H.J.; den Dunnen, W.F.; van Dijk, F.; Verschuuren-Bemelmans, C.; Hageman, G.; van de Vlies, P.; et al. Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann. Neurol. 2012, 72, 870–880. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Smets, K.; Duarri, A.; Deconinck, T.; Ceulemans, B.; van de Warrenburg, B.P.; Züchner, S.; Gonzalez, M.A.; Schüle, R.; Synofzik, M.; Van der Aa, N.; et al. First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy. BMC Med. Genet. 2015, 16, 51. [Google Scholar] [CrossRef] [Green Version]
- Coutelier, M.; Coarelli, G.; Monin, M.L.; Konop, J.; Davoine, C.S.; Tesson, C.; Valter, R.; Anheim, M.; Behin, A.; Castelnovo, G.; et al. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies. Brain 2017, 140, 1579–1594. [Google Scholar] [CrossRef]
- Huin, V.; Strubi-Vuillaume, I.; Dujardin, K.; Brion, M.; Delliaux, M.; Dellacherie, D.; Cuvellier, J.C.; Cuisset, J.M.; Riquet, A.; Moreau, C.; et al. Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy. Park. Relat. Disord. 2017, 45, 85–89. [Google Scholar] [CrossRef]
- Kurihara, M.; Ishiura, H.; Sasaki, T.; Otsuka, J.; Hayashi, T.; Terao, Y.; Matsukawa, T.; Mitsui, J.; Kaneko, J.; Nishiyama, K.; et al. Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia. Cerebellum 2018, 17, 237–242. [Google Scholar] [CrossRef]
- Paucar, M.; Bergendal, Å.; Gustavsson, P.; Nordenskjöld, M.; Laffita-Mesa, J.; Savitcheva, I.; Svenningsson, P. Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19. Cerebellum 2018, 17, 465–476. [Google Scholar] [CrossRef] [Green Version]
- Hsiao, C.T.; Fu, S.J.; Liu, Y.T.; Lu, Y.H.; Zhong, C.Y.; Tang, C.Y.; Soong, B.W.; Jeng, C.J. Novel SCA19/22-associated KCND3 mutations disrupt human K(V) 4.3 protein biosynthesis and channel gating. Hum. Mutat. 2019, 40, 2088–2107. [Google Scholar] [CrossRef]
- Paucar, M.; Ågren, R.; Li, T.; Lissmats, S.; Bergendal, Å.; Weinberg, J.; Nilsson, D.; Savichetva, I.; Sahlholm, K.; Nilsson, J.; et al. V374A KCND3 Pathogenic Variant Associated with Paroxysmal Ataxia Exacerbations. Neurol. Genet. 2021, 7, e546. [Google Scholar] [CrossRef]
- Zanni, G.; Hsiao, C.T.; Fu, S.J.; Tang, C.Y.; Capuano, A.; Bosco, L.; Graziola, F.; Bellacchio, E.; Servidei, S.; Primiano, G.; et al. Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K(V)4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties. Int. J. Mol. Sci. 2021, 22, 4986. [Google Scholar] [CrossRef] [PubMed]
- Hsiao, C.T.; Tropea, T.F.; Fu, S.J.; Bardakjian, T.M.; Gonzalez-Alegre, P.; Soong, B.W.; Tang, C.Y.; Jeng, C.J. Rare Gain-of-Function KCND3 Variant Associated with Cerebellar Ataxia, Parkinsonism, Cognitive Dysfunction, and Brain Iron Accumulation. Int. J. Mol. Sci. 2021, 22, 8247. [Google Scholar] [CrossRef] [PubMed]
- Li, M.; Liu, F.; Hao, X.; Fan, Y.; Li, J.; Hu, Z.; Shi, J.; Fan, L.; Zhang, S.; Ma, D.; et al. Rare KCND3 Loss-of-Function Mutation Associated With the SCA19/22. Front. Mol. Neurosci. 2022, 15, 919199. [Google Scholar] [CrossRef] [PubMed]
- Olesen, M.S.; Refsgaard, L.; Holst, A.G.; Larsen, A.P.; Grubb, S.; Haunsø, S.; Svendsen, J.H.; Olesen, S.P.; Schmitt, N.; Calloe, K. A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation. Cardiovasc. Res. 2013, 98, 488–495. [Google Scholar] [CrossRef]
- Giudicessi, J.R.; Ye, D.; Kritzberger, C.J.; Nesterenko, V.V.; Tester, D.J.; Antzelevitch, C.; Ackerman, M.J. Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death. Hum. Mutat. 2012, 33, 989–997. [Google Scholar] [CrossRef] [Green Version]
- Takayama, K.; Ohno, S.; Ding, W.G.; Ashihara, T.; Fukumoto, D.; Wada, Y.; Makiyama, T.; Kise, H.; Hoshiai, M.; Matsuura, H.; et al. A de novo gain-of-function KCND3 mutation in early repolarization syndrome. Heart Rhythm. 2019, 16, 1698–1706. [Google Scholar] [CrossRef]
- Duarri, A.; Lin, M.-C.A.; Fokkens, M.R.; Meijer, M.; Smeets, C.J.L.M.; Nibbeling, E.A.R.; Boddeke, E.; Sinke, R.J.; Kampinga, H.H.; Papazian, D.M.; et al. Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner. Cell. Mol. Life Sci. 2015, 72, 3387–3399. [Google Scholar] [CrossRef] [Green Version]
- Börjesson, S.I.; Elinder, F. Structure, function, and modification of the voltage sensor in voltage-gated ion channels. Cell. Biochem. Biophys. 2008, 52, 149–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Elinder, F.; Madeja, M.; Zeberg, H.; Arhem, P. Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1. Biophys. J. 2016, 111, 1679–1691. [Google Scholar] [CrossRef] [Green Version]
- Carvalho-de-Souza, J.L.; Bezanilla, F. Nonsensing residues in S3-S4 linker’s C terminus affect the voltage sensor set point in K(+) channels. J. Gen. Physiol. 2018, 150, 307–321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tang, C.Y.; Bezanilla, F.; Papazian, D.M. Extracellular Mg(2+) modulates slow gating transitions and the opening of Drosophila ether-à-Go-Go potassium channels. J. Gen. Physiol. 2000, 115, 319–338. [Google Scholar] [CrossRef] [PubMed]
- Johnson, J.P., Jr.; Balser, J.R.; Bennett, P.B. A novel extracellular calcium sensing mechanism in voltage-gated potassium ion channels. J. Neurosci. 2001, 21, 4143–4153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bahring, R.; Barghaan, J.; Westermeier, R.; Wollberg, J. Voltage sensor inactivation in potassium channels. Front. Pharmacol. 2012, 3, 100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Skerritt, M.R.; Campbell, D.L. Contribution of electrostatic and structural properties of Kv4.3 S4 arginine residues to the regulation of channel gating. Biochim. Biophys. Acta 2009, 1788, 458–469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015, 17, 405–424. [Google Scholar] [CrossRef] [Green Version]
- Wechsler, D. Wechsler Preschool and Primary Scale of Intelligence, 4th ed.; The Psychological Corporation: San Antonio, TX, USA, 2012. [Google Scholar]
- Jespersen, T.; Grunnet, M.; Angelo, K.; Klaerke, D.A.; Olesen, S.P. Dual-function vector for protein expression in both mammalian cells and Xenopus laevis oocytes. Biotechniques 2002, 32, 536–538. [Google Scholar] [CrossRef] [Green Version]
- Sahlholm, K.; Barchad-Avitzur, O.; Marcellino, D.; Gómez-Soler, M.; Fuxe, K.; Ciruela, F.; Arhem, P. Agonist-specific voltage sensitivity at the dopamine D2S receptor--molecular determinants and relevance to therapeutic ligands. Neuropharmacology 2011, 61, 937–949. [Google Scholar] [CrossRef] [Green Version]
- Ågren, R.; Sahlholm, K. Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors. Front. Pharmacol. 2020, 11, 1615. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ågren, R.; Geerdink, N.; Brunner, H.G.; Paucar, M.; Kamsteeg, E.-J.; Sahlholm, K. An E280K Missense Variant in KCND3/Kv4.3—Case Report and Functional Characterization. Int. J. Mol. Sci. 2023, 24, 10924. https://doi.org/10.3390/ijms241310924
Ågren R, Geerdink N, Brunner HG, Paucar M, Kamsteeg E-J, Sahlholm K. An E280K Missense Variant in KCND3/Kv4.3—Case Report and Functional Characterization. International Journal of Molecular Sciences. 2023; 24(13):10924. https://doi.org/10.3390/ijms241310924
Chicago/Turabian StyleÅgren, Richard, Niels Geerdink, Han G. Brunner, Martin Paucar, Erik-Jan Kamsteeg, and Kristoffer Sahlholm. 2023. "An E280K Missense Variant in KCND3/Kv4.3—Case Report and Functional Characterization" International Journal of Molecular Sciences 24, no. 13: 10924. https://doi.org/10.3390/ijms241310924