Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties
<i>KCND3</i> encodes the voltage-gated potassium channel K<sub>V</sub>4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K<sub>V</sub>4.3 mutations have been associated with dominant spino...
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/9/4986 |
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| author | Ginevra Zanni Cheng-Tsung Hsiao Ssu-Ju Fu Chih-Yung Tang Alessandro Capuano Luca Bosco Federica Graziola Emanuele Bellacchio Serenella Servidei Guido Primiano Bing-Wen Soong Chung-Jiuan Jeng |
| author_facet | Ginevra Zanni Cheng-Tsung Hsiao Ssu-Ju Fu Chih-Yung Tang Alessandro Capuano Luca Bosco Federica Graziola Emanuele Bellacchio Serenella Servidei Guido Primiano Bing-Wen Soong Chung-Jiuan Jeng |
| author_sort | Ginevra Zanni |
| collection | DOAJ |
| description | <i>KCND3</i> encodes the voltage-gated potassium channel K<sub>V</sub>4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K<sub>V</sub>4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel <i>KCND3</i> missense variants of the K<sub>V</sub>4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K<sub>V</sub>4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K<sub>V</sub>4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for <i>KCND3</i>-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia. |
| first_indexed | 2024-03-10T11:37:14Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:37:14Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-15759d31a21342909ceea688dad5cfb82023-11-21T18:43:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01229498610.3390/ijms22094986Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel PropertiesGinevra Zanni0Cheng-Tsung Hsiao1Ssu-Ju Fu2Chih-Yung Tang3Alessandro Capuano4Luca Bosco5Federica Graziola6Emanuele Bellacchio7Serenella Servidei8Guido Primiano9Bing-Wen Soong10Chung-Jiuan Jeng11Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, B. Gesù Children’s Hospital, IRCCS, 00146 Rome, ItalyDepartment of Physiology, College of Medicine, National Taiwan University, Taipei 100, TaiwanDepartment of Physiology, College of Medicine, National Taiwan University, Taipei 100, TaiwanDepartment of Physiology, College of Medicine, National Taiwan University, Taipei 100, TaiwanUnit of Neurology, B. Gesù Children’s Hospital, IRCCS, 00146 Rome, ItalyDepartment of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, B. Gesù Children’s Hospital, IRCCS, 00146 Rome, ItalyUnit of Neurology, B. Gesù Children’s Hospital, IRCCS, 00146 Rome, ItalyGenetics and Rare Diseases Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, ItalyDepartment of Neurosciences, Università Cattolica del S. Cuore, 00168 Rome, ItalyDepartment of Neurosciences, Università Cattolica del S. Cuore, 00168 Rome, ItalyDepartment of Neurology, School of Medicine, National Yang Ming Chiao Tung University College of Medicine, Taipei 112, TaiwanInstitute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan<i>KCND3</i> encodes the voltage-gated potassium channel K<sub>V</sub>4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K<sub>V</sub>4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel <i>KCND3</i> missense variants of the K<sub>V</sub>4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K<sub>V</sub>4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K<sub>V</sub>4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for <i>KCND3</i>-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.https://www.mdpi.com/1422-0067/22/9/4986<i>KCND3</i>Spinocerebellar Ataxia SCA19/22Congenital AtaxiaK<sub>V</sub>4.3 |
| spellingShingle | Ginevra Zanni Cheng-Tsung Hsiao Ssu-Ju Fu Chih-Yung Tang Alessandro Capuano Luca Bosco Federica Graziola Emanuele Bellacchio Serenella Servidei Guido Primiano Bing-Wen Soong Chung-Jiuan Jeng Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties International Journal of Molecular Sciences <i>KCND3</i> Spinocerebellar Ataxia SCA19/22 Congenital Ataxia K<sub>V</sub>4.3 |
| title | Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties |
| title_full | Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties |
| title_fullStr | Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties |
| title_full_unstemmed | Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties |
| title_short | Novel <em>KCND3</em> Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K<sub>V</sub>4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties |
| title_sort | novel em kcnd3 em variant underlying nonprogressive congenital ataxia or sca19 22 disrupt k sub v sub 4 3 protein expression and k currents with variable effects on channel properties |
| topic | <i>KCND3</i> Spinocerebellar Ataxia SCA19/22 Congenital Ataxia K<sub>V</sub>4.3 |
| url | https://www.mdpi.com/1422-0067/22/9/4986 |
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