KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum
Abstract A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants i...
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Online Access: | https://doi.org/10.1002/acn3.50799 |
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doaj-6c5fac79b9f542b2975de3d0a57bfdce2021-05-02T05:04:07ZengWileyAnnals of Clinical and Translational Neurology2328-95032019-07-01671319132610.1002/acn3.50799KCNC1‐related disorders: new de novo variants expand the phenotypic spectrumJoohyun Park0Mahmoud Koko1Ulrike B. S. Hedrich2Andreas Hermann3Kirsten Cremer4Edda Haberlandt5Mona Grimmel6Bader Alhaddad7Stefanie Beck‐Woedl8Merle Harrer9Daniela Karall10Lisa Kingelhoefer11Andreas Tzschach12Lars C. Matthies13Tim M. Strom14Erich Bernd Ringelstein15Marc Sturm16Hartmut Engels17Markus Wolff18Holger Lerche19Tobias B. Haack20Institute of Medical Genetics and Applied Genomics University of Tübingen Tübingen GermanyDepartment of Neurology and Epileptology Hertie Institute for Clinical Brain Research, University of Tübingen Tübingen GermanyDepartment of Neurology and Epileptology Hertie Institute for Clinical Brain Research, University of Tübingen Tübingen GermanyTranslational Neurodegeneration Section “Albrecht‐Kossel”, Department of Neurology and Center for Transdisciplinary Neurosciences Rostock (CTNR) University Medical Center Rostock, University of Rostock 18147 Rostock GermanyInstitute of Human Genetics University of Bonn, School of Medicine and University Hospital Bonn Bonn GermanyClinic for Pediatrics Krankenhaus Stadt Dornbirn Dornbirn AustriaInstitute of Medical Genetics and Applied Genomics University of Tübingen Tübingen GermanyInstitute of Human Genetics Technische Universität München Munich GermanyInstitute of Medical Genetics and Applied Genomics University of Tübingen Tübingen GermanyDepartment of Neurology and Epileptology Hertie Institute for Clinical Brain Research, University of Tübingen Tübingen GermanyClinic for Pediatrics, Division of Inherited Metabolic Disorders Medical University of Innsbruck Innsbruck AustriaDepartment of Neurology Technische Universität Dresden and German Center for Neurodegenerative Diseases, Research Side Dresden Dresden GermanyInstitute of Clinical Genetics Technische Universität Dresden Dresden GermanyInstitute of Human Genetics University of Bonn, School of Medicine and University Hospital Bonn Bonn GermanyInstitute of Human Genetics Technische Universität München Munich GermanyDepartment of Neurology University Hospital of Muenster Muenster GermanyInstitute of Medical Genetics and Applied Genomics University of Tübingen Tübingen GermanyInstitute of Human Genetics University of Bonn, School of Medicine and University Hospital Bonn Bonn GermanyDepartment of Neuropediatrics University of Tübingen Tübingen GermanyDepartment of Neurology and Epileptology Hertie Institute for Clinical Brain Research, University of Tübingen Tübingen GermanyInstitute of Medical Genetics and Applied Genomics University of Tübingen Tübingen GermanyAbstract A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.https://doi.org/10.1002/acn3.50799 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joohyun Park Mahmoud Koko Ulrike B. S. Hedrich Andreas Hermann Kirsten Cremer Edda Haberlandt Mona Grimmel Bader Alhaddad Stefanie Beck‐Woedl Merle Harrer Daniela Karall Lisa Kingelhoefer Andreas Tzschach Lars C. Matthies Tim M. Strom Erich Bernd Ringelstein Marc Sturm Hartmut Engels Markus Wolff Holger Lerche Tobias B. Haack |
spellingShingle |
Joohyun Park Mahmoud Koko Ulrike B. S. Hedrich Andreas Hermann Kirsten Cremer Edda Haberlandt Mona Grimmel Bader Alhaddad Stefanie Beck‐Woedl Merle Harrer Daniela Karall Lisa Kingelhoefer Andreas Tzschach Lars C. Matthies Tim M. Strom Erich Bernd Ringelstein Marc Sturm Hartmut Engels Markus Wolff Holger Lerche Tobias B. Haack KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum Annals of Clinical and Translational Neurology |
author_facet |
Joohyun Park Mahmoud Koko Ulrike B. S. Hedrich Andreas Hermann Kirsten Cremer Edda Haberlandt Mona Grimmel Bader Alhaddad Stefanie Beck‐Woedl Merle Harrer Daniela Karall Lisa Kingelhoefer Andreas Tzschach Lars C. Matthies Tim M. Strom Erich Bernd Ringelstein Marc Sturm Hartmut Engels Markus Wolff Holger Lerche Tobias B. Haack |
author_sort |
Joohyun Park |
title |
KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum |
title_short |
KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum |
title_full |
KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum |
title_fullStr |
KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum |
title_full_unstemmed |
KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum |
title_sort |
kcnc1‐related disorders: new de novo variants expand the phenotypic spectrum |
publisher |
Wiley |
series |
Annals of Clinical and Translational Neurology |
issn |
2328-9503 |
publishDate |
2019-07-01 |
description |
Abstract A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism. |
url |
https://doi.org/10.1002/acn3.50799 |
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