De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in patients with epilepsy

Epilepsia. 2023 Feb;64(2):443-455. doi: 10.1111/epi.17455.

Vincenzo Salpietro ¹ ², Valentina Galassi Deforie ¹, Stephanie Efthymiou ¹, Emer O'Connor ¹, Anna Marcé-Grau ³, Reza Maroofian ¹, Pasquale Striano ⁴ ⁵, Federico Zara ⁴ ⁶, Michelle M Morrow ⁷, SYNAPS Study Group, Adi Reich ⁷, Amy Blevins ⁷, Júlia Sala-Coromina ³, Andrea Accogli ⁴ ⁶, Sara Fortuna ⁸, Marie Alesandrini ⁹, P Y Billie Au ¹⁰, Nilika Shah Singhal ¹¹, Benjamin Cogne ¹² ¹³, Bertrand Isidor ¹² ¹³, Michael G Hanna ¹ ¹⁴, Alfons Macaya ³, Dimitri M Kullmann ¹⁵, Henry Houlden ¹, Roope Männikkö ¹

Affiliations

1 Department of Neuromuscular Disease, UCL Institute of Neurology, University College London, London, UK.
2 Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, L'Aquila, Italy.
3 Department of Paediatric Neurology, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
4 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, 16124 Genoa, Italy.
5 Unit of Pediatric Neurology, IRCCS, Istituto "Giannina Gaslini", Genoa 16123, Italy.
6 Medical Genetics Unit, IRCCS, Istituto "Giannina Gaslini", Genoa 16123, Italy.
7 GeneDx, Maryland, Gaithersburg, USA.
8 Istituto Italiano di Tecnologia (IIT), Genoa, Italy.
9 Neuropediatrics Unit, Centre Hospitalier Universitaire Nantes, Nantes, France.
10 Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada.
11 Departments of Neurology and Pediatrics, UCSF Benioff Children's Hospital, University of California, California, San Francisco, USA.
12 Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, Nantes, France.
13 Université de Nantes, CNRS, INSERM, L'Institut du Thorax, Nantes, France.
14 Queen Square Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK.
15 Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, University College London, London, UK.

PMID: 36318112 DOI: 10.1111/epi.17455

Abstract

Objective: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Methods: Following clinical diagnosis, we performed whole exome Sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage clamp.

Results: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore-lining S6 α-helix of K_V 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type K_V 1.6 or K_V 1.1 subunits.

Significance: This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Keywords

KV1 Shaker channel family; neurodevelopmental disorder; voltage-gated potassium channels; whole exome sequencing.

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