De novo KCNA6 variants with attenuated 1.6 channel deactivation in patients with epilepsy
Salpietro, Vincenzo (University of L'Aquila)
Galassi Deforie, Valentina (University College London)
Efthymiou, Stephanie (University College London)
O'Connor, Emer (University College London)
Marcé-Grau, Anna (Hospital Universitari Vall d'Hebron)
Maroofian, Reza (University College London)
Striano, Pasquale (Istituto "Giannina Gaslini")
Zara, Federico (Istituto "Giannina Gaslini")
Morrow, Michelle M. (GeneDx)
Reich, Adi (GeneDx)
Blevins, Amy (GeneDx)
Sala-Coromina, Júlia (Hospital Universitari Vall d'Hebron)
Accogli, Andrea (Istituto "Giannina Gaslini")
Fortuna, Sara (Istituto Italiano di Tecnologia (IIT))
Alesandrini, Marie (Centre Hospitalier Universitaire Nantes)
Au, P. Y. Billie (University of Calgary)
Singhal, Nilika Shah (University of California)
Cogne, Benjamin (L'Institut du Thorax)
Isidor, Bertrand (L'Institut du Thorax)
Hanna, Michael G. (National Hospital for Neurology and Neurosurgery)
Macaya Ruiz, Alfons (Hospital Universitari Vall d'Hebron)
Kullmann, Dimitri M. (University College London)
Houlden, Henry (University College London)
Männikkö, Roope (University College London)
Universitat Autònoma de Barcelona

Fecha:	2022
Resumen:	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. 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. 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 K1. 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 K1. 6 or K1. 1 subunits. 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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	K1 Shaker channel family ; Neurodevelopmental disorder ; Voltage-gated potassium channels ; Whole exome sequencing
Publicado en:	Epilepsia, Vol. 64 (december 2022) , p. 443-455, ISSN 1528-1167

DOI: 10.1111/epi.17455
PMID: 36318112

13 p, 9.1 MB

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