De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias - Sorbonne Université Access content directly
Journal Articles American Journal of Human Genetics Year : 2018

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Katherine Helbig (1) , Robert Lauerer (2) , Jacqueline Bahr (2) , Ivana Souza (3) , Candace Myers (4) , Betül Uysal (2) , Niklas Schwarz (2) , Maria Gandini (3) , Sun Huang (3) , Boris Keren (5) , Cyril Mignot (5, 6) , Alexandra Afenjar (7) , Thierry Billette de Villemeur (7, 8, 9) , Delphine Héron (10, 6) , Caroline Nava (6, 10) , Stéphanie Valence (10) , Julien Buratti (10) , Christina Fagerberg (11) , Kristina Soerensen (11) , Maria Kibaek (11) , Erik-Jan Kamsteeg (12) , David Koolen (12) , Boudewijn Gunning (13) , H Jurgen Schelhaas (14) , Michael Kruer (15) , Jordana Fox (15) , Somayeh Bakhtiari (15) , Randa Jarrar (15) , Sergio Padilla-Lopez (15) , Kristin Lindstrom , Sheng Chih Jin , Xue Zeng , Kaya Bilguvar , Antigone Papavasileiou , Qinghe Xing , Changlian Zhu , Katja Boysen , Filippo Vairo , Brendan Lanpher , Eric Klee , Jan-Mendelt Tillema , Eric Payne , Margot Cousin , Teresa Kruisselbrink , Myra Wick , Joshua Baker , Eric Haan , Nicholas Smith , Azita Sadeghpour , Azita Sadeghpour , Erica Davis , Erica Davis , Nicholas Katsanis , Nicholas Katsanis , Mark Corbett , Alastair Maclennan , Jozef Gecz , Saskia Biskup , Eva Goldmann , Lance Rodan , Elizabeth Kichula , Eric Segal , Kelly Jackson , Alexander Asamoah , David Dimmock , Julie Mccarrier , Lorenzo Botto , Francis Filloux , Tatiana Tvrdik , Gregory Cascino , Sherry Klingerman , Catherine Neumann , Raymond Wang , Jessie Jacobsen , Melinda Nolan , Russell Snell , Klaus Lehnert , Lynette Sadleir , Britt-Marie Anderlid , Malin Kvarnung , Renzo Guerrini , Michael Friez , Michael Lyons , Jennifer Leonhard , Gabriel Kringlen , Kari Casas , Christelle El Achkar , Lacey Smith , Alexander Rotenberg , Annapurna Poduri , Alba Sanchis-Juan , Keren Carss , Julia Rankin , Adam Zeman , F Lucy Raymond , Moira Blyth , Bronwyn Kerr , Karla Ruiz , Jill Urquhart , Imelda Hughes , Siddharth Banka , Ulrike Hedrich , Ingrid Scheffer , Ingo Helbig , Gerald Zamponi , Holger Lerche , Heather Mefford , Alexander Allori , Misha Angrist , Patricia Ashley , Margarita Bidegain , Brita Boyd , Eileen Chambers , Heidi Cope , C. Michael Cotten , Theresa Curington , Sarah Ellestad , Kimberley Fisher , Amanda French , William Gallentine , Ronald Goldberg , Kevin Hill , Sujay Kansagra , Sara Katsanis , Joanne Kurtzberg , Jeffrey Marcus , Marie Mcdonald , Mohammed Mikati , Stephen Miller , Amy Murtha , Yezmin Perilla , Carolyn Pizoli , Todd Purves , Sherry Ross , Edward Smith , John Wiener
Sun Huang
  • Function : Author
Kristin Lindstrom
  • Function : Author
Sheng Chih Jin
  • Function : Author
Xue Zeng
  • Function : Author
Kaya Bilguvar
  • Function : Author
Antigone Papavasileiou
  • Function : Author
Qinghe Xing
  • Function : Author
Changlian Zhu
  • Function : Author
Katja Boysen
  • Function : Author
Filippo Vairo
  • Function : Author
Brendan Lanpher
  • Function : Author
Eric Klee
  • Function : Author
Jan-Mendelt Tillema
  • Function : Author
Eric Payne
  • Function : Author
Margot Cousin
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Teresa Kruisselbrink
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Myra Wick
  • Function : Author
Joshua Baker
  • Function : Author
Eric Haan
  • Function : Author
Nicholas Smith
  • Function : Author
Azita Sadeghpour
  • Function : Author
Azita Sadeghpour
  • Function : Author
Erica Davis
  • Function : Author
Erica Davis
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Nicholas Katsanis
  • Function : Author
Nicholas Katsanis
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Mark Corbett
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Alastair Maclennan
  • Function : Author
Jozef Gecz
  • Function : Author
Saskia Biskup
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Eva Goldmann
  • Function : Author
Lance Rodan
  • Function : Author
Elizabeth Kichula
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Eric Segal
  • Function : Author
Kelly Jackson
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Alexander Asamoah
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David Dimmock
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Julie Mccarrier
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Lorenzo Botto
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Francis Filloux
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Tatiana Tvrdik
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Gregory Cascino
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Sherry Klingerman
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Catherine Neumann
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Raymond Wang
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Jessie Jacobsen
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Melinda Nolan
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Russell Snell
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Klaus Lehnert
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Lynette Sadleir
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Britt-Marie Anderlid
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Malin Kvarnung
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Renzo Guerrini
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Michael Friez
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Michael Lyons
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Jennifer Leonhard
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Gabriel Kringlen
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Kari Casas
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Christelle El Achkar
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Lacey Smith
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Alexander Rotenberg
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Annapurna Poduri
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Alba Sanchis-Juan
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Keren Carss
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Julia Rankin
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Adam Zeman
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F Lucy Raymond
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Moira Blyth
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Bronwyn Kerr
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Karla Ruiz
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Jill Urquhart
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Imelda Hughes
  • Function : Author
Siddharth Banka
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Ulrike Hedrich
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Ingrid Scheffer
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Ingo Helbig
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Gerald Zamponi
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Holger Lerche
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Heather Mefford
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Alexander Allori
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Misha Angrist
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Patricia Ashley
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Margarita Bidegain
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Brita Boyd
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Eileen Chambers
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Heidi Cope
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C. Michael Cotten
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Theresa Curington
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Sarah Ellestad
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Kimberley Fisher
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Amanda French
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William Gallentine
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Ronald Goldberg
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Kevin Hill
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Sujay Kansagra
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Sara Katsanis
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Joanne Kurtzberg
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Jeffrey Marcus
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Marie Mcdonald
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Mohammed Mikati
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Stephen Miller
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Amy Murtha
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Yezmin Perilla
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Carolyn Pizoli
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Todd Purves
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Sherry Ross
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Edward Smith
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John Wiener
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Abstract

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Dates and versions

hal-04557795 , version 1 (24-04-2024)

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Katherine Helbig, Robert Lauerer, Jacqueline Bahr, Ivana Souza, Candace Myers, et al.. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. American Journal of Human Genetics, 2018, 103 (5), pp.666-678. ⟨10.1016/j.ajhg.2018.09.006⟩. ⟨hal-04557795⟩
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