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

Katherine Helbig; Robert Lauerer; Jacqueline Bahr; Ivana Souza; Candace Myers; Betül Uysal; Niklas Schwarz; Maria Gandini; Sun Huang; Boris Keren; Cyril Mignot; Alexandra Afenjar; Thierry Billette de Villemeur; Delphine Héron; Caroline Nava; Stéphanie Valence; Julien Buratti; Christina Fagerberg; Kristina Soerensen; Maria Kibaek; Erik-Jan Kamsteeg; David Koolen; Boudewijn Gunning; H Jurgen Schelhaas; Michael Kruer; Jordana Fox; Somayeh Bakhtiari; Randa Jarrar; Sergio Padilla-Lopez; 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

doi:10.1016/j.ajhg.2018.09.006

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

(1) , (2) , (2) , (3) , (4) , (2) , (2) , (3) , (3) , (5) , (5, 6) , (7) , (7, 8, 9) , (10, 6) , (6, 10) , (10) , (10) , (11) , (11) , (11) , (12) , (12) , (13) , (14) , (15) , (15) , (15) , (15) , (15) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

Katherine Helbig

Function : Author

Children’s Hospital of Philadelphia

Robert Lauerer

Function : Author

Hertie Institute for Clinical Brain Research [Tubingen]

Jacqueline Bahr

Function : Author

Hertie Institute for Clinical Brain Research [Tubingen]

Ivana Souza

Function : Author

University of Calgary

Candace Myers

Function : Author

University of Washington [Seattle]

Betül Uysal

Function : Author

Hertie Institute for Clinical Brain Research [Tubingen]

Niklas Schwarz

Function : Author

Hertie Institute for Clinical Brain Research [Tubingen]

Maria Gandini

Function : Author

University of Calgary

Sun Huang

Function : Author

University of Calgary

Boris Keren

Function : Author

Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)

Cyril Mignot

Function : Author

Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)

Institut du Cerveau = Paris Brain Institute

Alexandra Afenjar

Function : Author

Pathologies Congénitales du Cervelet-LeucoDystrophies

Thierry Billette de Villemeur

Function : Author

Pathologies Congénitales du Cervelet-LeucoDystrophies

CHU Trousseau [APHP]

Maladies neurodéveloppementales et neurovasculaires

Delphine Héron

Function : Author

Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)

Institut du Cerveau = Paris Brain Institute

Caroline Nava

Function : Author

Institut du Cerveau = Paris Brain Institute

Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)

Stéphanie Valence

Function : Author

Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)

Julien Buratti

Function : Author

Groupe de Recherche Clinique : Génétique des Déficiences Intellectuelles de Causes Rares (associées ou non aux Troubles du Spectre Autistique)

Christina Fagerberg

Function : Author

Odense University Hospital

Kristina Soerensen

Function : Author

Odense University Hospital

Maria Kibaek

Function : Author

Odense University Hospital

Erik-Jan Kamsteeg

Function : Author

Radboud University Medical Center [Nijmegen]

David Koolen

Function : Author

Radboud University Medical Center [Nijmegen]

Boudewijn Gunning

Function : Author

Stichting Epilepsie Instellingen Nederland

H Jurgen Schelhaas

Function : Author

Academic Center for Epileptology Kempenhaeghe & Maastricht UMC+ [Heeze]

Michael Kruer

Function : Author

University of Arizona

Jordana Fox

Function : Author

University of Arizona

Somayeh Bakhtiari

Function : Author

University of Arizona

Randa Jarrar

Function : Author

University of Arizona

Sergio Padilla-Lopez

Function : Author

University of Arizona

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

Function : Author

Teresa Kruisselbrink

Function : Author

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

Function : Author

Nicholas Katsanis

Function : Author

Nicholas Katsanis

Function : Author

Mark Corbett

Function : Author

Alastair Maclennan

Function : Author

Jozef Gecz

Function : Author

Saskia Biskup

Function : Author

Eva Goldmann

Function : Author

Lance Rodan

Function : Author

Elizabeth Kichula

Function : Author

Eric Segal

Function : Author

Kelly Jackson

Function : Author

Alexander Asamoah

Function : Author

David Dimmock

Function : Author

Julie Mccarrier

Function : Author

Lorenzo Botto

Function : Author

Francis Filloux

Function : Author

Tatiana Tvrdik

Function : Author

Gregory Cascino

Function : Author

Sherry Klingerman

Function : Author

Catherine Neumann

Function : Author

Raymond Wang

Function : Author

Jessie Jacobsen

Function : Author

Melinda Nolan

Function : Author

Russell Snell

Function : Author

Klaus Lehnert

Function : Author

Lynette Sadleir

Function : Author

Britt-Marie Anderlid

Function : Author

Malin Kvarnung

Function : Author

Renzo Guerrini

Function : Author

Michael Friez

Function : Author

Michael Lyons

Function : Author

Jennifer Leonhard

Function : Author

Gabriel Kringlen

Function : Author

Kari Casas

Function : Author

Christelle El Achkar

Function : Author

Lacey Smith

Function : Author

Alexander Rotenberg

Function : Author

Annapurna Poduri

Function : Author

Alba Sanchis-Juan

Function : Author

Keren Carss

Function : Author

Julia Rankin

Function : Author

Adam Zeman

Function : Author

F Lucy Raymond

Function : Author

Moira Blyth

Function : Author

Bronwyn Kerr

Function : Author

Karla Ruiz

Function : Author

Jill Urquhart

Function : Author

Imelda Hughes

Function : Author

Siddharth Banka

Function : Author

Ulrike Hedrich

Function : Author

Ingrid Scheffer

Function : Author

Ingo Helbig

Function : Author

Gerald Zamponi

Function : Author

Holger Lerche

Function : Author

Heather Mefford

Function : Author

Alexander Allori

Function : Author

Misha Angrist

Function : Author

Patricia Ashley

Function : Author

Margarita Bidegain

Function : Author

Brita Boyd

Function : Author

Eileen Chambers

Function : Author

Heidi Cope

Function : Author

C. Michael Cotten

Function : Author

Theresa Curington

Function : Author

Sarah Ellestad

Function : Author

Kimberley Fisher

Function : Author

Amanda French

Function : Author

William Gallentine

Function : Author

Ronald Goldberg

Function : Author

Kevin Hill

Function : Author

Sujay Kansagra

Function : Author

Sara Katsanis

Function : Author

Joanne Kurtzberg

Function : Author

Jeffrey Marcus

Function : Author

Marie Mcdonald

Function : Author

Mohammed Mikati

Function : Author

Stephen Miller

Function : Author

Amy Murtha

Function : Author

Yezmin Perilla

Function : Author

Carolyn Pizoli

Function : Author

Todd Purves

Function : Author

Sherry Ross

Function : Author

Edward Smith

Function : Author

John Wiener

Function : Author

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.

Keywords

CACNA1E ion channel arthrogryposis calcium channel epilepsy

Domains

Life Sciences [q-bio]

Gestionnaire HAL 4 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04557795

Submitted on : Wednesday, April 24, 2024-2:38:54 PM

Last modification on : Wednesday, June 19, 2024-1:54:15 PM

Dates and versions

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

Identifiers

HAL Id : hal-04557795 , version 1
DOI : 10.1016/j.ajhg.2018.09.006
PUBMED : 30343943
PUBMEDCENTRAL : PMC6216110

Cite

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⟩

Export

BibTeX XML-TEI Dublin Core DC Terms EndNote DataCite

Collections

INSERM CNRS ICM SORBONNE-UNIVERSITE SU-MEDECINE UP-SANTE

7 View

0 Download

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

Abstract

Keywords

Domains

Dates and versions

Identifiers

Cite

Export

Collections

Altmetric

Share