%0 Journal Article
%T De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
%A Adam Zeman
%A Alastair H. MacLennan
%A Alba Sanchis-Juan
%A Alexander Asamoah
%A Alexander Rotenberg
%A Alexandra Afenjar
%A Annapurna Poduri
%A Antigone Papavasileiou
%A Bet¨¹l Uysal
%A Boris Keren
%A Boudewijn Gunning
%A Brendan C. Lanpher
%A Britt-Marie Anderlid
%A Bronwyn Kerr
%A Candace T. Myers
%A Caroline Nava
%A Catherine Neumann
%A Changlian Zhu
%A Christelle M. El Achkar
%A Christina R. Fagerberg
%A Cyril Mignot
%A David A. Koolen
%A David Dimmock
%A Deciphering Developmental Disorders Study
%A Delphine H¨¦ron
%A Elizabeth Kichula
%A Eric Haan
%A Eric Segal
%A Eric T. Payne
%A Eric W. Klee
%A Erik-Jan Kamsteeg
%A Eva Goldmann
%A F. Lucy Raymond
%A Filippo Vairo
%A Francis Filloux
%A Gabriel Kringlen
%A Gerald W. Zamponi
%A Gregory D. Cascino
%A H. Jurgen Schelhaas
%A Holger Lerche
%A Imelda Hughes
%A Ingo Helbig
%A Ingrid E. Scheffer
%A Ivana A. Souza
%A Jacqueline C. Bahr
%A Jan-Mendelt Tillema
%A Jennifer Leonhard
%A Jessie C. Jacobsen
%A Jill Urquhart
%A Jordana Fox
%A Joshua Baker
%A Jozef Gecz
%A Julia Rankin
%A Julie McCarrier
%A Julien Buratti
%A Kari Casas
%A Karla Ruiz
%A Katherine L. Helbig
%A Katja Boysen
%A Kaya Bilguvar
%A Kelly E. Jackson
%A Keren J. Carss
%A Klaus Lehnert
%A Kristin Lindstrom
%A Kristina P. Soerensen
%A Lacey A. Smith
%A Lance H. Rodan
%A Lorenzo D. Botto
%A Lynette G. Sadleir
%A Malin Kvarnung
%A Margot A. Cousin
%A Maria A. Gandini
%A Maria Kibaek
%A Mark A. Corbett
%A Melinda A. Nolan
%A Michael C. Kruer
%A Michael J. Friez
%A Michael J. Lyons
%A Moira Blyth
%A Myra J. Wick
%A Nicholas Smith
%A Niklas Schwarz
%A Qinghe Xin
%A Randa Jarrar
%A Raymond Wang
%A Renzo Guerrini
%A Robert J. Lauerer
%A Russell G. Snell
%A Saskia Biskup
%A Sergio Padilla-Lopez
%A Sheng Chih Jin
%A Sherry Klingerman
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2018.09.006
%X 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 ¦Á1-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
%K epilepsy
%K CACNA1E
%K ion channel
%K arthrogryposis
%K calcium channel
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216110/