Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/116564
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Type: Journal article
Title: De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias
Author: Helbig, K.
Lauerer, R.
Bahr, J.
Souza, I.
Myers, C.
Uysal, B.
Schwarz, N.
Gandini, M.
Huang, S.
Keren, B.
Mignot, C.
Afenjar, A.
Billette de Villemeur, T.
Héron, D.
Nava, C.
Valence, S.
Buratti, J.
Fagerberg, C.
Soerensen, K.
Kibaek, M.
et al.
Citation: American journal of human genetics, 2018; 103(5):666-678
Publisher: American Society of Human Genetics
Issue Date: 2018
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Katherine L. Helbig, Robert J. Lauerer, Jacqueline C. Bahr, Ivana A. Souza ... Mark Corbett, Jozef Gecz ... et al.
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: Deciphering Developmental Disorders Study
Rights: © 2018 American Society of Human Genetics
RMID: 0030100576
DOI: 10.1016/j.ajhg.2018.09.006
Appears in Collections:Medical Sciences publications

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