American journal of human genetics · 2018

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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Helbig Katherine L, Lauerer Robert J, Bahr Jacqueline C, Souza Ivana A, Myers Candace T, Uysal Betül, Schwarz Niklas, Gandini Maria A, Huang Sun, Keren Boris, Mignot Cyril, Afenjar Alexandra, Billette de Villemeur Thierry, Héron Delphine, Nava Caroline, Valence Stéphanie, Buratti Julien, Fagerberg Christina R, Soerensen Kristina P, Kibaek Maria, Kamsteeg Erik-Jan, Koolen David A, Gunning Boudewijn, Schelhaas H Jurgen, Kruer Michael C, Fox Jordana, Bakhtiari Somayeh, Jarrar Randa, Padilla-Lopez Sergio, Lindstrom Kristin, Jin Sheng Chih, Zeng Xue, Bilguvar Kaya, Papavasileiou Antigone, Xing Qinghe, Zhu Changlian, Boysen Katja, Vairo Filippo, Lanpher Brendan C, Klee Eric W, Tillema Jan-Mendelt, Payne Eric T, Cousin Margot A, Kruisselbrink Teresa M, Wick Myra J, Baker Joshua, Haan Eric, Smith Nicholas, Sadeghpour Azita, Davis Erica E, Katsanis Nicholas, Task Force for Neonatal Genomics, Corbett Mark A, MacLennan Alastair H, Gecz Jozef, Biskup Saskia, Goldmann Eva, Rodan Lance H, Kichula Elizabeth, Segal Eric, Jackson Kelly E, Asamoah Alexander, Dimmock David, McCarrier Julie, Botto Lorenzo D, Filloux Francis, Tvrdik Tatiana, Cascino Gregory D, Klingerman Sherry, Neumann Catherine, Wang Raymond, Jacobsen Jessie C, Nolan Melinda A, Snell Russell G, Lehnert Klaus, Sadleir Lynette G, Anderlid Britt-Marie, Kvarnung Malin, Guerrini Renzo, Friez Michael J, Lyons Michael J, Leonhard Jennifer, Kringlen Gabriel, Casas Kari, El Achkar Christelle M, Smith Lacey A, Rotenberg Alexander, Poduri Annapurna, Sanchis-Juan Alba, Carss Keren J, Rankin Julia, Zeman Adam, Raymond F Lucy, Blyth Moira, Kerr Bronwyn, Ruiz Karla, Urquhart Jill, Hughes Imelda, Banka Siddharth, Deciphering Developmental Disorders Study, Hedrich Ulrike B S, Scheffer Ingrid E, Helbig Ingo, Zamponi Gerald W, Lerche Holger, Mefford Heather C

Аннотация

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.

Предметные рубрики MeSH

Adolescent Adult Calcium Channels, R-Type Cation Transport Proteins Child Child, Preschool Contracture Dyskinesias Epilepsy Female Genetic Variation Humans Infant Male Megalencephaly Neurodevelopmental Disorders Spasms, Infantile

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

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Аннотация

Предметные рубрики MeSH