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

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; Blyth, Moira; Kerr, Bronwyn; Ruiz, Karla; Urquhart, Jill; Hughes, Imelda; Banka, Siddharth; Hedrich, Ulrike B S; Scheffer, Ingrid E; Helbig, Ingo; Zamponi, Gerald W; Lerche, Holger; Mefford, Heather C; 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; 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

doi:10.1016/j.ajhg.2018.09.006

Title

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

Publication Date

2018-11-01

Author(s)

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

Blyth, Moira

Kerr, Bronwyn

Ruiz, Karla

Urquhart, Jill

Hughes, Imelda

Banka, Siddharth

Hedrich, Ulrike B S

Scheffer, Ingrid E

Helbig, Ingo

Zamponi, Gerald W

Lerche, Holger

Mefford, Heather C

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

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

Subject

CACNA1E, ion channel

arthrogryposis

calcium channel

epilepsy

Type of document

Journal Article

OrcId

#PLACEHOLDER_PARENT_METADATA_VALUE#

DOI

10.1016/j.ajhg.2018.09.006

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.

Link

link

Citation

American journal of human genetics 2018; 103(5): 666-678

Jornal Title

American journal of human genetics

Austin Health

Files: