TY - JOUR
T1 - De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
AU - Deciphering Developmental Disorders Study
AU - Helbig, Katherine L.
AU - Lauerer, Robert J.
AU - Bahr, Jacqueline C.
AU - Souza, Ivana A.
AU - Myers, Candace T.
AU - Uysal, Betül
AU - Schwarz, Niklas
AU - Gandini, Maria A.
AU - Huang, Sun
AU - Keren, Boris
AU - Mignot, Cyril
AU - Afenjar, Alexandra
AU - Billette de Villemeur, Thierry
AU - Héron, Delphine
AU - Nava, Caroline
AU - Valence, Stéphanie
AU - Buratti, Julien
AU - Fagerberg, Christina R.
AU - Soerensen, Kristina P.
AU - Kibaek, Maria
AU - Kamsteeg, Erik Jan
AU - Koolen, David A.
AU - Gunning, Boudewijn
AU - Schelhaas, H. Jurgen
AU - Kruer, Michael C.
AU - Fox, Jordana
AU - Bakhtiari, Somayeh
AU - Jarrar, Randa
AU - Padilla-Lopez, Sergio
AU - Lindstrom, Kristin
AU - Jin, Sheng Chih
AU - Zeng, Xue
AU - Bilguvar, Kaya
AU - Papavasileiou, Antigone
AU - Xin, Qinghe
AU - Zhu, Changlian
AU - Boysen, Katja
AU - Vairo, Filippo
AU - Lanpher, Brendan C.
AU - Klee, Eric W.
AU - Tillema, Jan Mendelt
AU - Payne, Eric T.
AU - Cousin, Margot A.
AU - Kruisselbrink, Teresa M.
AU - Wick, Myra J.
AU - Baker, Joshua
AU - Haan, Eric
AU - Smith, Nicholas
AU - Corbett, Mark A.
AU - MacLennan, Alastair H.
N1 - Funding Information:
We thank the participants and families for participating in our study. R.J.L. is supported by a Siegmund-Kiener stipend for medical doctoral students at the Hertie Institute of Clinical Brain Research . C.T.M. is supported by the Lennox-Gastaut Syndrome Foundation (LGSF). M.A.G. holds fellowships from Alberta Innovates and CIHR . M.A. Corbett is supported by The Channel 7 Children’s Research Foundation and the Cerebral Palsy Alliance Research Foundation . R.W. is supported by The Brian and Caris Chan Family Foundation . J.C.J. is supported by a Rutherford Discovery Fellowship from the New Zealand Government , administered by the Royal Society of New Zealand. Bioinformatic analysis was supported by the New Zealand eScience Infrastructure. L.G.S. is supported by the Health Research Council of New Zealand and Cure Kids New Zealand . G.W.Z. is supported by the Canadian Institutes of Health Research (CIHR) and is a Canada Research Chair. A.S.-J., K.J.C., and F.L.R. were supported by Cambridge BRC and the National Institute for Health Research England (NIHR) for the NIHR BioResource (grant RG65966 ). I.E.S. is supported by the National Health and Medical Research Council of Australia , National Institutes of Health , Australian Research Council , Health Research Council of New Zealand , CURE , and March of Dimes . I. Helbig, U.B.S.H., and H.L. are supported by the DFG Research Unit FOR 2715 (grants He5415/7-1 , He8155/1-1 , Le1030/16-1 ). H.C.M. is supported by the NIH ( NINDS NS069605 ). We are thankful to the Deciphering Developmental Disorders (DDD) study. The DDD study (Cambridge South REC approval 10/H0305/83 and the Republic of Ireland REC GEN/284/12) presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003 ), a parallel funding partnership between the Wellcome Trust and the Department of Health , and the Wellcome Trust Sanger Institute (grant number WT098051 ). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health.
Funding Information:
We thank the participants and families for participating in our study. R.J.L. is supported by a Siegmund-Kiener stipend for medical doctoral students at the Hertie Institute of Clinical Brain Research. C.T.M. is supported by the Lennox-Gastaut Syndrome Foundation (LGSF). M.A.G. holds fellowships from Alberta Innovates and CIHR. M.A. Corbett is supported by The Channel 7 Children's Research Foundation and the Cerebral Palsy Alliance Research Foundation. R.W. is supported by The Brian and Caris Chan Family Foundation. J.C.J. is supported by a Rutherford Discovery Fellowship from the New Zealand Government, administered by the Royal Society of New Zealand. Bioinformatic analysis was supported by the New Zealand eScience Infrastructure. L.G.S. is supported by the Health Research Council of New Zealand and Cure Kids New Zealand. G.W.Z. is supported by the Canadian Institutes of Health Research (CIHR) and is a Canada Research Chair. A.S.-J., K.J.C., and F.L.R. were supported by Cambridge BRC and the National Institute for Health Research England (NIHR) for the NIHR BioResource (grant RG65966). I.E.S. is supported by the National Health and Medical Research Council of Australia, National Institutes of Health, Australian Research Council, Health Research Council of New Zealand, CURE, and March of Dimes. I. Helbig, U.B.S.H., and H.L. are supported by the DFG Research Unit FOR 2715 (grants He5415/7-1, He8155/1-1, Le1030/16-1). H.C.M. is supported by the NIH (NINDS NS069605). We are thankful to the Deciphering Developmental Disorders (DDD) study. The DDD study (Cambridge South REC approval 10/H0305/83 and the Republic of Ireland REC GEN/284/12) presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health.
Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
KW - CACNA1E, ion channel
KW - arthrogryposis
KW - calcium channel
KW - epilepsy
UR - http://www.scopus.com/inward/record.url?scp=85056059896&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.09.006
DO - 10.1016/j.ajhg.2018.09.006
M3 - Article
C2 - 30343943
AN - SCOPUS:85056059896
SN - 0002-9297
VL - 103
SP - 666
EP - 678
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -