Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 103, Issue 5, Pages 666-678Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2018.09.006
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Funding
- Hertie Institute of Clinical Brain Research
- Lennox-Gastaut Syndrome Foundation (LGSF)
- Alberta Innovates
- CIHR
- Channel 7 Children's Research Foundation
- Cerebral Palsy Alliance Research Foundation
- Brian and Caris Chan Family Foundation
- Rutherford Discovery Fellowship from the New Zealand Government
- New Zealand eScience Infrastructure
- Health Research Council of New Zealand
- Cure Kids New Zealand
- Canadian Institutes of Health Research (CIHR)
- Canada Research Chair
- Cambridge BRC
- National Institute for Health Research England (NIHR) for the NIHR BioResource [RG65966]
- National Health and Medical Research Council of Australia
- National Institutes of Health
- March of Dimes
- DFG Research Unit [FOR 2715, He5415/7-1, He8155/1-1, Le1030/16-1]
- NIH [NINDS NS069605]
- Health Innovation Challenge Fund [HICF-1009-003, REC GEN/284/12, 10/H0305/83]
- Wellcome Trust
- Department of Health
- Wellcome Trust Sanger Institute [WT098051]
- Australian Research Council
- CURE
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS069605] Funding Source: NIH RePORTER
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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 alpha(1)-subunit of the voltage-gated Ca(V)2.3 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 Ca(V)2.3 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.
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