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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620903
Title:
De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
Authors:
Helbig, K. L. [et al]; Rankin, Julia; Zemen, Adam
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.
Citation:
De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. 2018 Nov 1;103(5):666-678 American Journal of Human Genetics
Publisher:
Cell Press
Journal:
American journal of human genetics
Issue Date:
Nov-2018
URI:
http://hdl.handle.net/11287/620903
DOI:
10.1016/j.ajhg.2018.09.006
PubMed ID:
30343943
Additional Links:
https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(18)30317-3
Type:
Journal Article
Language:
en
Appears in Collections:
Neurology; Clinical Genetics (Peninsula Genetics); 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorHelbig, K. L. [et al]en
dc.contributor.authorRankin, Juliaen
dc.contributor.authorZemen, Adamen
dc.date.accessioned2018-11-08T12:16:20Z-
dc.date.available2018-11-08T12:16:20Z-
dc.date.issued2018-11-
dc.identifier.citationDe Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. 2018 Nov 1;103(5):666-678 American Journal of Human Geneticsen
dc.identifier.pmid30343943-
dc.identifier.doi10.1016/j.ajhg.2018.09.006-
dc.identifier.urihttp://hdl.handle.net/11287/620903-
dc.description.abstractDevelopmental 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.en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S0002-9297(18)30317-3en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Neurologyen
dc.titleDe Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesiasen
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of human geneticsen
dc.type.versionPublisheden

Related articles on PubMed

All Items in RD&E Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.