De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy
Language English Country England, Great Britain Media electronic
Document type Journal Article
PubMed
34399820
PubMed Central
PMC8365958
DOI
10.1186/s13041-021-00838-y
PII: 10.1186/s13041-021-00838-y
Knihovny.cz E-resources
- Keywords
- CACNA1H, Calcium channel, Cav3.2 channel, Channelopathy, Encephalopathy, Epilepsy, Ion channels, Nav1.6 channel, SCN8A, Sodium channel,
- MeSH
- Gain of Function Mutation MeSH
- Point Mutation MeSH
- Gene Duplication MeSH
- Epilepsy, Tonic-Clonic genetics MeSH
- Ion Channel Gating genetics physiology MeSH
- Genetic Predisposition to Disease MeSH
- Humans MeSH
- Mutation, Missense MeSH
- Abnormalities, Multiple genetics MeSH
- NAV1.6 Voltage-Gated Sodium Channel genetics physiology MeSH
- Infant, Newborn MeSH
- Drug Resistant Epilepsy genetics MeSH
- Pedigree MeSH
- Scoliosis genetics MeSH
- Calcium Channels, T-Type genetics physiology MeSH
- Developmental Disabilities genetics MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- CACNA1H protein, human MeSH Browser
- NAV1.6 Voltage-Gated Sodium Channel MeSH
- SCN8A protein, human MeSH Browser
- Calcium Channels, T-Type MeSH
Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873-4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.
Department of Pathophysiology 3rd Faculty of Medicine Charles University Prague Czech Republic
Department of Pediatric Neurology Mafraq Hospital Abu Dhabi United Arab Emirates
Department of Pediatrics Tawam Hospital Al Ain United Arab Emirates
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic
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The T-type calcium channelosome
