Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome.
CACNA1A
CaV2.1
Lennox-Gastaut syndrome
de novo mutations
epilepsy
epileptic encephalopathies
immunofluorescence
patch-clamp
structural modeling
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
30
05
2018
revised:
26
07
2019
accepted:
29
07
2019
pubmed:
31
8
2019
medline:
15
4
2020
entrez:
31
8
2019
Statut:
ppublish
Résumé
Developmental epileptic encephalopathies (DEEs) are genetically heterogeneous severe childhood-onset epilepsies with developmental delay or cognitive deficits. In this study, we explored the pathogenic mechanisms of DEE-associated de novo mutations in the CACNA1A gene. We studied the functional impact of four de novo DEE-associated CACNA1A mutations, including the previously described p.A713T variant and three novel variants (p.V1396M, p.G230V, and p.I1357S). Mutant cDNAs were expressed in HEK293 cells, and whole-cell voltage-clamp recordings were conducted to test the impacts on Ca We find that the G230V and I1357S mutations result in loss-of-function effects with reduced whole-cell current densities and decreased channel expression at the cell membrane. By contrast, the A713T and V1396M variants resulted in gain-of-function effects with increased whole-cell currents and facilitated current activation (hyperpolarized shift). The A713T variant also resulted in slower current decay. 3D modeling predicts conformational changes favoring channel opening for A713T and V1396M. Our findings suggest that both gain-of-function and loss-of-function CACNA1A mutations are associated with similarly severe DEEs and that functional validation is required to clarify the underlying molecular mechanisms and to guide therapies.
Substances chimiques
CACNA1A protein, human
0
Calcium Channels
0
Banques de données
GENBANK
['AY714490', 'BC026479.1']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1881-1894Subventions
Organisme : CIHR
ID : 10848
Pays : Canada
Organisme : CIHR
ID : 119553
Pays : Canada
Organisme : CIHR
ID : 125985
Pays : Canada
Organisme : Réseau de Médecine Génétique Appliquée (RMGA)
Pays : International
Organisme : Fonds de la Recherche du Québec en Santé (FRQS)
Pays : International
Organisme : Savoy Foundation
Pays : International
Organisme : CIHR
ID : 10848
Pays : Canada
Organisme : CIHR
ID : 119553
Pays : Canada
Organisme : CIHR
ID : 125985
Pays : Canada
Informations de copyright
Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.
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