Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome.
Epilepsia
; 60(9): 1881-1894, 2019 09.
Article
en En
| MEDLINE
| ID: mdl-31468518
ABSTRACT
OBJECTIVE:
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.METHODS:
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 CaV 2.1 channel function. Channel localization and structure were assessed with immunofluorescence microscopy and three-dimensional (3D) modeling.RESULTS:
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.SIGNIFICANCE:
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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Espasmos Infantiles
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Encefalopatías
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Canales de Calcio
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Síndrome de Lennox-Gastaut
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Mutación con Ganancia de Función
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Mutación con Pérdida de Función
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Infant
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Male
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Newborn
Idioma:
En
Año:
2019
Tipo del documento:
Article