Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes.
Channelopathy
Electrophysiology
Epilepsy
Epileptic encephalopathy
Intellectual disability
Nav1.2
Patch-clamp
SCN2A
Structural modelling
Journal
Molecular medicine (Cambridge, Mass.)
ISSN: 1528-3658
Titre abrégé: Mol Med
Pays: England
ID NLM: 9501023
Informations de publication
Date de publication:
27 02 2019
27 02 2019
Historique:
received:
29
10
2018
accepted:
05
02
2019
entrez:
1
3
2019
pubmed:
1
3
2019
medline:
14
8
2019
Statut:
epublish
Résumé
Deleterious variants in the voltage-gated sodium channel type 2 (Na To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling. The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings. Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Na
Sections du résumé
BACKGROUND
Deleterious variants in the voltage-gated sodium channel type 2 (Na
METHODS
To further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling.
RESULTS
The two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings.
CONCLUSIONS
Our findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Na
Identifiants
pubmed: 30813884
doi: 10.1186/s10020-019-0073-6
pii: 10.1186/s10020-019-0073-6
pmc: PMC6391808
doi:
Substances chimiques
NAV1.2 Voltage-Gated Sodium Channel
0
SCN2A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
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