Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes

Molecular Medicine
Anaïs BegemannAnita Rauch

Abstract

Deleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood. 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, ...Continue Reading

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Citations

May 14, 2020·Molecular Genetics & Genomic Medicine·Pu MiaoJianhua Feng
Apr 16, 2020·The Journal of General Physiology·Grace K Muller
Apr 1, 2020·Developmental Medicine and Child Neurology·Andreas Brunklaus, Dennis Lal
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Mar 19, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Katherine CrawfordIngo Helbig
Dec 12, 2021·American Journal of Medical Genetics. Part a·Ruth RichardsonMeena Balasubramanian

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Methods Mentioned

BETA
exome sequencing
transfection
transgenic

Software Mentioned

NeuroMatic
RasMol
Igor Pro
Modeller
GraphPad Prism
Patchmaster

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