A Novel Missense Mutation in the DI-DII Linker of the nav1.6 Channel Causes Neurodevelopment Disorder and Profound Dysregulation of Na+ Currents
Abstract number :
1.035
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2024
Submission ID :
1164
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Mikhail Tarasov, PhD – The Ohio State University
Brian Wilson, PhD – THE NEWCASTLE UPON TYNE HOSPITALS NHS FOUNDATION TRUST
Przemysław Radwański, PharmD, PhD – The Ohio State University
Rationale: Mutations in SCN8A are linked to a range of neurodevelopmental syndromes. While usually gain-of-function SCN8A variants are associated with developmental epileptic encephalopathy, loss-of-function variants of SCN8A have been linked to developmental delays without seizures. Here we report biophysical consequences of the novel SCN8A variant (c.1817G >C), encoding the voltage-gated sodium channel NaV1.6 (R606P). This amino acid substitution in the DI-DII linker of the NaV1.6 channel was identified in the patient with a serious neurodevelopmental presentation and results in a complex biophysical behavior combining features of both loss- and gain-of-function.
Methods: Whole exome sequencing, cell culture and transfection, patch-clamp
Results: An infant presented with generalized hypertonia at birth, which persisted, associated with bulbar dysfunction and dysphagia. Furthermore, startle reflex was exaggerated in this patient. MRI and EEG were normal. Trio whole exome sequencing identified a heterozygous variant in SCN8A (c.1817G >C p.(Arg606Pro). One of the parents, who was clinically asymptomatic, was found to be low level mosaic (5%) for this variant. Transient co-transfected of the NaV1.6-R606P with NaV-β1 (Scn1B) in Chinese hamster ovary (CHO) cells revealed a two-fold reduction in peak Na+ currents (INa) relative to wild-type (WT) NaV1.6. This reduction in INa was accompanied by a 10 mV depolarizing shift in both steady-state activation and inactivation in NaV1.6-R606P relative to NaV1.6-WT. In line with impaired inactivation of the NaV1.6-R606P, this mutation evidenced a significant increase in availability at depolarized potentials (- 10 mV) relative to the NaV1.6-WT. Surprisingly, persistent INa was not enhanced in the NaV1.6-R606P.
Conclusions: This study provides a first report of a novel pathogenic mutation in the Scn8a gene associated with a neurodevelopmental phenotype that results in a dysregulation of both the NaV1.6 activation and inactivation.
Funding: NIH grants R01HL155378 and R01 NS121234, American Heart Association grant 22POST915300
Basic Mechanisms