| Title: |
Nav1.2 channel mutations preventing fast inactivation lead to SCN2A encephalopathy |
| Authors: |
Berecki, G; Tao, E; Howell, KB; Coorg, RK; Andersen, E; Kahlig, K; Wolff, M; Corry, B; Petrou, S |
| Publisher Information: |
OXFORD UNIV PRESS |
| Publication Year: |
2025 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
SCN2A gene-related early-infantile developmental and epileptic encephalopathy (EI-DEE) is a rare and severe disorder that manifests in early infancy. SCN2A mutations affecting the fast inactivation gating mechanism can result in altered voltage dependence and incomplete inactivation of the encoded neuronal Nav1.2 channel and lead to abnormal neuronal excitability. In this study, we evaluated clinical data of seven missense Nav1.2 variants associated with DEE and performed molecular dynamics simulations, patch-clamp electrophysiology and dynamic clamp real-time neuronal modelling to elucidate the molecular and neuron-scale phenotypic consequences of the mutations. The N1662D mutation almost completely prevented fast inactivation without affecting activation. The comparison of wild-type and N1662D channel structures suggested that the ambifunctional hydrogen bond formation between residues N1662 and Q1494 is essential for fast inactivation. Fast inactivation could also be prevented with engineered Q1494A or Q1494L Nav1.2 channel variants, whereas Q1494E or Q149K variants resulted in incomplete inactivation and persistent current. Molecular dynamics simulations revealed a reduced affinity of the hydrophobic IFM-motif to its receptor site with N1662D and Q1494L variants relative to wild-type. These results demonstrate that the interactions between N1662 and Q1494 underpin the stability and the orientation of the inactivation gate and are essential for the development of fast inactivation. Six DEE-associated Nav1.2 variants, with mutations mapped to channel segments known to be implicated in fast inactivation were also evaluated. Remarkably, the L1657P variant also prevented fast inactivation and produced biophysical characteristics that were similar to those of N1662D, whereas the M1501V, M1501T, F1651C, P1658S and A1659V variants resulted in biophysical properties that were consistent with gain-of-function and enhanced action potential firing of hybrid neurons in dynamic action potential clamp experiments. ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
0006-8950 |
| Relation: |
pii: 7700937; https://hdl.handle.net/11343/358305 |
| Availability: |
https://hdl.handle.net/11343/358305 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.DA4439A5 |
| Database: |
BASE |