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Distinctive In Vitro Phenotypes in iPSC-Derived Neurons From Patients With Gain- and Loss-of-Function SCN2A Developmental and Epileptic Encephalopathy.

Authors :
Miaomiao Mao
Mattei, Cristiana
Rollo, Ben
Byars, Sean
Cuddy, Claire
Berecki, Geza
Heighway, Jacqueline
Pachernegg, Svenja
Menheniott, Trevelyan
Apted, Danielle
Linghan Jia
Dalby, Kelley
Nemiroff, Alex
Mullen, Saul
Reid, Christopher A.
Maljevic, Snezana
Petrou, Steven
Source :
Journal of Neuroscience. 2/21/2024, Vol. 44 Issue 8, p1-16. 16p.
Publication Year :
2024

Abstract

SCN2A encodes NaV1.2, an excitatory neuron voltage-gated sodium channel and a major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with the nature of SCN2A variant dysfunction and can be divided into gain-of-function (GoF) cases with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age. We established and assessed patient induced pluripotent stem cell (iPSC) - derived neuronal models for two recurrent SCN2A DEE variants with GoF R1882Q and LoF R853Q associated with early- and late-onset DEE, respectively. Two male patient-derived iPSC isogenic pairs were differentiated using Neurogenin-2 overexpression yielding populations of cortical-like glutamatergic neurons. Functional properties were assessed using patch clamp and multielectrode array recordings and transcriptomic profiles obtained with total mRNA sequencing after 2-4 weeks in culture. At 3 weeks of differentiation, increased neuronal activity at cellular and network levels was observed for R1882Q iPSC-derived neurons. In contrast, R853Q neurons showed only subtle changes in excitability after 4 weeks and an overall reduced network activity after 7 weeks in vitro. Consistent with the reported efficacy in some GoF SCN2A patients, phe-nytoin (sodium channel blocker) reduced the excitability of neurons to the control levels in R1882Q neuronal cultures. Transcriptomic alterations in neurons were detected for each variant and convergent pathways suggested potential shared mechanisms underlying SCN2A DEE. In summary, patient iPSC-derived neuronal models of SCN2A GoF and LoF pathogenic variants causing DEE show specific functional and transcriptomic in vitro phenotypes. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02706474
Volume :
44
Issue :
8
Database :
Academic Search Index
Journal :
Journal of Neuroscience
Publication Type :
Academic Journal
Accession number :
175590321
Full Text :
https://doi.org/10.1523/JNEUROSCI.0692-23.2023