Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation

Xie, Yunyao; Ng, Nathan; Safrina, Olga; Ramos, Carmen M.; Ess, Kevin C.; Schwartz, Philip H.; Smith, Martin A.; O’Dowd, Diane K.

doi:10.1016/j.nbd.2019.104627

Cited by 30 publications

(29 citation statements)

References 71 publications

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“…SCN1A mutations are the most prevalent amongst all VGSCs mutations in epilepsy and over 1,250 pathogenic variants are responsible for various epilepsies (44). In fact, amongst all epilepsy genes, SCN1A mutations are the most implicated (6,45).…”

Section: Scn1a: Role In Epilepsy and Epilepsy Managementmentioning

confidence: 99%

“…Furthermore, neurons are more suitable for expressing channel biophysical properties than other mammalian cells and they serve as better models. Xie et al (44) recently demonstrated the high potential of using hiPSCneurons for functional studies by applying the K1270 SCN1A mutation. They observed a reduced depolarization signal in the mutant channel which suggested loss-of-function.…”

Section: Scn1a: Role In Epilepsy and Epilepsy Managementmentioning

confidence: 99%

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Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

et al. 2021

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Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

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Section: Scn1a: Role In Epilepsy and Epilepsy Managementmentioning

confidence: 99%

Section: Scn1a: Role In Epilepsy and Epilepsy Managementmentioning

confidence: 99%

Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

et al. 2021

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“…A single pathogenic variant in a single gene may initiate a disease process. Such a disease process in a person takes place in the context of the rest of that person's whole genome, with all its other variations and dynamicity of regulation and expression in both normal (eg, developmental) and response (eg, compensatory) programs 19–21 . Moreover, by the time a disease is manifest and a molecular genetic diagnosis established, the pathogenic variant in question will have been active (or active and then quiescent) for some time.…”

Section: Complexitymentioning

confidence: 99%

“…SISODIYA and response (eg, compensatory) programs. [19][20][21] Moreover, by the time a disease is manifest and a molecular genetic diagnosis established, the pathogenic variant in question will have been active (or active and then quiescent) for some time. If the gene in question is involved in processes of development, [22][23][24] then many fundamental organisational changes may have occurred 25 -as may have irreversible changes and some degree of functional compensation.…”

Section: S97mentioning

confidence: 99%

Precision medicine and therapies of the future

Sisodiya

2020

Epilepsia

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Precision medicine in the epilepsies has gathered much attention, especially with gene discovery pushing forward new understanding of disease biology. Several targeted treatments are emerging, some with considerable sophistication and individual‐level tailoring. There have been rare achievements in improving short‐term outcomes in a few very select patients with epilepsy. The prospects for further targeted, repurposed, or novel treatments seem promising. Along with much‐needed success, difficulties are also arising. Precision treatments do not always work, and sometimes are inaccessible or do not yet exist. Failures of precision medicine may not find their way to broader scrutiny. Precision medicine is not a new concept: It has been boosted by genetics and is often focused on genetically determined epilepsies, typically considered to be driven in an individual by a single genetic variant. Often the mechanisms generating the full clinical phenotype from such a perceived single cause are incompletely understood. The impact of additional genetic variation and other factors that might influence the clinical presentation represent complexities that are not usually considered. Precision success and precision failure are usually equally incompletely explained. There is a need for more comprehensive evaluation and a more rigorous framework, bringing together information that is both necessary and sufficient to explain clinical presentation and clinical responses to precision treatment in a precision approach that considers the full picture not only of the effects of a single variant, but also of its genomic and other measurable environment, within the context of the whole person. As we may be on the brink of a treatment revolution, progress must be considered and reasoned: One possible framework is proposed for the evaluation of precision treatments.

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“…In both fly and hiPSC models of K1270T, the mutation causes reduced firing in inhibitory neurons and increased firing in excitatory neurons in heterozygotes, although the deficits in fruit-flies occur at elevated temperatures and those in human iPSC-derived neurons at room temperature. In addition, in the K1270T mutant flies, reduced firing in inhibitory neurons is driven by a temperature dependent hyperpolarized shift in deactivation threshold of persistent sodium currents (Sun et al, 2012), while reduced firing in iPSC-derived inhibitory neurons results from reduction in sodium current density (Xie et al, 2019). In the current study of K1270T mouse, PV inhibitory firing frequency is not reduced however the AP threshold is shifted to a more depolarized potential and AP amplitude is significantly reduced.…”

Section: Comparison With the Existing Models Of K1270t Mutationmentioning

confidence: 99%

Interneuron dysfunction in a new knock-in mouse model of SCN1A GEFS+

Zhu

Xie

et al. 2019

Preprint

Self Cite

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Advances in genome sequencing have identified over 1300 mutations in the SCN1A sodium channel gene that result in genetic epilepsies. However, how individual mutations within SCN1A produce seizures remains elusive for most mutations. Previous work from our lab has shown that the K1270T (KT) mutation, which is linked to GEFS+ (Genetic Epilepsy with Febrile Seizure plus) in humans, causes reduced firing of GABAergic neurons in a Drosophila knock-in model. To examine the effect of this mutation in mammals, we introduced the equivalent KT mutation into the mouse Scn1a (Scn1a KT ) gene using CRISPR/Cas9. Mouse lines carrying this mutation were examined in two widely used genetic backgrounds, C57BL/6NJ and 129X1/SvJ. In both backgrounds, homozygous mutants had spontaneous seizures and died by postnatal day 23. There was no difference in the lifespan of mice heterozygous for the mutation in either background when compared to wild-type littermates up to 6 months. Heterozygous mutants had heat-induced seizures at ~42 deg. Celsius, a temperature that did not induce seizures in wild-type littermates. In acute hippocampal slices, current-clamp recordings revealed a significant depolarized shift in action potential threshold and reduced action potential amplitude in parvalbumin-expressing inhibitory interneurons in Scn1a KT/+ mice. There was no change in the firing properties of excitatory CA1 pyramidal neurons. Our results indicate that Scn1a KT/+ mice develop seizures, and impaired action potential firing of inhibitory interneurons in Scn1a KT/+ mice may produce hyperexcitability in the hippocampus.

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Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation

Cited by 30 publications

References 71 publications

Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

Precision medicine and therapies of the future

Interneuron dysfunction in a new knock-in mouse model of SCN1A GEFS+

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