Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis

Schattling, Benjamin; Fazeli, Walid; Engeland, Birgit; Liu, Yuanyuan; Lerche, Holger; Isbrandt, Dirk; Friese, Manuel A.

doi:10.1172/jci.insight.89810

Cited by 26 publications

(18 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recordings from hippocampal pyramidal neurons exhibit an enhanced persistent Na + current (Kearney et al, 2001). The Na V 1.2 (A263V) knock-in mouse line, which is homozygous for a mild disease gain-of-function mutation, presents with frequent seizures and increased mortality (Schattling et al, 2016). At the cellular level, current clamp recordings in slices reveal increased excitability in hippocampal pyramidal neurons (Schattling et al, 2016).…”

Section: A Voltage-gated Na + Channelsmentioning

confidence: 99%

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Oyrer¹,

Maljevic²,

Scheffer³

et al. 2017

Pharmacol Rev

212

190

View full text Add to dashboard Cite

Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.

show abstract

Section: A Voltage-gated Na + Channelsmentioning

confidence: 99%

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Oyrer¹,

Maljevic²,

Scheffer³

et al. 2017

Pharmacol Rev

212

190

View full text Add to dashboard Cite

show abstract

“…10 The pathophysiological mechanisms underlying this heterogeneity are poorly understood and need further investigations, using both clinical data and basic science approaches, e.g., SCN2A mouse models such as the one we have generated and recently described. 18 The phenotype shows a considerable overlap between the index patient and his mother, with recurrent episodes of ataxia lasting around 3 weeks, impairment of speech development, and lack of epileptic seizures. Despite this overlap, it is not justified to suggest a strong genotype-phenotype correlation, because this same mutation (SCN2A, p.L1650P) was also reported in a patient with early-infantile epileptic encephalopathy (EIEE).…”

Section: Discussionmentioning

confidence: 99%

Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development

et al. 2018

Self Cite

View full text Add to dashboard Cite

Mutations in are associated with a heterogeneous clinical spectrum including epilepsy and autism. Here, we have identified a peculiar phenotype associated with vaccination related exacerbations of ataxia. We report the first family with three individuals affected by-associated episodic ataxia (EA) with impaired speech development. The index patient manifested his first episode of subacute cerebellar ataxia at the age of 12 months, 3 weeks after vaccinations for measles, mumps, rubella, and varicella. Cranial magnetic resonance imaging showed a lesion of the left cerebellar hemisphere, which was first considered as a potential cause of the ataxia. The patient fully recovered within 3 weeks, but developed three very similar episodes of transient ataxia within the following 24 months. Whole exome sequencing of the index patient revealed a heterozygous autosomal-dominant mutation in (NM_021007, c.4949T> C; p.L1650P), which was confirmed in the likewise affected mother, and was then also identified in the younger brother who developed the first episode of ataxia. We hereby extend the recently described spectrum of -associated neurologic disorders, emphasizing that mutations should also be considered in familial cases of EA. Coincidental imaging findings or other associated events such as immunizations should not protract genetic investigations.

show abstract

“…A knockin of the GoF variant p.Ala263Val causing an increase in the Na V 1.2‐mediated persistent sodium current in a heterologous system and neonatal onset seizures and late onset episodic ataxia revealed hyperexcitability of hippocampal CA1 pyramidal neurons in heterozygous mice compared to their wild‐type littermates. In contrast to homozygous mutant mice, heterozygous animals had a normal survival rate and did not show frequent epileptic seizures . Although the GoF effects could be detected in both Scn2a mouse models, many questions remain unclear.…”

Section: Modelsmentioning

confidence: 97%

SCN2A channelopathies: Mechanisms and models

2019

Self Cite

View full text Add to dashboard Cite

Summary Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders.

show abstract

Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis

Cited by 26 publications

References 42 publications

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development

SCN2A channelopathies: Mechanisms and models

Contact Info

Product

Resources

About