&lt;i&gt;KCNQ2&lt;/i&gt;- and &lt;i&gt;KCNQ3&lt;/i&gt;-Associated Epilepsy

doi:10.1017/9781009278270

Cited by 5 publications

References 135 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

<i>SCN2A</i>-Related Disorders

Abbott,

Bender,

Brunklaus

et al. 2024

View full text Add to dashboard Cite

SCN2A encodes a voltage-gated sodium channel (designated NaV1.2) vital for generating neuronal action potentials. Pathogenic SCN2A variants are associated with a diverse array of neurodevelopmental disorders featuring neonatal or infantile onset epilepsy, developmental delay, autism, intellectual disability and movement disorders. SCN2A is a high confidence risk gene for autism spectrum disorder and a commonly discovered cause of neonatal onset epilepsy. This remarkable clinical heterogeneity is mirrored by extensive allelic heterogeneity and complex genotype-phenotype relationships partially explained by divergent functional consequences of pathogenic variants. Emerging therapeutic strategies targeted to specific patterns of NaV1.2 dysfunction offer hope to improving the lives of individuals affected by SCN2A-related disorders. This Element provides a review of the clinical features, genetic basis, pathophysiology, pharmacology and treatment of these genetic conditions authored by leading experts in the field and accompanied by perspectives shared by affected families. This title is also available as Open Access on Cambridge Core.

show abstract

<i>SCN2A</i>-Related Disorders

Abbott,

Bender,

Brunklaus

et al. 2024

View full text Add to dashboard Cite

show abstract

Plural molecular and cellular mechanisms of pore domainKCNQ2encephalopathy

Abreo,

Thompson,

Madabushi

et al. 2024

Preprint

View full text Add to dashboard Cite

KCNQ2variants in children with neurodevelopmental impairment are difficult to assess due their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, andKCNQ2G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as keystone of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Recorded in G256W/+ mouse brain slices, CA1 pyramidal cells show increased neuronal excitability. Hippocampal pyramidal cell KCNQ2 and KCNQ3 immunolabeling is significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse neocortical KCNQ2 protein levels are reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies reveal pore “turret arch” bonding as a KCNQ structural novelty and introduce a valid animal model ofKCNQ2encephalopathy. Our results, spanning structure to behavior, may be broadly informative since the majority ofKCNQ2encephalopathy patients share variants near the selectivity filter.

show abstract

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy

Abreo,

Thompson,

Madabushi

et al. 2024

Preprint

View full text Add to dashboard Cite

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as keystone of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies reveal pore “turret arch” bonding as a KCNQ structural novelty and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

show abstract

<i>KCNQ2</i>- and <i>KCNQ3</i>-Associated Epilepsy

Cited by 5 publications

References 135 publications

<i>SCN2A</i>-Related Disorders

<i>SCN2A</i>-Related Disorders

Plural molecular and cellular mechanisms of pore domainKCNQ2encephalopathy

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy

Contact Info

Product

Resources

About