Cis-Attenuation of Pathogenic Scn8a Variant Causing Childhood Epilepsy Reveals Opposing Transcriptional Programs Driving NaV1.6 Gain and Loss of Function Phenotypes

A De Novo, Intragenic Modifier in Cis Rescues Scn8a-N1768D Epilepsy and Defines a Therapeutic Window Bounded by Gain- and Loss-of-Function

Gene therapy with doxycycline-controlled expression of human Kv1.1 reduces neuronal excitability and increases sociability of Scn2a -deficient mice

Genetic loss-of-function (LoF) variants in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been identified as one of the foremost monogenic causes of autism spectrum disorder (ASD). ASD encompasses a broad spectrum of behavioral phenotypes, with impaired sociability as a core characteristic. We hav...

Epilepsy and premature mortality driven by inhibitory neuron dysfunction in a mouse model of SCN1A gain-of-function neurodevelopmental disorder

The first mouse model of SCN1A GoF epilepsy with heterozygous Cre-dependent expression of the recurrent patient variant Scn1a-p.R1636Q is developed, the first study of SCN1A GoF epilepsy in a preclinical model in vivo and further investigation in the Scn1aflox(R1636Q)mouse will yield new mechanistic insights into disea...

Nav1.5 Beyond Genetics: Loss of Cardiac Sodium-Channel Function in Brugada Syndrome.

Brugada syndrome is usually interpreted through SCN5A genetics, yet many patients with a Brugada phenotype carry no clearly pathogenic SCN5A variant and penetrance among carriers is incomplete. Cardiac sodium-channel function is therefore not a direct readout of coding sequence but an integrated property shaped by the...

Functional and pharmacological characterization of the SCN2A variant p.C258R with mixed gain and loss of function causing developmental and epileptic encephalopathy type 11

Pathogenic variants in SCN2A cause dysfunction of the NaV1.2 voltage-gated sodium channel and are associated with neurodevelopmental disorders with or without epilepsy. Treatment of epilepsy in these patients is challenging and depends on whether the variant results in a gain (GoF) or loss of function (LoF). We describ...

SCN4A Channelopathies: From Disease Mechanisms to Variant Interpretation

SCN4A encodes the skeletal-muscle voltage-gated sodium channel NaV1.4. Pathogenic variation in this gene produces fundamentally different disease mechanisms, including dominant alpha-pore gain of function, dominant S4 gating-pore currents, and reduced channel availability, with severe biallelic loss of function causing...