Sodium voltage-gated channel alpha subunit 2 mutant messenger RNA (SCN2A mutant mRNA)

Sodium voltage-gated channel alpha subunit 2 (SCN2A) mutant messenger RNA is the transcript produced from a mutated SCN2A gene, which encodes the Nav1.2 voltage-gated sodium channel (UniProt P35498). Nav1.2 is primarily expressed in the axon initial segment of neurons and is essential for action potential generation and propagation in the developing brain (Sanders et al., 2018). Pathogenic gain-of-function mutations in the SCN2A gene lead to an overactive Nav1.2 channel, causing severe neurodevelopmental disorders characterized by early-onset seizures, such as early infantile epileptic encephalopathy type 11 (NIH/GARD). Targeting the mutant mRNA with antisense oligonucleotides (ASOs), such as PRAX-222 or ION859, allows for the specific reduction of the aberrant protein, potentially mitigating the hyperexcitability associated with the disease (Praxis Precision Medicines; Ionis Pharmaceuticals). This precision medicine approach is particularly relevant for gain-of-function variants where reducing the dosage of the mutant protein can restore the balance of neuronal activity. Conversely, loss-of-function mutations are associated with autism spectrum disorder, where different RNA-based strategies might be employed to increase protein levels.

Other names

Nav1.2 mutant mRNASodium channel protein type 2 subunit alpha mutant mRNASCN2A mRNA

Antisense oligonucleotide-mediated degradation of mutant mRNA via RNase H recruitment or splice-switching to reduce the expression of gain-of-function Nav1.2 protein.