Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain

Journal article

AbstractBackgroundGenetic variants in the voltage-gated sodium channelsSCN1A,SCN2A,SCN3A, andSCN8Aare leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported inSCN8Aonly (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain.MethodsRNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples.ResultsIn the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. ForSCN2A,SCN3A, andSCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. InSCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories.ConclusionsExon usage inSCN1A,SCN2A,SCN3A, andSCN8Achanges dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.

Authors: Liang, L; Fazel Darbandi, S; Pochareddy, S; Gulden, FO; Gilson, MC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: Genome Medicine
• Volume: 13
• Issue: 1
• Pages: 135-135
• Article number: 135
• Publication date: 2021-08-23
• DOI: 10.1186/s13073-021-00949-0
• EISSN: 1756-994X
• ISSN: 1756-994X
• Language: English
• Keywords: Intron; Sodium channel; Gene isoform; RNA splicing; Genetics; Exon; Human brain; Alternative splicing; Coding region; Gene; Neocortex; Exon trapping; Chemistry; Neuroscience; Biology; Sodium; RNA