NOVA1/2 genes and alternative splicing in neurodevelopment

NOVA1 and NOVA2 are neuron-specific RNA-binding proteins essential for alternative splicing (AS), influencing neurodevelopment by regulating transcript diversity. These proteins recognize YCAY sequences on pre-mRNA, regulating exon inclusion or skipping, intron retention, and alternative polyadenylation. Despite their 75% sequence identity, NOVA1 and NOVA2 exhibit distinct spatiotemporal expression patterns and target specificities, with NOVA2 predominantly expressed in cortical regions and NOVA1 in the cerebellum and spinal cord. De novo truncating variants in NOVA2 are responsible for a severe neurodevelopmental disorder (NDD), characterized by intellectual developmental disorder, motor delay, autistic features, and corpus callosum hypoplasia. Loss of Nova2 in animal models results in brain development anomalies, such as corpus callosum agenesis in mice, which mirrors the human neurodevelopmental phenotype. If direct evidence remains limited, emerging data suggest that mutations in NOVA1 might also be involved in neurological disorders. The contribution of other mRNA-binding proteins to NDD further underscores the critical role of regulation of RNA processing in neurodevelopment. This review explores the diverse functions of NOVA proteins, their impact on AS during brain development, and their implications in brain disorders.