Relevance to Autism

Bereshneh et al., 2026 identified five unrelated individuals carrying de novo heterozygous variants (three missense variants, a frameshift variant, and a nonsense variant) in the RAPGEF2 gene presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral abnormalities (including autism in two individuals), seizures, and dysmorphic features; functional assessment of the three missense variants and the nonsense variant in PDZ-GEF mutant Drosophila found that, while wild-type RAPGEF2 was able to rescue phenotypes associated with loss of PDZ (lethality, severe locomotion defects, aberrant microtubular stability in motor neurons axons, and synaptic overgrowth at neuromuscular junctions in third instar larvae), mutant RAPGEF2 with these variants failed to do so, indicating a loss-of-function effect. De novo missense variants in the RAPGEF2 gene have been previously reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort (De Rubeis et al., 2014; Yuen et al., 2017; Zhou et al., 2022).

Molecular Function

Members of the RAS subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF2, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation.

External Links

References