Relevance to Autism

Chen et al., 2025 integrated cortex cell-specific cis-regulatory element annotations, a deep learning-based variant prediction model, and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 non-coding de novo mutations (ncDNMs) in ASD probands from Simons Simplex Collection (SSC) and Autism Speaks MSSNG resource (MSSNG) cohorts and identified a ncDNM that down-regulated expression of the DENND2B gene in a MSSNG proband. Additional de novo variants, including a loss-of-function variant and several missense variants, have been identified in this gene in ASD probands (Satterstrom et al., 2020; Zhou et al., 2022; Tan et al., 2024). Murthy et al., 2025 described 11 individuals with monoallelic variants in DENND2B with a shared constellation of features (developmental delay, intellectual disability and psychiatric/behavioral concerns, and episodes of psychosis and/or catatonia); 3/8 were reported to have an ASD diagnosis, and nine of the ten observed patient variants were confirmed to result in loss of DENND2B function in zebrafish.

Molecular Function

This gene was identified by its ability to suppress the tumorigenicity of Hela cells in nude mice. The protein encoded by this gene contains a C-terminal region that shares similarity with the Rab 3 family of small GTP binding proteins. This protein preferentially binds to the SH3 domain of c-Abl kinase, and acts as a regulator of MAPK1/ERK2 kinase, which may contribute to its ability to reduce the tumorigenic phenotype in cells.

External Links

References