Truncated ASXL3 Alters Chromatin Accessibility and Epigenetic Landscape in Bainbridge-Ropers Syndrome Suggesting a Gain-of-Function Etiology

Bainbridge-Ropers syndrome (BRS) is a rare neurodevelopmental disorder caused by mutations in the ASXL3 gene, which regulates epigenetic processes. Research using patient-derived cells and mouse models showed that some pathogenic ASXL3 variants escape natural protein degradation (NMD), leading to accumulation of truncated proteins and widespread epigenetic changes. These changes include increased chromatin accessibility and global DNA hypomethylation, particularly at promoter regions and imprinted loci. A mouse model carrying an ASXL3 mutation corresponding to one found in BRS patients reproduced the molecular features observed in patient cells, including NMD escape and dysregulation related to Polycomb Repressive Complex 2 (PRC2). In contrast, mice with heterozygous ASXL3 knockout showed no phenotype, suggesting that truncated ASXL3 acts through a dominant-negative mechanism. The research also demonstrated that antisense oligonucleotides (ASO) targeting the mutated allele partially restored the proteomic profile in patient cells, suggesting a potential therapeutic strategy.