Truncated ASXL3 alters chromatin accessibility and epigenetic landscape in Bainbridge-Ropers syndrome suggesting a gain-of-function etiology

Several truncating ASXL3 variants escape nonsense-mediated decay, possibly leading to accumulation of a truncated protein exerting a dominant-negative effect, with increased chromatin accessibility and global DNA hypomethylation.

Bainbridge-Ropers syndrome is a rare neurodevelopmental disorder caused by truncating mutations in the epigenetic regulator ASXL3, traditionally considered a haploinsufficiency disorder. Combining patient-derived cell lines and novel mouse models, the authors show that several pathogenic ASXL3 variants escape nonsense-mediated decay, with widespread epigenetic changes and distinct transcriptomic and proteomic profiles, including increased chromatin accessibility and global DNA hypomethylation, particularly at promoters and imprinted loci. A knock-in mouse carrying a mutation corresponding to one diagnosed in a patient recapitulates these molecular features, including escape from nonsense-mediated decay and PRC2-related transcriptomic dysregulation, whereas heterozygous Asxl3 knockout mice and transient knockdown models show no phenotype. Allele-specific antisense oligonucleotides, used in patient-derived cells to downregulate the mutant allele, induced partial recovery of the proteomic profile.

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If the mechanism holds, the consequence is not academic: a truncating ASXL3 variant can no longer be read as ordinary loss of function, and its position — hence whether or not it escapes nonsense-mediated decay — becomes an interpretive criterion. The contrast between the knock-in mouse and the heterozygous knockout mouse is the most convincing argument of the work, but it rests on a single knock-in mutation and the demonstration remains molecular, with no behavioural or neuroanatomical phenotype reported. This is a preprint that has not been peer reviewed, and the allele-specific antisense strategy, tested in patient cells with only partial recovery, is at proof-of-concept stage.

Analysis by Dr Thibaut Benquey