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Researchers investigated Bainbridge-Ropers syndrome (BRS), a rare neurodevelopmental disorder caused by mutations in the ASXL3 gene, previously thought to result from loss of gene function. Using patient cells and mouse models, they discovered that disease-causing mutations produce truncated proteins that escape cellular degradation and cause widespread epigenetic disruption, including altered chromatin accessibility and DNA methylation patterns. The study demonstrates that these truncated proteins act through a dominant-negative mechanism rather than simple loss of function, and shows that allele-specific antisense oligonucleotides can partially reverse the molecular abnormalities in patient cells.
Why it matters
This finding fundamentally changes our understanding of BRS disease mechanism and opens a new therapeutic avenue using allele-specific treatments to silence the mutated gene copy while preserving normal gene function. The approach could be relevant for other genetic disorders previously misclassified as haploinsufficiency conditions.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Bainbridge-Ropers syndrome (BRS) is a rare neurodevelopmental disorder caused by truncating mutations in the epigenetic regulator ASXL3. While traditionally considered a haploinsufficiency disorder, the precise molecular mechanisms driving BRS remain poorly understood. Here, we combine patient-derived cellular lines and novel mouse models to elucidate the molecular function of disease-associated ASXL3 variants. We show that several pathogenic ASXL3 variants escape nonsense-mediated decay (NMD), possibly leading to the accumulation of truncated protein, and widespread epigenetic changes, resulting in distinct transcriptomic and proteomic profiles. These changes include increased chromatin accessibility and global DNA hypomethylation, particularly at promoters and imprinted loci. A knock-in Asxl3 mouse model harboring a mutation corresponding to one diagnosed in BRS-patient recapitulated the molecular features BRS-patient derived cellular model, including the escape from NMD and Polycomb Repressive Complex 2 (PRC2)-related transcriptomic dysregulation. In contrast, heterozygous Asxl3 knockout mice and transient knockdown models showed no phenotype, indicating that truncated ASXL3 that may exert dominant-negative effects rather than simple loss of function. This molecular dissection offers new venues for treatment, including allele-specific Antisense Oligonucleotides (ASO), which were used by us in patient-derived cells to downregulate the expression of the mutated allele, and were able to induce partial recovery of the proteomic profile. Taken together, our results support a dominant-negative mechanism for BRS causing truncating mutations, offering a compelling rationale for allele-specific ASO therapeutic strategy.