ASXL3 truncating patient variants mediate transcriptional gain-of-function and are antisense oligonucleotide-responsive

Truncating ASXL3 variants that, by virtue of their location in the gene body, escape nonsense-mediated decay and Cullin 4-dependent degradation: aberrant protein accumulation, widespread transcriptional dysregulation and altered chromatin accessibility — a gain of function rather than haploinsufficiency.

Truncating variants in ASXL genes are frequent in clonal haematopoiesis and in severe dominant neurodevelopmental syndromes and are usually assumed to be loss-of-function alleles, even though numerous loss-of-function alleles are documented in healthy individuals. The authors show that ASXL3 truncations seen in Bainbridge-Ropers syndrome, by virtue of their distinct location in the gene body, instead mediate gain of function by escaping nonsense-mediated decay and Cullin 4-dependent degradation, resulting in aberrant protein accumulation, widespread transcriptional dysregulation and altered chromatin accessibility. Patient-derived cell lines combined with CRISPR knock-in of patient versus population truncations excluded simple haploinsufficiency, and a broad C-terminal destabilising region explains the 3' clustering of benign truncations. Forced expression of full-length ASXL3 failed to rescue the disease-associated expression signature, whereas antisense oligonucleotides targeting ASXL3 largely normalised it.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A result that disturbs habits: a truncating variant is not synonymous with loss of function, and position within the gene becomes an interpretation parameter in its own right. In practice, the C-terminal destabilising region provides an argument against automatically classifying a 3' ASXL3 truncation as pathogenic, which is directly useful in exome analysis. This is a preprint and the antisense work remains entirely cellular: a convincing mechanistic conclusion, but a still hypothetical therapeutic perspective.

Analysis by Dr Thibaut Benquey