Trends Genet. 2026 Mar 31:S0168-9525(26)00038-7. doi: 10.1016/j.tig.2026.02.003. Online ahead of print.
ABSTRACT
The human ASXL gene family consists of ASXL1, ASXL2, and ASXL3, first described as the additional sex combs (Asx) in Drosophila. The encoded proteins scaffold BAP1-mediated histone H2A deubiquitination. ASXL genes are implicated in pre-cancerous, cancerous, and neurodevelopmental conditions. Truncating mutations predominate and were originally predicted to result in protein loss of function (LOF); however, mounting evidence from population genetics and in vitro studies supports gain-of-function (GOF) mechanisms. Sequence analysis suggests that such mechanisms require both escape from nonsense-mediated mRNA decay and removal of a putative C-terminal degron signal within ASXL proteins. We propose GOF as a generalized mechanism for ASXL mutations, resulting in increased protein stability and altered histone modifications, with implications for diagnosis and therapy for these medical conditions.
PMID:41925445 | DOI:10.1016/j.tig.2026.02.003