CREBBP variants underlying Menke–Hennekam syndrome exhibit histone acetyltransferase hyperactivity with divergent phase behaviors
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Menke–Hennekam syndrome (MKHK) is a neurodevelopmental disease characterized by specific pathogenic regions within the transcriptional coactivator CREB-binding protein ( CREBBP ). CREBBP regulates gene expression through histone acetyltransferase (HAT) activity and involves IDR-dependent transcriptional condensates. Although domain-specific phenotypes and distinct DNA methylation episignatures have been recognized in MKHK, the underlying molecular mechanisms remain widely unclear. In this study, we identified a recurrent missense variant, p.(R1868W) [R1868W] and a novel splice variant r.5963_5969del,p.(Cys1723Thrfs*19) [C1723fs] in two families clinically diagnosed with MKHK and manifesting developmental delay, characteristic facial features, and growth impairment. R1868W and C1723fs exhibited increased auto-, nonhistone protein, and histone acetylation. Despite these shared enzymatic abnormalities, the variants promoted divergent disruption in liquid–liquid phase separation. The recurrent CBP-ID4 variant R1868W activated the formation of low-mobility aberrant nuclear condensates, whereas the C-terminal, truncating variant C1723fs, impaired condensate formation and showed diffuse nuclear localization. Treatment with the selective p300/CBP HAT inhibitor A485 partially restored condensate dynamics and fusion-relaxation behavior in R1868W. Furthermore, R1868W recruited BRD4 around condensates in an acetylation-dependent manner, which was suppressed by the BET inhibitor JQ1. Together, these findings suggest that aberrant condensate material properties arising from disrupted CREBBP IDR-dependent regulation play a critical role in the molecular pathogenesis of MKHK.
Significance Statement
Pathogenic variants in specific regions of the transcriptional coactivator CREBBP underlie the Menke–Hennekam syndrome (MKHK), but its molecular basis is poorly understood. Here, we show that two CREBBP variants responsible for MKHK share a common feature of increased histone acetyltransferase (HAT) activity but disrupt liquid–liquid phase separation in distinct ways. The recurrent CBP-ID4 missense variant R1868W promoted the formation of low-mobility aberrant condensates and acetylation-dependent recruitment of BRD4, as opposed to the C-terminal truncating variant C1723fs. Notably, HAT inhibition restored condensate dynamics in R1868W, suggesting that condensate properties are reversibly regulated by enzymatic activity. These findings reveal a framework linking pathogenic variants affecting CREBBP IDR-dependent regulation to aberrant condensate material properties in MKHK.
