CREBBP variants underlying Menke-Hennekam syndrome exhibit histone acetyltransferase hyperactivity with divergent phase behaviors

In two families with Menke-Hennekam syndrome, CREBBP variants p.(R1868W) and r.5963_5969del,p.(Cys1723Thrfs*19) show increased histone acetylation but divergent effects on IDR-dependent condensate phase behavior.

• Why it matters: Domain-specific phenotypes and DNA methylation episignatures exist for MKHK, yet the molecular mechanisms linking CREBBP dysfunction to transcriptional condensate disruption remain unclear.
• What they did: The study identified p.(R1868W) and C1723fs in MKHK families and measured increased auto-, nonhistone protein, and histone acetylation, then assessed liquid-liquid phase separation and condensate dynamics; A485 and JQ1 were used to test rescue and acetylation/BET dependence.
• The result: R1868W promoted low-mobility aberrant nuclear condensates, while C1723fs impaired condensate formation with diffuse nuclear localization; A485 partially restored R1868W condensate dynamics, and BRD4 recruitment around condensates was acetylation-dependent and suppressed by JQ1.