Aberrant Phase Separation of Endothelial MAML1 Causes Congenital Heart Disease by Suppressing Notch Activity.

Aberrant phase separation of MAML1 impairs Notch signaling, causing congenital heart defects in mice and humans, with 3 key variants disrupting MAML1 condensates.

• Why it matters: Understanding how MAML1 dysfunction leads to congenital heart disease fills a critical gap in knowledge about molecular mechanisms underlying this common birth defect, potentially guiding targeted therapies.
• What they did: The study used patient-derived mutations, mouse models, and human heart organoids to investigate MAML1's role, focusing on liquid-liquid phase separation (LLPS) and its regulation by phosphorylation, analyzing cardiac phenotypes and molecular interactions.
• The result: Disruption of MAML1 LLPS due to charge-altering variants or phosphorylation impairs Notch signaling, leading to septal and valvular defects, and establishing MAML1 phase separation as essential for normal cardiac development.