Aberrant Phase Separation of Endothelial MAML1 Causes Congenital Heart Disease by Suppressing Notch Activity
Authors' conclusion
These findings support MAML1 as a candidate gene for CHD and identify MAML1 LLPS as a critical biophysical determinant of Notch transcriptional output in endocardial cells.
Study context
- Population
- Patients with congenital heart disease (CHD) (clinical cohort); Maml1 Q401K knock-in and endocardium-specific knockout mice; human heart organoids
Methodological detailsknock-in mouse model, endocardium-specific knockout mouse model, CRISPR-edited human heart organoids
- Knock-in mouse model
- Endocardium-specific knockout mouse model
- CRISPR-edited human heart organoids
Main finding
As reported in the abstract
- Rare missense MAML1 variants associated with ventricular septal defects in CHD cohort
- Q401K variant recapitulated key ventricular septal defect-related phenotypes in knock-in mice and human heart organoids
- Endocardium-specific MAML1 knockout (mice) and MAML1 deletion (organoids) caused septal and valvular defects by disrupting Notch-driven endocardial-to-mesenchymal transition
- MAML1 activity depends on liquid-liquid phase separation (LLPS) forming nuclear condensates, required for interaction with NOTCH1 intracellular domain and activation of downstream targets
- Patient-derived variants incl. Q401K are charge-altering mutations in intrinsically disordered region 2 that abrogate LLPS and downregulate Notch signaling
- PKN2 phosphorylates MAML1 at Ser314, destabilising condensates and attenuating Notch transcriptional output
Original publication
Aberrant Phase Separation of Endothelial MAML1 Causes Congenital Heart Disease by Suppressing Notch Activity. Circulation. Published 5 June 2026. doi:10.
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