SEPTIN7 Deficiency Disrupts Endothelial Integrity and Causes Myxomatous Valve Disease in Juvenile Mice

Myxomatous valve degeneration is a major contributor to adult-onset valvular disease, with congenital valve abnormalities being a predisposing factor. However, the molecular networks that govern heart valve development, particularly postnatal valve maturation, remain poorly understood. This study was designed to investigate the role of GTP‑binding SEPTIN proteins in heart valve formation.

We generated endocardial lineage-specific conditional knockout mouse models targeting Septin2, Septin7, or Septin9. Cardiac phenotypes were assessed using histopathology, immunohistochemistry, and molecular analyses.

Mice lacking Septin2 or Septin9 developed normally without detectable abnormalities. In contrast, Septin7 mutant mice exhibited juvenile lethality due to congestive heart failure caused by severe aortic stenosis. Although valve structure appeared normal at birth, Septin7 mutants progressively developed myxomatous degeneration, characterized by leaflet thickening, extracellular matrix (ECM) disorganization, and inflammatory infiltration. Loss of Septin7 disrupted valvular endothelial integrity, with increased intercellular gaps and reduced expression of cell-cell junction proteins. Mechanistically, Septin7 ablation inhibited endothelial cell proliferation, most likely through upregulation of the cell cycle inhibitor p21.

Altogether, our findings identify a previously unrecognized role of SEPTIN7 in postnatal heart valve maturation and homeostasis, wherein it safeguards endothelial integrity. This discovery provides critical mechanistic insights into the pathogenesis of pediatric myxomatous valve disease.