The finding that KLF2/4 function prevents MVD by restraining TGF-β signaling is remarkable in light of human and mouse MVD conferred by mutations in FBN1 associated with Marfan syndrome, as well as increased TGF-β/Smad signaling observed in human and canine myxomatous valves that arise in the absence of known Marfan syndrome mutations (7, 12, 13, 37, 50–54). Here, KLF2 is linked to Marfan syndrome.