Mitral Valve Prolapse Caused by TLL1 Gain-of-Function Mutation

Our genetic and biochemical studies show that a TLL1 gain-of-function mutation, prolonging the half-life of TLL1 active protein in the extracellular matrix, causes autosomal dominant MVP with variable expressivity. TLL1 encodes an extracellular metalloprotease regulating extracellular matrix composition and maintenance. In previous work, heterozygous loss-of-function TLL1 mutations have been shown to cause autosomal dominant atrial septal defects. Our findings enable novel insights into the molecular pathways of valvular physiology and disease, the role of TLL1 in human development, and the differing phenotypes in loss-of-function and gain-of-function mutations of the same gene.