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

Mitral valve prolapse (MVP) is a common cardiac valvular anomaly that can be caused by mutations in genes of various biologic pathways. Individuals of 3 generations of a kindred presented with an apparently dominant heredity of isolated MVP.

Clinical evaluation and echocardiography were performed for all complying members of a family (n = 13). Whole exome and genome sequencing data of 2 affected individuals were analyzed, delineating shared heterozygous variants, and then further tested for segregation within the kindred (Sanger sequencing). Tolloid-like 1 (TLL1) enzymatic activity was assayed in media of HEK293 cells transfected with wild-type vs mutant TLL1.

The only heterozygous variant segregating in the affected kindred as expected for dominant heredity of MVP was p.T253A, within the catalytic domain of TLL1. Of 8 heterozygotes, 6 had MVP and 2 had trivial mitral regurgitation. An activity assay in the extracellular media of the HEK293-transfected cells showed that, over time (12 hours), the enzymatic activity of the mutated TLL1 protein was 3.4-fold higher than that of the wild-type.

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.