Functional characterization of Adamts19, a novel gene for human heart valve defects

• Applicant: Professor Dr. Marc-Phillip Hitz, Ph.D.
• Subject Area: Cardiac and Vascular Surgery ; Human Genetics ; Pediatric and Adolescent Medicine
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397520201

On a global perspective, defects of the heart valves are one of the most common cardiac abnormalities in humans, with a considerable number of them requiring surgical intervention once in their lifetime. A number of mechanisms have been proposed including developmental, genetic and acquired causes, but for the majority of cases a genetic explanation is still lacking. To identify genetic causes, we have conducted two large genetic screens in singletons and extended multiplex families. We were able to detect a homozygous deletion and a homozygous loss of function mutation in two independent families in ADAMTS19, a novel candidate gene for valvular heart defects. To investigate its role in heart valve development, we designed a transgenic mouse model that reconstitutes the loss of function (LOF) in Adamts19 found in the human pedigrees. Cardiac valves initially form through a process called Endothelial-to-Mesenchymal Transition (EMT) then subsequently elongate and mature during early juvenile life. Expression analysis throughout embryonic and postnatal stages of Adamts19-/- mice discovered an expression in all cardiac valves after valve formation. High resolution, digital echocardiography showed that mice without Adamts19 expression develop dysfunctional aortic valves early in life, reminiscent of the human phenotype. Remarkably, the expression of Adamts19 in the valve was restricted to a specific subpopulation of cardiac cells, the valvular interstitial cells (VIC) and not observed in endothelial cells. Our analysis using proteomics and histology suggests that the presence of Adamts19 is necessary to maintain extracellular matrix remodelling during valve development and its maturation. Not only do the LOF mice fully recapitulate the human phenotype, but they also highlight Adamts19 as a novel marker for VICs to specifically target initial post-EMT processes as well as serve as an important model to understand an ageing valve phenotype in humans.The aim of this application is to characterise not only the phenotypic presentation of Adamts19 LOF, but also analyse known molecular genetic networks, as well as previously unknown molecular processes on the protein and transcriptome level in heart valve tissue and on the single cell level to gain a more detailed understanding of human valve disease.

• DFG Programme: Research Grants