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

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
 
Final Report Year 2023

Final Report Abstract

Malformations of the heart valves are the most common form of congenital heart defects (CHD) and often require surgical correction. Using large genomic databases, we identified families with heart valve defects (VHD) affected by the loss of function of the ADAMTS19 gene. A subsequently established transgenic mouse model, which can also not produce ADAMTS19 in a manner analogous to humans, showed an identical phenotype in mice. Characterization of this mouse model and the changes found in humans revealed the importance of ADAMTS19 during the development of valvular heart defects (VHD). Thus, the spatiotemporal expression of ADAMTS19 determined that the population of valvular interstitial cells (VICs) is directly involved in the process of disease development. Using single-cell sequencing, it was shown that Adamts19 is a novel and highly specific marker for the VICs and the regulation of this gene is linked to the WNT pathway. The results indicate that ADAMTS19 plays a critical role during valve maturation and growth, and loss of ADAMTS19 leads to non-syndromic heart valve defects. Functional characterization of the ADAMTS19 protein in cell culture experiments revealed the secretion of ADAMTS19 as a protein yet to be processed. The maturation process of ADAMTS19 does appear to be autocatalytic. Cloning and subsequent expression analysis of disease-causing variants identified in humans showed that they (R656*, R653*, and R1180*) are secreted. Identification of a specific peptide target has yet to be successful to date. Possible targets to consider with the current experiments are VTN, HSPG2, COMP, and MFAP4. This association is supported by the significant enrichment of heterozygous variants in patients with VHD and CHD in the genes COMP and VTN. The work performed in this project represents an advance in our understanding of the genetic aetiology of polyvalvular diseases by highlighting a significant influence of a specific cell type on a disease mechanism and illuminating the underlying biochemical processes. The work catalyzes future studies that can expand the disease spectrum to include CHD and elucidate the involvement of newly identified genes in this process. A detailed understanding of the genes/networks involved may lead to developing potential therapeutic strategies.

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