Journal Article

Loss of ADAMTS19 causes progressive non-syndromic heart valve disease

Wünnemann, Florian, Thibeault, Maryse, Ta-Shma, Asaf, Lincoln, Joy, Hofmann, Philipp, van Vliet, Patrick Piet, Audain, Enrique, Elpeleg, Orly, Pucéat, Michel, Nir, Amiram, Fournier, Anne, Kramer, Hans-Heiner, Comes, Johanna, Osinska, Hanna, Leclerc, Severine, Hurles, Matthew, Andelfinger, Gregor, Makalowski, Wojciech, Scharfenberg, Franka, Nordquist, Emily, Becker-Pauly, Christoph, Gerety, Sebastian S., Oneglia, Andrea, Hoff, Kirstin, Robins, Jeffrey, Preuss, Christoph, Hitz, Marc-Phillip

2020

Overview

Valvular heart disease is observed in approximately 2% of the general population 1 . Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease 2 – 7 . Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt–Adamts19–Klf2 axis is required for proper valve maturation and maintenance. Mutations in ADAMTS19 lead to progressive heart valve disease in humans. Analysis of mice lacking Adamts19 highlights the role of a Wnt–Adamts19–Klf2 axis in proper valve function.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/28 / 13/51 / 45/23 / 45/91 / 631/1647/2163 / 631/208 / 631/208/1516 / 64/60 / 692/699/75/591 / ADAMTS Proteins - genetics / ADAMTS Proteins - metabolism / Agriculture / Animal Genetics and Genomics / Animals / Aorta / Aortic valve / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiovascular disease / Cardiovascular diseases / Collagen / Coronary artery disease / Families & family life / Family / Female / Gene expression / Gene Expression Regulation, Developmental / Gene Function / Gene sequencing / Genes / Genotype & phenotype / Heart / Heart diseases / Heart Valve Diseases - etiology / Heart Valve Diseases - pathology / Heart valves / Hemodynamics / Homeostasis / Human Genetics / Humans / Interstitial cells / Krueppel-like factor / Kruppel-Like Transcription Factors - genetics / Kruppel-Like Transcription Factors - metabolism / Letter / Life Sciences / Male / Mice / Mice, Knockout / Mitral valve / Mutation / Pedigree / Perturbation / Phenotypes / Rheumatic heart disease / Ribonucleic acid / RNA / RNA sequencing / Rodents / Signal transduction / Single-Cell Analysis / Surgery / Wnt protein / Wnt Signaling Pathway