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Nat Genet. 2020 Jan;52(1):40-47. doi: 10.1038/s41588-019-0536-2. Epub 2019 Dec 16.

Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.

Author information

1
Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, Quebec, Canada.
2
Institute of Bioinformatics, University of Münster, Münster, Germany.
3
Department of Pediatric Cardiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
4
Monique and Jacques Robo Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
5
The Jackson Laboratory, Bar Harbor, ME, USA.
6
LIA (International Associated Laboratory) Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada.
7
LIA (International Associated Laboratory) INSERM, Marseille, France.
8
Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA.
9
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
10
Division of Pediatric Cardiology, Herma Heart Institute, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
11
Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
12
Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Kiel, Germany.
13
German Centre for Cardiovascular Research (DZHK), Kiel, Germany.
14
Wellcome Sanger Institute, Cambridge, UK.
15
Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
16
Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
17
Université Aix-Marseille, INSERM U-1251, Marseille, France.
18
Department of Human Genetics, University Medical Center Schleswig-Holstein, Kiel, Germany.
19
Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, Quebec, Canada. gregor.andelfinger@recherche-ste-justine.qc.ca.
20
Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada. gregor.andelfinger@recherche-ste-justine.qc.ca.
21
Department of Biochemistry, University of Montreal, Montreal, Quebec, Canada. gregor.andelfinger@recherche-ste-justine.qc.ca.

Abstract

Valvular heart disease is observed in approximately 2% of the general population1. 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 disease2-7. 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.

PMID:
31844321
DOI:
10.1038/s41588-019-0536-2

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