TY - JOUR
T1 - Loss of ADAMTS19 causes progressive non-syndromic heart valve disease
AU - MIBAVA Leducq Consortium principal investigators
AU - Wünnemann, Florian
AU - Ta-Shma, Asaf
AU - Preuss, Christoph
AU - Leclerc, Severine
AU - van Vliet, Patrick Piet
AU - Oneglia, Andrea
AU - Thibeault, Maryse
AU - Nordquist, Emily
AU - Lincoln, Joy
AU - Scharfenberg, Franka
AU - Becker-Pauly, Christoph
AU - Hofmann, Philipp
AU - Hoff, Kirstin
AU - Audain, Enrique
AU - Kramer, Hans Heiner
AU - Makalowski, Wojciech
AU - Nir, Amiram
AU - Gerety, Sebastian S.
AU - Hurles, Matthew
AU - Comes, Johanna
AU - Fournier, Anne
AU - Osinska, Hanna
AU - Robins, Jeffrey
AU - Pucéat, Michel
AU - Dietz, Harry C.
AU - McCallion, Andrew S.
AU - Andelfinger, Gregor
AU - Loeys, Bart L.
AU - Van Laer, Lut
AU - Eriksson, Per
AU - Mohamed, Salah A.
AU - Mertens, Luc
AU - Franco-Cereceda, Anders
AU - Mital, Seema
AU - Elpeleg, Orly
AU - Hitz, Marc Phillip
AU - Andelfinger, Gregor
N1 - Funding Information:
We thank the families who participated in this study for their contribution to this project. A grant-in-aid from the Heart and Stroke Foundation of Canada (no. G-17-0019170) as well as the Leducq Foundation (no. MIBAVA-Leducq 12CVD03) supported this study. Additional funding was provided by Banque Nationale through a Research Excellence Chair in Cardiovascular Genetics to G.A. G.A. was supported by a Senior Research Scholarship from Fonds de Recherche Santé Québec (no. 27335). The authors thank the University of Washington Center for Mendelian Genomics and all contributors to Geno2MP for use of the data included in Geno2MP. The authors thank the gnomAD and the groups who provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org. We thank the Wellcome Sanger Institute Mouse Genetics Project and its funders for providing the mutant mouse line (Adamts19tm4a(EUCOMM)Wtsi). Funding information may be found at the Mouse Resource Portal (www.sanger.ac.uk/mouseportal); associated primary phenotypic information can be obtained from the IMPC (www.mousephenotype.org). We thank J. Huber at the IRIC genomic platform for performing the Illumina sequencing for the Drop-seq libraries and P. Gendron at the IRIC Bioinformatics platform for data demultiplexing. We also thank M. Bertagnolli and A.M. Nuyt for help with and providing equipment for mouse echocardiography. We thank S. L’Espérance, K. Jolibois-Ouellete and D. Deraspe for help in maintaining the mouse colonies. Funding was also provided by the Wellcome Sanger Institute (grant no. WT098051). Additional support was provided by the German Centre for Cardiovascular Research (DZHK), partner sites Berlin and Kiel, and the Competence Network for Congenital Heart Defects and National Register for Congenital Heart Defects: sample collection, sample management and patient follow-up were supported by the Competence Network for Congenital Heart Defects and the National Register for Congenital Heart Defects, which are financially supported by the DZHK. Work in the lab of M.P.H. was financially supported by the DZHK partner side Kiel. This work was further supported by a grant of the German Research Council (Deutsche Forschungsgemeinschaft) no. DFG-HI 1579/2-1 to M.P.H. This research was enabled in part by support provided by Calcul Quebec (https://www. calculquebec.ca/en/) and Compute Canada (www.computecanada.ca).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-019-0536-2
DO - 10.1038/s41588-019-0536-2
M3 - Letter
C2 - 31844321
AN - SCOPUS:85076909295
SN - 1061-4036
VL - 52
SP - 40
EP - 47
JO - Nature genetics
JF - Nature genetics
IS - 1
ER -