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 disease2,3,4,5,6,7. 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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The data discussed in this publication have been deposited with the NCBI’s Gene Expression Omnibus57 and are accessible through accession number GSE109247. Whole-exome sequencing data are not publicly available due to consent restrictions.
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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).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
A) Copy number variation (CNV) count from ExAC Browser (accessed 2019-01-06, release 0.3.1) for ADAMTS19. One deletion, spanning ADAMTS19 exons 1 to 8 (chr5:128796101-128932362) is detected in one individual that is annotated as being of American ancestry. The count for this deletion is 1 and the deletion therefore likely represents a heterozygous individual having the same exons deleted from ADAMTS19 as observed in Family 1. B) Overview of counts for synonymous, missense and loss of function (LoF) variants, as well as CNVs found in ExAC compared to expected numbers and genome-wide z-scores as calculated by ExAC. Notably, ADAMTS19 has an LoF intolerance score of pLI=0.95, making it a gene extremely intolerant to LoF variation1. CNV image and variant counts extracted and modified from ExAC Browser webpage (http://exac.broadinstitute.org).
Alleles for Adamts19 knockout (Adamts19tm4a(EUCOMM)Wtsi referred to as Adamts19tm4a and Adamts19tm4b) and wild-type mice and the genotyping strategies with primer locations used in this study are shown. Adamts19tm4b were created by crossing Adamts19tm4a mice with CMV-Cre mice (see Methods) to recombine loxP sites and subsequently delete the Neo cassette alongside the critical Adamts19 exon 3. Numbered gray boxes represent coding exons for Adamts19. Forward primers are colored green and reverse primers are colored red. Corresponding primer sequences can be found in Supplementary Table 9. SA = splice acceptor, En2 = En2 exon, IRES = internal ribosomal entry site.
Supplementary Fig. 3 Comparison of ECM architecture between wild-type and Adamts19KO/KO aortic valves at hinges.
Ultrastructural comparison of representative, matched regions of the valve hinges between wildtype (left column) and Adamts19KO/KO mice (right column), with increasing magnification from A, B) 1000x (top row) and C, D) 3000x (middle row) to E, F) 5000x (bottom row). Top row (A,B): in wild-type animals, mesenchymal, chondrocyte-like cells (arrowheads) are uniform in size and shape, embedded in homogenously structured ECM (left). In Adamts19KO/KO animals, these cells have highly divergent cell sizes, surrounded by inhomogeneous ECM. Middle row (C,D): wildtype hinges contain only a very sparse amount of vesicle remnants embedded in ECM (arrowheads). In Adamts19KO/KO animals, we find large amounts of vesicular structures embedded in inhomogeneous ECM (asterisk), as well as accumulations of cellular debris (pound sign). Bottom row (E,F): greater magnification of normal (left) versus disheveled ECM with vesicles and debris. Ultrastructural findings were reproduced for 3 independent, healthy Adamts19+/+ and 3 independent AdamtsKO/KO mice with HVD.
A) Mutant hinges contain unusually thick fibers, which do not exhibit the characteristics of typical collagen or elastin fibers (*), which can be seen at high magnification (10000x). More typically looking elastin fibers are in close proximity (&). Proteoglycans attached to collagen fibrils can be seen (black arrowheads). Cellular debris is present (#). B) Road-like accumulation of extracellular vesicular structures was found in several instances (black arrowheads, 5000x). Ultrastructural findings were reproduced for 3 independent, healthy Adamts19+/+ and 3 independent Adamts19KO/KO mice with HVD.
Immunohistochemistry (IHC) for candidate extracellular matrix proteins for aortic valves from Adamts19KO/KO (B,D,F,H,J) and aged matched wild-type (A,C,E,G,I) mice at 9 months of age. n = 3 mice for each tested protein. Scale bar for all images = 50μM.
A) RNA in-situ hybridization for Adamts19 in the developing mouse embryo at E14.5. Adamts19 mRNA is localized to the ventricular layer of the cerebral cortex and the heart. Eurexpress template ID for Adamts19: T37546. Number in top right corner of each image represents image number (XX) from eurexpress: euxassay_011355_XX B) Magnification of regions indicated in the images above, showing the developing heart and valves. TV: tricuspid valve, PV: pulmonary valve, AOV: aortic valve, MV: mitral valve. All raw images are available from eurexpress.org, under the entry for Adamts19 2.
A,B) Whole mount X-gal staining of E10.5 and E12.5 mouse embryos. A) At E10.5, no positive lacZ staining is observed in the heart region of the embryo but weak staining is observed at regions of cartilage formation (black arrow). B) At E12.5, strong positive lacZ staining is present in the developing bones and joints (black arrow). C) At E12.5, diffuse lacZ staining is present in the heart, specifically in the left ventricle, the left atrium and the regions of the cardiac cushions. LacZ staining was replicated in > 6 independent mice per time point.
A, D) LacZ activity in atria and partially translucent ventricles is detected at P1. All four cardiac valves strongly express lacZ. B, E) At P21, the myocardial wall has thickened, and no staining is observed in the ventricular wall while lacZ activity can still be seen in the atria as well as all four valves. C, F) LacZ activity persists throughout adult stages and is still active at 5 months of age in all valves as well as both atria. Scale bar for P1 = 100 μM, P21 and 5 months = 500μM. LacZ staining was replicated in > 6 independent mice per time point.
A) Violin plots for the number of genes (nGene), number of UMIs (nUMI) and the percentage of mitochondrial encoded genes expressed are shown per all replicates for Adamts19+/+ (+/+) and Adamts19KO/KO (KO/KO) hearts. B) The fraction of cell types per replicate for both genotypes is shown. No difference in relative abundance of cell types is observed between Adamts19+/+ (+/+) and Adamts19KO/KO (KO/KO) mice. Boxplots show the interquartile range (IQR, 25th to 75th percentile) with 50th percentile as solid line. Whiskers represent 1.5 * IQR. N = 7 for Adamts19+/+ and n = 8 for Adamts19KO/KO.
A) Dimensional reduction (UMAP) of single-cell transcriptomes integrated across Adamts19 genotypes reveals cardiac cell types for wildtype (+/+) and knockout cells (KO/KO) at E14.5. B) Dot plot of traditional markers for cardiac cell types alongside computationally identified markers from single-cell transcriptomics data. Expression is shown for cell types in both genotypes Adamts19+/+ (+/+) and Adamts19KO/KO (KO/KO). Color intensity represents relative expression and dot point size the percentage of cells expressing the marker.
A) Spliced reads spanning the exon-intron junction between endogenous exon 2 and 3 of wild-type Adamts19 are readily detected in homozygous wild-type mice but absent in tm4a and tm4b alleles. B) Unspliced reads, mapping to endogenous exon 3 of Adamts19 are quantified. Homozygous wild-type and homozygous tm4a mice have unspliced reads on exon 3, while this exon is deleted in homozygous tm4b mice and thus has no reads in this genotype. C) Spliced reads between the endogenous exon 2 of Adamts19 and the inserted lacZ cassette (En2 exon, IRES, lacZ) with a strong splice acceptor of the En2 gene at the 5’ end of the cassette is shown. Boxplots show the interquartile range (IQR, 25th to 75th percentile) with 50th percentile as solid line. Whiskers represent 1.5 * IQR. D) Expression of Adamts19 and LacZ over all cell types for Adamts19+/+ (WT), tm4a and tm4b (Adamts19KO/KO) single-cell transcriptomes. N = 7 for Adamts19+/+ and n = 8 for Adamts19KO/KO.
Supplementary Fig. 12 Fluorescent RNA in-situ hybridization for Adamts19 and Lef1 in mouse aortic valves at E12.5 and E14.5.
A, A’) RNAscope for Adamts19 at E12.5 shows weak positive staining in the cardiac cushions of the outflow tract. B, B’) Strong positive staining is observed for Adamts19 RNA in the aortic valve mesenchyme at E14.5. C, C’) Lef1 in-situ hybridization on the same slide as Adamts19 shows positive Lef1 staining in the same cells as Adamts19 at E12.5. D, D’) Similar, at E14.5, Lef1 expression is observed in VICs of the aortic valve at E14.5. E - F’) DAPI staining of DNA for corresponding slides A-D’. G-H’) Merged composite images of Adamts19, Lef1 and DAPI staining. RNAscope detects single molecules of RNA and therefore color signals for Adamts19 and Lef1 don’t exactly overlap despite co-expression in the same cells. A’-H’ represent magnified views of areas marked by dashed boxes in 10x images. Histological staining was replicated in 3 independent mice.
A, B) CHIP-seq peaks from Estaras et al. 3 for LEF1 and beta-Catenin in hESC untreated and treated with Wnt3a alongside input control at A) ADAMTS19 and B) AXIN2 proximal promoters. Both ADAMTS19 and AXIN2 show specific binding peaks of beta-Catenin following Wnt3a treatment, indicating WNT responsiveness of both genes and transcriptional activation via LEF1 and the transcriptional co-activator beta-Catenin. C) Relative fold-change of ADAMTS19 and AXIN2 in human in vitro differentiated VICs following treatment with WNT3a and Spondin 3 for 48h. Gene expression was measured using qPCR in biological duplicates. Two independent differentiation and stimulation experiments were performed in total. Dots represent mean of three triplicate replicate qPCR measurements.
Supplementary Fig. 14 Differential expression analysis between Adamts19+/+ and Adamts19KO/KO cells per cell type.
A) Correlation of average expression between wild-type (x-axis) and Adamts19KO/KO cells (y-axis) per cell type. Each dot represents a gene. B) Volcano plots of differentially expressed genes between Adamts19+/+ Adamts19KO/KO cells per cell type. Adamts19 and LacZ are marked in the VIC cell cluster. All genes with an average log fold change of > 0.1 are shown. N = 7 for Adamts19+/+ and n = 8 for Adamts19KO/KO.
Supplementary Figures 1–14, Note and Tables1–4, 9 and 10
Quantitative mouse echocardiography measurements.
Cardiac cell-type marker based on scRNA-seq from E14.5 mouse hearts.
SCENIC predicted regulons that contain Adamts19 as a downstream regulated gene.
Differentially expressed genes between wild-type and Adamts19KO/KO cells for all cell types at E14.5.
Color Doppler mode of left ventricular outflow tract at the level of the aortic valve for individual Family 2:II-4 at 6 years of age. Blood flow through the aortic valve during diastole highlights aortic regurgitation
Color Doppler mode of left ventricular outflow tract at the level of the aortic valve for individual Family 2:II-4 at 9 years of age. Progressive regurgitation and stenosis are observed compared to Vide S1.
Same view as Videos S1 and S2 at 15 years of age. Increas reverse blood flow through the aortic valve in diastole indicates furthe progressive aortic valve regurgitation and disease.
Color Doppler mode of modified ascending aortic view in a 9 month old homozygous Adamts19KO/KO mouse, showing blood flow through the aortic valve. During systole there is marked turbulence in the ascending aorta while aortic regurgitation is visible during diastole by blue backflow into the left ventricle through the aortic valve.
Pulsed-wave Doppler mode of aortic outflow showing aortic regurgitation in a 9 month old homozygous Adamts19KO/KO mouse.
Color Doppler mode of modified ascending aortic view revealing aortic stenosis in a 9 month old homozygous Adamts19KO/KO mouse
Pulsed-wave Doppler acquisition showing strong aortic stenosis with a maximum velocity of up to 3900 mm/s in systole.
Color Doppler of modified ascending aortic view for wild-type mouse at 9 months of age showing normal blood flow without any turbulence or regurgitation at the level of the aortic valve.
Pulsed-wave Doppler of aortic outflow in a 9 month old wild-type mouse without any stenosis or regurgitation.
ECG-gated Kilohertz Visualization (EKV) of short axis view for the aortic valve of a 9 month old homozygous Adamts19KO/KO with severe stenosis highlighting BAV like opening of aortic valve that resembles “fish mouth” opening. Only 2 commissures are visible when valve is closed.
ECG-gated Kilohertz Visualization (EKV) of short axis view for the aortic valve of a 9 month old homozygous Adamts19KO/KO with aortic regurgitation highlighting tricuspid aortic valve with partially fused leaflets. Three commissures are clearly visible when valve is closed but two leaflets appear partially fused as valve opens incompletely.
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Wünnemann, F., Ta-Shma, A., Preuss, C. et al. Loss of ADAMTS19 causes progressive non-syndromic heart valve disease. Nat Genet 52, 40–47 (2020). https://doi.org/10.1038/s41588-019-0536-2