Faculty Collaboration Database

Loss of ADAMTS19 causes progressive non-syndromic heart valve disease. Nat Genet 2020 Jan;52(1):40-47

Date

12/18/2019

Pubmed ID

31844321

Pubmed Central ID

PMC7197892

DOI

10.1038/s41588-019-0536-2

Scopus ID

2-s2.0-85076909295 (requires institutional sign-in at Scopus site)   40 Citations

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 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.

Author List

Wünnemann F, Ta-Shma A, Preuss C, Leclerc S, van Vliet PP, Oneglia A, Thibeault M, Nordquist E, Lincoln J, Scharfenberg F, Becker-Pauly C, Hofmann P, Hoff K, Audain E, Kramer HH, Makalowski W, Nir A, Gerety SS, Hurles M, Comes J, Fournier A, Osinska H, Robins J, Pucéat M, MIBAVA Leducq Consortium principal investigators, Elpeleg O, Hitz MP, Andelfinger G

Author

Joy Lincoln PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ADAMTS Proteins
Animals
Family
Female
Gene Expression Regulation, Developmental
Heart Valve Diseases
Humans
Kruppel-Like Transcription Factors
Male
Mice
Mice, Knockout
Pedigree
Single-Cell Analysis
Wnt Signaling Pathway