{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:56:22Z","timestamp":1790751382529,"version":"4.1.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Bicuspid aortic valve (BAV) is one of the most common congenital heart defects but its genetic basis remains incompletely defined. Extracellular matrix components play key roles in outflow tract (OFT) and valve development, but their contribution to BAV is not fully established. Following the analysis of a cohort of BAV patients, we identified a family harbouring a rare human ELASTIN (ELN) variant (p.Gln691X). Here, we investigated the pathogenicity of this variant using an in vivo zebrafish model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated a zebrafish elna\/b double knockout (KO) using an RNAless CRISPR Cas9 strategy to avoid genetic compensation. Cardiovascular morphology and function were assessed in mutant embryos. To evaluate pathogenicity of the human ELN p.Gln691X variant, mutant and control embryos were rescued by mRNA injection encoding either WT human ELN or the p.Gln691X variant.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>elna\/b double KO zebrafish exhibited cardiovascular defects including OFT anomalies, reduced stroke volume and dysmorphic aortic valves, highlighting Elastin's critical role in cardiac development. We then used this model to test the ELN variant identified in the BAV family. We found that wild-type ELN mRNA was able to restore normal cardiac function and morphology, whereas the variant ELN mRNA failed to do so.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our study establishes a robust in vivo model to assess ELN variant pathogenicity and provides evidence linking ELASTIN to BAV, opening new avenues for uncovering the genetic mechanisms underlying BAV.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1851376","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:06:50Z","timestamp":1790748410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathogenicity assessment of a bicuspid aortic valve\u2013associated ELASTIN variant using a zebrafish model"],"prefix":"10.3389","volume":"13","author":[{"given":"Victor G.","family":"Bernard","sequence":"first","affiliation":[{"name":"IGF, Univ Montpellier, CNRS, INSERM","place":["Montpellier, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Th\u00e9ron","sequence":"additional","affiliation":[{"name":"Aix Marseille University, INSERM, Marseille Medical Genetics (MMG)","place":["Marseille, France"]},{"name":"Service de Chirurgie Cardio-Thoracique, AP-HM, H\u00f4pital de la Timone","place":["Marseille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien","family":"Drouard","sequence":"additional","affiliation":[{"name":"IGF, Univ Montpellier, CNRS, INSERM","place":["Montpellier, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Avierinos","sequence":"additional","affiliation":[{"name":"Aix Marseille University, INSERM, Marseille Medical Genetics (MMG)","place":["Marseille, France"]},{"name":"Service de Cardiologie, AP-HM, H\u00f4pital de la Timone","place":["Marseille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Jopling","sequence":"additional","affiliation":[{"name":"IGF, Univ Montpellier, CNRS, INSERM","place":["Montpellier, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Zaffran","sequence":"additional","affiliation":[{"name":"Aix Marseille University, INSERM, Marseille Medical Genetics (MMG)","place":["Marseille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ad\u00e8le","family":"Faucherre","sequence":"additional","affiliation":[{"name":"IGF, Univ Montpellier, CNRS, INSERM","place":["Montpellier, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.1016\/j.jacc.2009.12.068","article-title":"Bicuspid aortic valve disease","volume":"55","author":"Siu","year":"2010","journal-title":"J Am Coll Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1161\/CIRCGENETICS.112.962894","article-title":"Genetic basis of familial valvular heart disease","volume":"5","author":"Padang","year":"2012","journal-title":"Circ Cardiovasc Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"926975","DOI":"10.1155\/2012\/926975","article-title":"Bicuspid aortic valve and thoracic aortic aneurysm: three patient populations, two disease phenotypes, and one shared genotype","volume":"2012","author":"Hinton","year":"2012","journal-title":"Cardiol Res Pract"},{"key":"B4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev-physiol-012110-142145","article-title":"Heart valve structure and function in development and disease","volume":"73","author":"Hinton","year":"2011","journal-title":"Annu Rev Physiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.1024049","article-title":"Perspectives on pediatric congenital aortic valve stenosis: extracellular matrix proteins, post translational modifications, and proteomic strategies","volume":"9","author":"Clift","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.matbio.2004.03.005","article-title":"Comparative study of cellular and extracellular matrix composition of native and tissue engineered heart valves","volume":"23","author":"Schenke-Layland","year":"2004","journal-title":"Matrix Biol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1161\/CIRCGENETICS.112.962860","article-title":"Supravalvular aortic stenosis: elastin arteriopathy","volume":"5","author":"Merla","year":"2012","journal-title":"Circ Cardiovasc Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"C875","DOI":"10.1152\/ajpcell.00448.2021","article-title":"Elastin, arterial mechanics, and stenosis","volume":"322","author":"Lin","year":"2022","journal-title":"Am J Physiol-Cell Physiol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/1750-1172-8-36","article-title":"Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity","volume":"8","author":"Hadj-Rabia","year":"2013","journal-title":"Orphanet J Rare Dis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1161\/CIRCRESAHA.110.221358","article-title":"Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model","volume":"107","author":"Hinton","year":"2010","journal-title":"Circ Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1111\/j.1749-6632.1990.tb13201.x","article-title":"Elastogenic cells in the developing cardiovascular system: smooth muscle nonmuscle cardiac neural crest","volume":"588","author":"Rosenquist","year":"1990","journal-title":"Ann N Y Acad Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.yjmcc.2020.03.013","article-title":"Piezo1 is required for outflow tract and aortic valve development","volume":"143","author":"Faucherre","year":"2020","journal-title":"J Mol Cell Cardiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s10554-021-02366-1","article-title":"Clinical insights into a tertiary care center cohort of patients with bicuspid aortic valve","volume":"38","author":"Th\u00e9ron","year":"2022","journal-title":"Int J Cardiovasc Imaging"},{"key":"B14","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.diff.2012.05.005","article-title":"Zebrafish models in cardiac development and congenital heart birth defects","volume":"84","author":"Tu","year":"2012","journal-title":"Differ Res Biol Divers"},{"key":"B15","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e319","DOI":"10.1002\/ctm2.319","article-title":"Deciphering DSC2 arrhythmogenic cardiomyopathy electrical instability: from ion channels to ECG and tailored drug therapy","volume":"11","author":"Moreau","year":"2021","journal-title":"Clin Transl Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1038\/s41467-023-37110-x","article-title":"Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish","volume":"14","author":"Odelin","year":"2023","journal-title":"Nat Commun"},{"key":"B18","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1161\/CIRCGEN.122.003881","article-title":"Biallelic PRKAG2 truncating variants are associated with severe neonatal cardiomyopathies","volume":"16","author":"Janin","year":"2023","journal-title":"Circ Genomic Precis Med"},{"key":"B19","doi-asserted-by":"publisher","first-page":"W545","DOI":"10.1093\/nar\/gky471","article-title":"VarAFT: a variant annotation and filtration system for human next generation sequencing data","volume":"46","author":"Desvignes","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1177\/0023677219869037","article-title":"Zebrafish: housing and husbandry recommendations","volume":"54","author":"Alestr\u00f6m","year":"2020","journal-title":"Lab Anim"},{"key":"B21","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/nprot.2007.514","article-title":"High-resolution in situ hybridization to whole-mount zebrafish embryos","volume":"3","author":"Thisse","year":"2008","journal-title":"Nat Protoc"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e59683","DOI":"10.7554\/eLife.59683","article-title":"A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes","volume":"10","author":"Kroll","year":"2021","journal-title":"eLife"},{"key":"B23","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.devcel.2019.10.004","article-title":"Highly efficient CRISPR-Cas9-based methods for generating deletion mutations and F0 embryos that lack gene function in zebrafish","volume":"51","author":"Hoshijima","year":"2019","journal-title":"Dev Cell"},{"key":"B24","first-page":"76","article-title":"Shikata\u2019s orcein stain - A routine stain for liver biopsies","volume":"4","author":"Henwood","year":"1983","journal-title":"Aust J Med Lab Sci"},{"key":"B25","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1093\/ejcts\/ezab038","article-title":"International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes","volume":"60","author":"Michelena","year":"2021","journal-title":"Eur J Cardio-Thorac Surg Off J Eur Assoc Cardio-Thorac Surg"},{"key":"B26","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1002\/humu.22965","article-title":"UMD-predictor: a high-throughput sequencing compliant system for pathogenicity prediction of any human cDNA substitution","volume":"37","author":"Salgado","year":"2016","journal-title":"Hum Mutat"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.3390\/cells12101436","article-title":"Characterization of the zebrafish elastin a (elnasa12235) mutant: a new model of elastinopathy leading to heart valve defects","volume":"12","author":"Hoareau","year":"2023","journal-title":"Cells"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1851376\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:06:52Z","timestamp":1790748412000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2026.1851376\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":27,"alternative-id":["10.3389\/fcvm.2026.1851376"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2026.1851376","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"article-number":"1851376"}}