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We identified a heterozygous missense variant p.L245P in the<jats:italic>MMP10<\/jats:italic>gene in two families with premature myocardial infarction using whole-exome sequencing. The aim of this study was to investigate the consequences of this variant using in-silico and functional in-vitro assays. Molecular dynamics simulations were used to analyze protein interactions, calculate free binding energy, and measure the volume of the substrate-binding cleft of MMP10-TIMP1 models. The p.L245P variant showed an altered protein surface, different intra- and intermolecular interactions of MMP10-TIMP1, a lower total free binding energy between MMP10-TIMP1, and a volume-minimized substrate-binding cleft of MMP10 compared to the wild-type. For the functional assays, human THP-1 cells were transfected with plasmids containing<jats:italic>MMP10<\/jats:italic>cDNA carrying the p.L245P and wild-type variant and differentiated into macrophages. Macrophage adhesion and migration assays were then conducted, and pro-inflammatory chemokine levels were evaluated. The p.L245P variant led to macrophages that were more adherent, less migratory, and secreted higher levels of the pro-inflammatory chemokines CXCL1 and CXCL8 than wild-type macrophages. Thus, the p.L245P variant in<jats:italic>MMP10<\/jats:italic>may influence the pathogenesis of atherosclerosis in families with premature myocardial infarction by altering protein\u00a0-\u00a0protein interactions, macrophage adhesion and migration, and expression of pro-inflammatory chemokines, which may increase plaque rupture. These results could contribute to the development of selective MMP10 inhibitors and reduce the risk of atherosclerosis in families with a history of premature myocardial infarction.<\/jats:p>","DOI":"10.1038\/s41598-024-62878-3","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T18:24:05Z","timestamp":1716920645000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of a functional missense variant in the matrix metallopeptidase 10 (MMP10) gene in two families with premature myocardial infarction"],"prefix":"10.1038","volume":"14","author":[{"given":"Viktor","family":"Verovenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Tennstedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Kleinecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Kessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heribert","family":"Schunkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette","family":"Erdmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Ensminger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zouhair","family":"Aherrahrou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,28]]},"reference":[{"key":"62878_CR1","unstructured":"The top 10 causes of death. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/the-top-10-causes-of-death (2023)."},{"key":"62878_CR2","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1093\/eurheartj\/ehz425","volume":"41","author":"J Knuuti","year":"2020","unstructured":"Knuuti, J. et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The task force for the diagnosis and management of chronic coronary syndromes of the european society of cardiology (ESC). 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