{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:37:22Z","timestamp":1768567042304,"version":"3.49.0"},"posted":{"date-parts":[[2024,3,1]]},"group-title":"Cardiovascular Medicine","reference-count":4,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,1]]},"abstract":"Abstract<\/jats:title>\n \n MTSS1 (metastasis suppressor 1) is an I-BAR protein that regulates cytoskeleton dynamics through interactions with actin, Rac, and actin-associated proteins. In a prior study, we identified genetic variants in a cardiac-specific enhancer upstream of\n MTSS1<\/jats:italic>\n that reduce human left ventricular (LV) MTSS1 expression and associate with protection against dilated cardiomyopathy (DCM). We sought to probe these effects further using population genomics and\n in vivo<\/jats:italic>\n murine models. We crossed\n Mtss1<\/jats:italic>\n \n -\/-<\/jats:italic>\n <\/jats:sup>\n mice with a transgenic (\n Tg<\/jats:italic>\n ) murine model of human DCM caused by the D230N pathogenic mutation in\n Tpm1<\/jats:italic>\n (tropomyosin 1). In females,\n Tg\/Mtss1<\/jats:italic>\n +\/-<\/jats:sup>\n mice had significantly increased LV ejection fraction and reduced LV volumes relative to their\n Tg\/Mtss1<\/jats:italic>\n +\/+<\/jats:sup>\n counterparts, signifying partial rescue of DCM due to\n Mtss1<\/jats:italic>\n haploinsufficiency. No differences were observed in males. To study effects in humans, we fine-mapped the\n MTSS1<\/jats:italic>\n locus with 82 cardiac magnetic resonance (CMR) traits in 22,381 UK Biobank participants.\n MTSS1<\/jats:italic>\n enhancer variants showed interaction with biological sex in their associations with several CMR traits. After stratification by biological sex, associations with CMR traits and colocalization with\n MTSS1<\/jats:italic>\n expression in the Genotype-Tissue Expression (GTEx) Project were observed principally in women and were substantially weaker in men. These findings suggest sex dimorphism in the effects of MTSS1-lowering alleles, and parallel the increased LV ejection fraction and reduced LV volumes observed female\n Tg\/Mtss1<\/jats:italic>\n +\/-<\/jats:sup>\n mice. Together, our findings at the\n MTSS1<\/jats:italic>\n locus suggest a genetic basis for sex dimorphism in cardiac remodeling and motivate sex-specific study of common variants associated with cardiac traits and disease.\n <\/jats:p>","DOI":"10.1101\/2024.02.28.24303451","type":"posted-content","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T22:15:11Z","timestamp":1709331311000},"source":"Crossref","is-referenced-by-count":1,"title":["Sex-Specific Effect of MTSS1 Downregulation on Dilated Cardiomyopathy"],"prefix":"10.64898","author":[{"given":"Dongwook","family":"Choe","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Burke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey A","family":"Brandimarto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid","family":"Marti-Pamies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaime","family":"Yob","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P","family":"Morley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theodore G.","family":"Drivas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharlene","family":"Day","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Damrauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas P","family":"Cappola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024030422400691000_2024.02.28.24303451v1.1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202106081"},{"key":"2024030422400691000_2024.02.28.24303451v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2635-8"},{"key":"2024030422400691000_2024.02.28.24303451v1.3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.037939"},{"key":"2024030422400691000_2024.02.28.24303451v1.4","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.yjmcc.2017.06.001","article-title":"The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy","volume":"108","year":"2017","journal-title":"J Mol Cell Cardiol"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.02.28.24303451","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:53:42Z","timestamp":1768506822000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.02.28.24303451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,1]]},"references-count":4,"URL":"https:\/\/doi.org\/10.1101\/2024.02.28.24303451","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1161\/CIRCULATIONAHA.124.070418","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,3,1]]},"subtype":"preprint"}}