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We identified a familial form of isolated ASDII that affects four individuals in a family of five and shows autosomal dominant inheritance. By whole genome sequencing, we discovered a new mutation (c.*1784T\u2009&gt;\u2009C) in the 3\u2032-untranslated region (3\u2032UTR) of <jats:italic>ACTC1<\/jats:italic>, which encodes the predominant actin in the embryonic heart. Further analysis demonstrated that the c.*1784T\u2009&gt;\u2009C mutation results in a new target site for miRNA-139-5p, a microRNA that is involved in cell migration, invasion, and proliferation. Functional analysis demonstrated that the c.*1784T\u2009&gt;\u2009C mutation specifically downregulates gene expression in a luciferase assay. Additionally, miR-139-5p mimic causes further decrease, whereas miR-139-5p inhibitor can dramatically rescue the decline in gene expression caused by this mutation. These findings suggest that the familial ASDII may be a result of an <jats:italic>ACTC1<\/jats:italic> 3\u2032UTR gain-of-function mutation caused by the introduction of a new miR-139-5p target site. Our results provide the first evidence of a pathogenic mutation in the <jats:italic>ACTC1<\/jats:italic> 3\u2032UTR that may be associated with familial isolated ASDII.<\/jats:p>","DOI":"10.1038\/srep25404","type":"journal-article","created":{"date-parts":[[2016,5,3]],"date-time":"2016-05-03T09:13:42Z","timestamp":1462266822000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A gain-of-function ACTC1 3\u2032UTR mutation that introduces a miR-139-5p target site may be associated with a dominant familial atrial septal defect"],"prefix":"10.1038","volume":"6","author":[{"given":"Ye","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaiwei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lincai","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifa","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,3]]},"reference":[{"key":"BFsrep25404_CR1","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1001\/jama.2011.12","volume":"305","author":"P Sullivan","year":"2011","unstructured":"Sullivan, P. & Goldmann, D. 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