title: A gain-of-function ACTC1 3'UTR mutation that introduces a miR-139-5p target site may be associated with a dominant familial atrial septal defect.
abstract: The ostium secundum atrial septal defect (ASDII) is the most common type of congenital heart disease and is characterized by a left to right shunting of oxygenated blood caused by incomplete closure of the septum secundum. 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 > C) in the 3'-untranslated region (3'UTR) of ACTC1, which encodes the predominant actin in the embryonic heart. Further analysis demonstrated that the c.*1784T > C 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 > C 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 ACTC1 3'UTR 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 ACTC1 3'UTR that may be associated with familial isolated ASDII.
authors.affiliation: Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Cardiothoracic Surgery Department, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Du
authors.affiliation: Boshi360 Department, WuXi App Tec Co., Ltd., Shanghai, 200131, China.
authors.forename: Zaiwei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.|Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
authors.forename: Lincai
authors.initials: L
authors.lastname: Ye
authors.affiliation: The Cardiothoracic Surgery Department, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.|Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China.
authors.forename: Haifa
authors.initials: H
authors.lastname: Hong
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000199:Actins / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004452:Echocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D000073336:Whole Genome Sequencing
chemical_list: D020413:3' Untranslated Regions; C526913:ACTC1 protein, human; D000199:Actins; C555098:MIRN139 microRNA, human; D035683:MicroRNAs