{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:24:27Z","timestamp":1790835867206,"version":"4.1.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Congenital heart disease (CHD) is the most common developmental abnormality, and is the leading noninfectious cause of mortality in neonates. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD. However, CHD exhibits substantial heterogeneity, and the genetic determinants for CHD remain unknown in the overwhelming majority of cases. In the current study, the coding exons and flanking introns of the HAND2 gene, which encodes a basic helix-loop-helix transcription factor essential for normal cardiovascular development, were sequenced in 192 unrelated patients with CHD, and a novel heterozygous mutation, p.S65I, was identified in a patient with congenital ventricular septal defect (VSD). Genetic analysis of the index patient\u2019s pedigree revealed that the mutation was present in all seven affected family members available, but absent in the 13 unaffected family members examined. Besides, in addition to VSD, five of the proband\u2019s close relatives also had pulmonary stenosis (PS), and the proband\u2019s son also had double outlet right ventricle (DORV). The missense mutation, which altered an evolutionarily conserved amino acid, was absent in 300 unrelated, ethnically matched healthy individuals. Biological analyses using a dual-luciferase reporter assay system showed that the mutant HAND2 was associated with significantly diminished transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND2 and GATA4, as well as NKX2.5\u2014two other cardiac core transcriptional factors that have been causally linked to CHD. These findings indicate that HAND2 loss-of-function mutation contributes to human CHD, perhaps via its interaction with GATA4 and NKX2.5.<\/jats:p>","DOI":"10.1534\/g3.115.026518","type":"journal-article","created":{"date-parts":[[2016,3,8]],"date-time":"2016-03-08T02:51:29Z","timestamp":1457405489000},"page":"987-992","source":"Crossref","is-referenced-by-count":52,"title":["A HAND2 Loss-of-Function Mutation Causes Familial Ventricular Septal Defect and Pulmonary Stenosis"],"prefix":"10.1093","volume":"6","author":[{"given":"Yu-Min","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Cardiology, Jing\u2019an District Central Hospital, 200040 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Jing\u2019an District Central Hospital, 200040 Shanghai, China"},{"name":"Department of Cardiology, Jing\u2019an District Central Hospital, 200040 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Biao","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo-Gu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Jia","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Kai","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Yu","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-Min","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ri-Tai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Qing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,4,1]]},"reference":[{"key":"2021042012212814200_bib1","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.ajhg.2014.03.007","article-title":"Rare variants in NR2F2 cause congenital heart defects in humans.","volume":"94","author":"Al Turki","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"2021042012212814200_bib2","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1007\/s00018-013-1430-1","article-title":"Of mice and men: molecular genetics of congenital heart disease.","volume":"71","author":"Andersen","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"2021042012212814200_bib3","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.cca.2011.10.014","article-title":"Two novel HAND1 mutations in Chinese patients with ventricular septal defect.","volume":"413","author":"Cheng","year":"2012","journal-title":"Clin. Chim. Acta"},{"key":"2021042012212814200_bib4","doi-asserted-by":"crossref","first-page":"12604","DOI":"10.1074\/jbc.M200283200","article-title":"The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer.","volume":"2277","author":"Dai","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021042012212814200_bib5","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/S0735-1097(02)01886-7","article-title":"The incidence of congenital heart disease.","volume":"39","author":"Hoffman","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021042012212814200_bib6","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/B978-0-12-387786-4.00008-7","article-title":"Transcription factor pathways and congenital heart disease.","volume":"100","author":"McCulley","year":"2012","journal-title":"Curr. Top. Dev. Biol."},{"key":"2021042012212814200_bib7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1242\/dev.01562","article-title":"The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner.","volume":"132","author":"McFadden","year":"2005","journal-title":"Development"},{"key":"2021042012212814200_bib8","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1161\/CIRCRESAHA.108.180083","article-title":"Cardiac neural crest expression of Hand2 regulates outflow and second heart field development.","volume":"103","author":"Morikawa","year":"2008","journal-title":"Circ. Res."},{"key":"2021042012212814200_bib9","first-page":"e29","article-title":"American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics\u20142015 update: a report from the American Heart Association.","volume":"131","author":"Mozaffarian","year":"2015","journal-title":"Circulation"},{"key":"2021042012212814200_bib10","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1534\/g3.115.019943","article-title":"Genome-wide association study of Down syndrome-associated atrioventricular septal defects.","volume":"5","author":"Ramachandran","year":"2015","journal-title":"G3 (Bethesda)"},{"key":"2021042012212814200_bib11","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1093\/hmg\/ddn027","article-title":"A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts.","volume":"17","author":"Reamon-Buettner","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2021042012212814200_bib12","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1093\/hmg\/ddp305","article-title":"A functional genetic study identifies HAND1 mutations in septation defects of the human heart.","volume":"18","author":"Reamon-Buettner","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2021042012212814200_bib13","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S0167-4781(98)00237-1","article-title":"Molecular cloning of the human HAND2 gene.","volume":"1443","author":"Russell","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"2021042012212814200_bib14","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.3760\/cma.j.issn.0366-6999.2010.13.002","article-title":"Transcription factor HAND2 mutations in sporadic Chinese patients with congenital heart disease.","volume":"123","author":"Shen","year":"2010","journal-title":"Chin. Med. J. (Engl.)"},{"key":"2021042012212814200_bib15","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.3892\/ijmm.2014.1700","article-title":"GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve.","volume":"33","author":"Shi","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"2021042012212814200_bib16","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.ajhg.2012.08.003","article-title":"Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease.","volume":"91","author":"Soemedi","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"2021042012212814200_bib17","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/35025190","article-title":"A genetic blueprint for cardiac development.","volume":"407","author":"Srivastava","year":"2000","journal-title":"Nature"},{"key":"2021042012212814200_bib18","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1126\/science.270.5244.1995","article-title":"A subclass of bHLH proteins required for cardiac morphogenesis.","volume":"270","author":"Srivastava","year":"1995","journal-title":"Science"},{"key":"2021042012212814200_bib19","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/ng0697-154","article-title":"Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND.","volume":"16","author":"Srivastava","year":"1997","journal-title":"Nat. Genet."},{"key":"2021042012212814200_bib20","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1136\/jmedgenet-2013-102100","article-title":"Conotruncal malformations and absent thymus due to a deleterious NKX2\u20136 mutation.","volume":"51","author":"Ta-Shma","year":"2014","journal-title":"J. Med. Genet."},{"key":"2021042012212814200_bib21","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1006\/jmcc.2002.2085","article-title":"The basic-helix-loop-helix transcription factor HAND2 directly regulates transcription of the atrial naturetic peptide gene.","volume":"34","author":"Thattaliyath","year":"2002","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2021042012212814200_bib22","doi-asserted-by":"crossref","first-page":"e95453","DOI":"10.1371\/journal.pone.0095453","article-title":"Functionally significant, rare transcription factor variants in tetralogy of Fallot.","volume":"9","author":"T\u00f6pf","year":"2014","journal-title":"PLoS One"},{"key":"2021042012212814200_bib23","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ydbio.2010.12.023","article-title":"Hand2 function in second heart field progenitors is essential for cardiogenesis.","volume":"351","author":"Tsuchihashi","year":"2011","journal-title":"Dev. Biol."},{"key":"2021042012212814200_bib24","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1016\/j.celrep.2014.11.021","article-title":"Hand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium.","volume":"9","author":"VanDusen","year":"2014","journal-title":"Cell Reports"},{"key":"2021042012212814200_bib25","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/bdra.20796","article-title":"Hand factors as regulators of cardiac morphogenesis and implications for congenital heart defects.","volume":"291","author":"Vincentz","year":"2011","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"2021042012212814200_bib26","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1002\/humu.22688","article-title":"Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease.","volume":"35","author":"Werner","year":"2014","journal-title":"Hum. Mutat."},{"key":"2021042012212814200_bib27","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1242\/dev.127.12.2573","article-title":"The bHLH transcription factor hand2 plays parallel roles in zebrafish heart and pectoral fin development.","volume":"127","author":"Yelon","year":"2000","journal-title":"Development"},{"key":"2021042012212814200_bib28","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1002\/jcb.20225","article-title":"Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C.","volume":"93","author":"Zang","year":"2004","journal-title":"J. Cell. Biochem."}],"container-title":["G3 Genes|Genomes|Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/g3journal\/article-pdf\/6\/4\/987\/37188320\/g3journal0987.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/g3journal\/article-pdf\/6\/4\/987\/37188320\/g3journal0987.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T21:23:11Z","timestamp":1718400191000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/g3journal\/article\/6\/4\/987\/6055616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,1]]},"references-count":28,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2016,4,1]]}},"URL":"https:\/\/doi.org\/10.1534\/g3.115.026518","relation":{},"ISSN":["2160-1836"],"issn-type":[{"value":"2160-1836","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,4,1]]},"published":{"date-parts":[[2016,4,1]]}}}