{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:11:39Z","timestamp":1792645899518,"version":"4.5.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2008,9,26]]},"abstract":"<jats:p>\n            Congenital heart diseases are traditionally considered to be multifactorial in pathogenesis resulting from environmental and genetic interactions that determine penetrance and expressivity within a genetically predisposed family. Recent evidence suggests that genetic contributions have been significantly underestimated. However, single gene defects occur only in a minority of cases, and multigenetic causes of congenital heart diseases have not been fully demonstrated. Here, we show that interactions between alleles of 3\n            <jats:italic>Pbx<\/jats:italic>\n            genes, which encode homeodomain transcription factors, are sufficient to determine the phenotypic presentation of congenital heart diseases in mice. A major role is served by\n            <jats:italic>Pbx1<\/jats:italic>\n            , whose inactivation results in persistent truncus arteriosus. Reduction or absence of\n            <jats:italic>Pbx2 or Pbx3<\/jats:italic>\n            leads to\n            <jats:italic>Pbx1<\/jats:italic>\n            haploinsufficiency and specific malformations that resemble tetralogy of Fallot, overriding aorta with ventricular septal defect, and bicuspid aortic valves. Disruption of\n            <jats:italic>Meis1<\/jats:italic>\n            , which encodes a Pbx DNA-binding partner, results in cardiac anomalies that resemble those caused by\n            <jats:italic>Pbx<\/jats:italic>\n            mutations. Each of the observed cardiac defects represents developmental abnormalities affecting distinct stages of cardiac outflow tract development and corresponds to specific types of human congenital heart disease. Thus, varied deficiencies in the\n            <jats:italic>Pbx<\/jats:italic>\n            gene family produce a full spectrum of cardiac defects involving the outflow tract, providing a framework for determining multigenetic causes of congenital heart anomalies.\n          <\/jats:p>","DOI":"10.1161\/circresaha.108.175489","type":"journal-article","created":{"date-parts":[[2008,8,22]],"date-time":"2008-08-22T02:18:33Z","timestamp":1219371513000},"page":"702-709","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":151,"title":["Pbx\/Meis Deficiencies Demonstrate Multigenetic Origins of Congenital Heart Disease"],"prefix":"10.1161","volume":"103","author":[{"given":"Kryn","family":"Stankunas","sequence":"first","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching","family":"Shang","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen Y.","family":"Twu","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Chu","family":"Kao","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy A.","family":"Jenkins","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal G.","family":"Copeland","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrinmoy","family":"Sanyal","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Licia","family":"Selleri","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Cleary","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Pin","family":"Chang","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Medicine (K.S., C.S., K.Y.T., S.-C.K., C.-P.C.), Department of Medicine; and Department of Pathology (M.S., M.L.C.), Stanford University School of Medicine, Calif; Institute of Molecular and Cell Biology (N.A.J., N.G.C.), Singapore; and Department of Cell and Developmental Biology (L.S.), Cornell University Weill Medical School, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.183056"},{"key":"e_1_3_3_2_2","unstructured":"Sandler T. Langman\u2019s Medical Embryology. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200002033420507"},{"key":"e_1_3_3_4_2","doi-asserted-by":"crossref","unstructured":"Kirby ML. Cardiac Development. New York: Oxford University Press; 2007.","DOI":"10.1093\/oso\/9780195178197.001.0001"},{"key":"e_1_3_3_5_2","unstructured":"Rudolph AM. Congenital Diseases of the Heart: Clinical-Physiological Considerations. 2 ed. 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