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(Circulation Research. 2008;103:702.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Pbx/Meis Deficiencies Demonstrate Multigenetic Origins of Congenital Heart Disease

Kryn Stankunas^*, Ching Shang^*, Karen Y. Twu, Shih-Chu Kao, Nancy A. Jenkins, Neal G. Copeland, Mrinmoy Sanyal, Licia Selleri, Michael L. Cleary, Ching-Pin Chang

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.

Correspondence to Ching-Pin Chang, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305. E-mail chingpin{at}stanford.edu

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 Pbx 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 Pbx1, whose inactivation results in persistent truncus arteriosus. Reduction or absence of Pbx2 or Pbx3 leads to Pbx1 haploinsufficiency and specific malformations that resemble tetralogy of Fallot, overriding aorta with ventricular septal defect, and bicuspid aortic valves. Disruption of Meis1, which encodes a Pbx DNA-binding partner, results in cardiac anomalies that resemble those caused by Pbx 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 Pbx gene family produce a full spectrum of cardiac defects involving the outflow tract, providing a framework for determining multigenetic causes of congenital heart anomalies.

Key Words: Pbx • Meis • Hox • heart development • congenital heart disease

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