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      Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.

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          Abstract

          Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.

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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          0092-8674
          0092-8674
          Apr 30 2004
          : 117
          : 3
          Affiliations
          [1 ] UCSD Institute of Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
          Article
          S0092867404004052
          10.1016/s0092-8674(04)00405-2
          15109497
          b6811ac0-151c-495f-ba7e-1013972baa98
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