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A syndrome of tricuspid atresia in mice with a targeted mutation of the gene encoding Fog-2

Nature Genetics volume 25, pages 353–356 (2000)Cite this article

Abstract

Tricuspid atresia (TA) is a common form of congenital heart disease, accounting for 1–3% of congenital cardiac disorders1. TA is characterized by the congenital agenesis of the tricuspid valve connecting the right atrium to the right ventricle and both an atrial septal defect (ASD) and a ventricular septal defect2 (VSD). Some patients also have pulmonic stenosis, persistence of a left-sided superior vena cava or transposition of the great arteries. Most cases of TA are sporadic, but familial occurrences with disease in multiple siblings have been reported3,4,5. Gata4 is a zinc-finger transcription factor with a role in early cardiac development. Gata4-deficient mice fail to form a ventral heart tube and die of circulatory failure at embryonic day (E) 8.5 (refs 6,7). Zfpm2 (also known as Fog-2) is a multi-zinc-finger protein that is co-expressed with Gata4 in the developing heart beginning at E8.5 (refs 8–10). Zfpm2 interacts specifically with the N-terminal zinc finger of Gata4 and represses Gata4-dependent transcription8,9,10. Here we use targeted mutagenesis to explore the role of Zfpm2 in normal cardiac development. Zfpm2-deficient mice died of congestive heart failure at E13 with a syndrome of tricuspid atresia that includes an absent tricuspid valve, a large ASD, a VSD, an elongated left ventricular outflow tract, rightward displacement of the aortic valve and pulmonic stenosis. These mice also display hypoplasia of the compact zone of the left ventricle. Our findings indicate the importance of Zfpm2 in the normal looping and septation of the heart and suggest a genetic basis for the syndrome of tricuspid atresia.

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Figure 1: Targeted disruption of Zfpm2.
Figure 2: Phenotypic analysis of Zfpm2−/− mice.
Figure 3: Histological analysis of Zfpm2−/− embryonic heart. Sections from E12.5–13.5 wild-type and Zfpm2−/− embryos stained with haematoxylin and eosin (a–h).
Figure 4: In situ hybridization analysis of Zfpm2−/− heart.

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Acknowledgements

We thank T. Lis for help with the preparation of illustrations; D. Zhang for help with the preparation of histological sections; and R. Van Praagh for help with the review of histological sections from Zfpm2−/− mice. This work was supported in part by grants from the NIH to J.M.L. (HL 54592) and G.S.H. (HL 03667).

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Authors and Affiliations

  1. Department of Medicine, University of Chicago, Chicago, Illinois, USA

    Eric C. Svensson, Cynthia Clendenin, Fang Jiang, Rachel Tufts & Fred B. Dardik

  2. Harvard School of Public Health, Boston, Massachusettts, USA

    Gordon S. Huggins, Hua Lin & Jeffrey M. Leiden

  3. Harvard Medical School, Boston, Massachusettts, USA

    Gordon S. Huggins & Jeffrey M. Leiden

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  1. Eric C. Svensson
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Correspondence to Jeffrey M. Leiden.

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Svensson, E., Huggins, G., Lin, H. et al. A syndrome of tricuspid atresia in mice with a targeted mutation of the gene encoding Fog-2. Nat Genet 25, 353–356 (2000). https://doi.org/10.1038/77146

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