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Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein
Hideko Kasahara, … , Charles I. Berul, Seigo Izumo
Hideko Kasahara, … , Charles I. Berul, Seigo Izumo
Published July 15, 2001
Citation Information: J Clin Invest. 2001;108(2):189-201. https://doi.org/10.1172/JCI12694.
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Article

Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein

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Abstract

A DNA nonbinding mutant of the NK2 class homeoprotein Nkx2.5 dominantly inhibits cardiogenesis in Xenopus embryos, causing a small heart to develop or blocking heart formation entirely. Recently, ten heterozygous CSX/NKX2.5 homeoprotein mutations were identified in patients with congenital atrioventricular (AV) conduction defects. All four missense mutations identified in the human homeodomain led to markedly reduced DNA binding. To examine the effect of a DNA binding–impaired mutant of mouse Csx/Nkx2.5 in the embryonic heart, we generated transgenic mice expressing one such allele, I183P, under the β-myosin heavy chain promoter. Unexpectedly, transgenic mice were born apparently normal, but the accumulation of Csx/Nkx2.5(I183P) mutant protein in the embryo, neonate, and adult myocardium resulted in progressive and profound cardiac conduction defects and heart failure. P-R prolongation observed at 2 weeks of age rapidly progressed into complete AV block as early as 4 weeks of age. Expression of connexins 40 and 43 was dramatically decreased in the transgenic heart, which may contribute to the conduction defects in the transgenic mice. This transgenic mouse model may be useful in the study of the pathogenesis of cardiac dysfunction associated with CSX/NKX2.5 mutations in humans.

Authors

Hideko Kasahara, Hiroko Wakimoto, Margaret Liu, Colin T. Maguire, Kimber L. Converso, Tetsuo Shioi, Weei-Yuarn Huang, Warren J. Manning, David Paul, Joel Lawitts, Charles I. Berul, Seigo Izumo

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Figure 5

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Reduced expression of connexin 40 in TG heart. (a) Northern blot analysi...
Reduced expression of connexin 40 in TG heart. (a) Northern blot analysis of connexin 40 in neonates (lanes 1 and 2) and mice 3 weeks of age (lanes 3 and 4). Connexin 40 mRNA expression is similar between NTG (lane 1) and TG (lane 2) at the neonatal stage, but was barely detectable in the TG heart at 3 weeks of age (lane 4), compared with the NTG heart (lane 3). RNA was extracted from the whole neonatal heart and from the atria of 3-week-old mice. GAPDH expression is also shown. (b) Western blot of connexin 40 for atria at neonates (lanes 1 and 2), and at 2 weeks (lanes 3 and 4) and 3 weeks of age (lanes 5 and 6). Connexin 40 protein expression in TG atria is markedly reduced at 2 weeks (lane 4) and 3 weeks of age (lane 6). (c–h) Immunofluorescent staining of connexin 40 (FITC) and sarcomeric actinin (rhodamine) on the neonatal heart. Only merged images are shown. Connexin 40 was expressed in atria (c and d), intraventricular septum (IVS; e and f), and Purkinje fiber in the ventricle (g and h). Bars, 300 μm. (i–p) Connexin 40 (FITC) and sarcomeric actinin (rhodamine) staining of 3-week-old NTG (i, k, m, and o) and TG heart (j, l, n, and p). Connexin 40 (FITC) was observed in NTG atrium (arrows) localized in cell-cell junctions, whereas connexin 40 expression in TG atrium was occasionally detectable (j and l). Ventricular expression of connexin 40 (FITC) in NTG heart (m and o) compared with TG heart (n and p). Bars, 50 μm.
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