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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 6

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Histopathological analysis of heart failure. (a–f) Heart sections from 3...
Histopathological analysis of heart failure. (a–f) Heart sections from 3- and 5-week-old mice stained with hematoxylin/eosin (a–d) and Masson’s trichrome (e and f). Hematoxylin/eosin–stained sections showed no apparent differences in 3-week-old TG mouse heart (b) and NTG (a). Degenerated cardiomyocytes evidenced by swelling of nucleus and myofibrils (arrows in d) were detected at 5 weeks of age. Intercellular space of TG heart is wider than NTG heart (d). Masson’s trichrome–stained heart sections were obtained from NTG (e) and TG (f). Arrowheads (f) point to interstitial fibrosis (blue). Bars, 50 μm. (g–p) Electron micrographs of the left ventricles from NTG (g, i, k, m, and o) mice and TG (h, j, l, n, and p) at 8 weeks of age. (g and h) Myofibrils of the TG heart were sparsely distributed compared with NTG heart. Sarcomere (i and j) and intercalated discs (k and l) were well-organized in the TG hearts similar to the NTG heart. Mitochondria were swollen and mitochondrial cristae were slightly broken. Mitochondria showed oval structures suggestive of mitochondrial deformation (m and n). The location of electron-dense small vesicles were perinuclear as well as cytoplasmic (p). Bars, 1.66 μm in g and h; 0.97 μm in i–p. (q–t) The longitudinal zones of the intercellular junction occupied by desmosome (arrowheads) and gap junction (arrows) in NTG (q and s) and TG heart (r and t). Higher magnification of gap junction in NTG heart demonstrates three electron-dense lines indicating two membranes contacting at the middle (s). In the TG heart, intercellular contact at the gap junction was barely detected (t). Bars, 0.15 μm.
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