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

A DNA nonbinding mutant of the NK2 class homeoprotein Nkx2.5 dominantly inh ibits cardiogenesis in Xenopus embryos, causing a small heart to develop or blocking heart formation entirely. Recently, ten heterozygous CSX/NKX2.5 h omeoprotein mutations were identified in patients with congenital atriovent ricular (AV) conduction defects. All four missense mutations identified in the human homeodomain led to markedly reduced DNA binding. To examine the e ffect of a DNA binding-impaired mutant of mouse Csx/Nkx2.5 in the embryonic heart, we generated transgenic mice expressing one such allele, I183P, und er the beta -myosin heavy chain promoter. Unexpectedly, transgenic mice wer e born apparently normal, but the accumulation of Csx/Nkx2.5(I183P) mutant protein in the embryo, neonate, and adult myocardium resulted in progressiv e and profound cardiac conduction defects and heart failure. P-R prolongati on 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 i n the study of the pathogenesis of cardiac dysfunction associated with CSX/ NKX2.5 mutations in humans.