Nkx2-5 haploinsufficiency in mice results in half the normal number of cells in the cardiac conduction system and the absence of a specific cell population in the atrioventricular node.
Nkx2-5 haploinsufficiency causes anatomic hypoplasia of the cardiac conduction system, providing a mechanistic explanation for atrioventricular conduction defects observed in humans with this mutation.
Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause atrioventricular conduction defects in humans by unknown mechanisms. We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage. Null mutant embryos appear to lack the primordium of the atrioventricular node. In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells. In addition, an entire population of connexin40(-)/connexin45(+) cells is missing in the atrioventricular node of Nkx2-5 heterozygous KO mice. Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system. Surprisingly, the cellular expression of connexin40, the major gap junction isoform of Purkinje fibers and a putative Nkx2-5 target, is unaffected, consistent with normal conduction times through the His-Purkinje system measured in vivo. Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system.
Jay et al. (2004) studied Atrioventricular conduction defects. Nkx2-5 mutation (knockout/haploinsufficiency) vs. Normal gene dosage was evaluated on Number of cells in the cardiac conduction system and anatomic development. Nkx2-5 haploinsufficiency in mice results in half the normal number of cells in the cardiac conduction system and the absence of a specific cell population in the atrioventricular node.
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