Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system

Abstract

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. 1130The Nonstandard abbreviations used: AV nodal effective refractory period (AVERP); connexin40 (Cx40); embryonic day (E); interventricular septum (IVS); intracardiac electrogram (IEGM); stimulus (S).

Identification of a new lamin A/C mutation in a chinese family affected with atrioventricular block as the prominent phenotype

“…Mutations in two genes, the cardiac sodium channel gene SCN5A on chromosome 3p21 and a cardiac transcription factor gene NKX2.5 on 5q34, were identified in some patients with cardiac conduction disease [27][28][29] . Thus, we first determined whether the Chinese family was linked to one of these two genes by linkage analysis with markers D3S1277 and D5S400.…”

Biochemical analyses of eight NKX2.5 homeodomain missense mutations causing atrioventricular block and cardiac anomalies

“…However, the possibility that dominant negative effects, modifying alleles or environmental factors contribute to other phenotypes cannot be completely excluded because of the small sample size per mutation. Resolution of these questions will require careful analysis in experimental models permitting tight dosing control of NKX2.5 wild-type and mutant proteins [37,38].…”

Clinical and genetic investigation of pediatric cases of Wolff-Parkinson-White syndrome in Tunisian families

“…Studies in Nkx2-5-deficient mice showed that Nkx2-5 insufficiency perturbs the conduction system during development, resulting in hypoplasia of the atrioventricular node, the His bundle, and the Purkinje system, and that it manifests as a postnatal conduction defect. 21,22 Taking that report into account, and because of the relatively small size of the NKX2-5 gene, mutation screening was performed in 1 patient from each study family. Searching for mutations within the NKX2-5 gene failed to reveal sequence alterations.…”