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).

Genetics and Genetic Testing in Congenital Heart Disease

“…The resulting web of interactions supports a highly complex milieu in which individual or multiple risk factors can act to disrupt normal heart morphogenesis. An ideal example is provided by the cardiac transcription factor, Nkx2.5, which has key functions in regulating proliferation of SHF cells through repression of Bmp2 signaling 30 and in conduction system development 31 . Nkx2.5 also physically and functionally interacts with the major cardiac transcription factors Gata4 32 , Tbx5 33 , and Mef2c 34 , each of which forms additional unique and shared connections with other molecular, genetic, and signaling components ( Figure 1).…”

A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype?

“…Two mouse models have helped to understand the molecular basis of the cardiac defects observed in patients carrying CSX/NKX2-5 mutations. 13,14 In heterozygous Csx/ Nkx2-5 knockout (KO) mice, the number of cells in the cardiac conduction system is directly related to Csx/Nkx2-5 gene dosage, and it was stipulated that the specific functional defects associated with Csx/Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system. Mice homozygous for a ventricular restricted KO of Csx/Nkx2-5 actually displayed no structural defects, yet had a massive overgrowth of trabecular muscle and progressive complete heart block owing to hypoplastic AV node at birth.…”

Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression

“…Studies have uncovered that several transcription factors, including TBX5, NKX2.5, GATA4, and SALL4, cooperate to direct the cardiac cell lineage commitment and/or morphogenesis through the regulation of proteins characteristic of cardiomyocytes and that mutations in these transcription factors are responsible for many cases of CHD (3)(4)(5)(6)(7). Recent data have also suggested the significant roles of these transcription factors for maintenance of the functional heart in postnatal life as well (8)(9)(10)(11)(12). In the past decade, zebrafish (Danio rerio) has emerged as a valuable model system to study many developmental processes, including heart development, and a number of important insights have been gained from analyses of zebrafish mutants (13)(14)(15)(16)(17).…”