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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.

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References
1.
Cheng G, Litchenberg W, Cole G, Mikawa T, Thompson R, Gourdie R . Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage. Development. 1999; 126(22):5041-9. DOI: 10.1242/dev.126.22.5041. View

2.
Gage P, Suh H, Camper S . Dosage requirement of Pitx2 for development of multiple organs. Development. 1999; 126(20):4643-51. DOI: 10.1242/dev.126.20.4643. View

3.
Litchenberg W, Norman L, Holwell A, Martin K, Hewett K, Gourdie R . The rate and anisotropy of impulse propagation in the postnatal terminal crest are correlated with remodeling of Cx43 gap junction pattern. Cardiovasc Res. 2000; 45(2):379-87. DOI: 10.1016/s0008-6363(99)00363-6. View

4.
Maguire C, Bevilacqua L, Wakimoto H, Gehrmann J, Berul C . Maturational atrioventricular nodal physiology in the mouse. J Cardiovasc Electrophysiol. 2000; 11(5):557-64. DOI: 10.1111/j.1540-8167.2000.tb00009.x. View

5.
Biben C, Weber R, Kesteven S, Stanley E, McDonald L, Elliott D . Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res. 2000; 87(10):888-95. DOI: 10.1161/01.res.87.10.888. View