Nkx2-5 Mutation Causes Anatomic Hypoplasia of the Cardiac Conduction System

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2004 Apr 16

PMID 15085192

Citations 105

Authors

Patrick Y Jay

Brett S Harris

Colin T Maguire

Antje Buerger

Hiroko Wakimoto

Makoto Tanaka

Sabina Kupershmidt

Dan M Roden

Thomas M Schultheiss

Terrence X OBrien

Robert G Gourdie

Charles I Berul

Seigo Izumo

Affiliations

Soon will be listed here.

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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