Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system
Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system
复制标题
DOI：
10.1172/jci200419846
复制
发表时间：
2004-04-01
影响因子：
15.9
通讯作者：
Izumo, S
中科院分区：
文献类型：
--
作者：
Jay, PY;Harris, BS;Izumo, S
心脏转录因子Nkx2-5的杂合突变以未知的机制导致人类房室传导缺陷。我们在KO小鼠中发现，心脏传导系统细胞数量与Nkx2-5基因剂量直接相关。零突变胚胎似乎缺乏房室结原基。在Nkx2-5单倍体功能不全时，传导系统的细胞数量是正常的一半。此外，在Nkx2-5杂合型KO小鼠的房室结中缺失了一整群connexin40(-)/connexin45（+）细胞。与Nkx2-5功能丧失相关的特定功能缺陷可归因于传导系统中相关结构的发育不良。令人惊讶的是，连接蛋白40（浦肯野纤维的主要间隙连接异构体和假定的Nkx2-5靶点）的细胞表达不受影响，这与通过体内测量的his -浦肯野系统正常传导时间一致。Nkx2-5突变中的出生后传导缺陷可能至少部分是由于控制胚胎心肌细胞在传导系统中募集或保留的遗传程序的缺陷造成的。
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.