A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation.
A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation.
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DOI：
10.1161/circgenetics.113.000281
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Kasahara H
中科院分区：
文献类型：
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作者：
Ashraf H;Pradhan L;Chang EI;Terada R;Ryan NJ;Briggs LE;Chowdhury R;Zárate MA;Sugi Y;Nam HJ;Benson DW;Anderson RH;Kasahara H
人类NKX2-5杂合突变具有很高的渗透性，并与各种先天性心脏病相关。相比之下，小鼠Nkx2-5杂合基因敲除的心脏畸形较少，疾病外显率也较低。我们试图研究人类和老鼠基因之间的这种明显的差异。由于NKX2-5同源域(DNA结合域)中的错义突变是最常见的人类突变类型，我们在小鼠敲入模型中复制了这种遗传缺陷。我们通过敲入先前在人类中发现的Nkx2-5同源域错义突变，在129/Sv的遗传背景中产生了一个小鼠模型。该突变位于同源结构域52Arg→Gly(R52G)。所有杂合子新生Nkx2-5+/R52G小鼠都显示出室壁明显的小梁层，即所谓的致密化不全，并伴有各种心脏畸形，包括房室间隔缺陷、三尖瓣埃布斯坦畸形以及膜周和/或肌部室间隔缺陷。此外，与对照Nkx2-5+/−或Nkx2-5+/R52G小鼠相比，P10Nkx2-5+/R52G小鼠表现出房间隔异常，心房间交通和卵圆窝大小显著增加，瓣膜长度缩短。我们的研究结果表明，小鼠Nkx2-5同源域(R52G)的杂合性错义突变是高度渗透性的，并导致多效性心脏效应。因此，与杂合的Nkx2-5基因敲除小鼠相比，杂合敲入的影响与NKX2-5同源域杂合错义突变的人类的研究结果相似。
Heterozygous human mutations of NKX2-5 are highly penetrant and associated with varied congenital heart defects. The heterozygous knockout of murine Nkx2-5, in contrast, manifests less profound cardiac malformations, with low disease penetrance. We sought to study this apparent discrepancy between human and mouse genetics. Since missense mutations in the NKX2-5 homeodomain (DNA binding domain) are the most frequently reported type of human mutation, we replicated this genetic defect in a murine knock-in model. We generated a murine model in a 129/Sv genetic background by knocking-in an Nkx2-5 homeodomain missense mutation previously identified in humans. The mutation was located at homeodomain position 52Arg→Gly (R52G). All the heterozygous neonatal Nkx2-5+/R52G mice demonstrated a prominent trabecular layer in the ventricular wall, so called noncompaction, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein’s malformation of the tricuspid valve, and perimembranous and/or muscular ventricular septal defects. In addition, P10 Nkx2-5+/R52G mice demonstrated atrial septal anomalies, with significant increase in the size of the inter-atrial communication and fossa ovalis, and decrease in the length of the flap valve compared to control Nkx2-5+/+ or Nkx2-5+/− mice. The results of our study demonstrate that heterozygous missense mutation in the murine Nkx2-5 homeodomain (R52G) are highly penetrant, and result in pleiotropic cardiac effects. Thus, in contrast to heterozygous Nkx2-5 knockout mice, the effects of the heterozygous knock-in mimic findings in humans with heterozygous missense mutation in NKX2-5 homeodomain.