Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return
Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return
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DOI：
10.1002/humu.20711
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发表时间：
2008-04-01
期刊：
影响因子：
3.9
通讯作者：
Acquatil, Francesco
中科院分区：
文献类型：
--
作者：
Cinquetti, Raffaella;Badi, Ileana;Acquatil, Francesco
完全性肺静脉回流异常（TAPVR）是一种先天性心脏病，其中肺静脉无法进入左心房，而是流入右心房或其静脉支流之一。虽然TAPVR的遗传基础早已被认识，但迄今为止还没有确定参与这种疾病发病机制的单一基因。我们先前报告了一个TAPVR患者轴承从头10;21平衡易位。在这项工作中，我们克隆了这名患者的两个易位断点，并绘制了ANKRD 1基因，编码心脏转录调节因子，130 kb近端染色体10上的断点。对小鼠胚胎进行的原位杂交分析显示，ANKRD 1在发育中的肺静脉中表达，表明该基因在TAPVR发病机制中可能发挥作用。此外，ANKRD 1表达水平被发现在来自易位携带先证者和第二个独立的散发性TAPVR患者的淋巴母细胞系中高度增加，表明正常ANKRD 1表达模式的破坏与TAPVR相关。最后，在第三个散发性TAPVR患者中发现了ANKRD 1基因的非保守性错义突变。在体外钙蛋白酶介导的降解测定，再加上报告基因分析转染的HeLa细胞，强烈表明，这种突变增强了ANKRD 1/CARP蛋白的稳定性和心脏，特异性心房利钠因子（ANF）启动子后的转录抑制活性。总之，这些结果将ANKRD 1定义为TAPVR发病机制的可能候选基因。
Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect in which the pulmonary veins fail to enter the left atrium and drain instead into the right atrium or one of its venous tributaries. Although a genetic basis for TAPVR has long been recognized, no single gene involved in the pathogenesis of this disease has been identified to date. We previously reported a TAPVR patient bearing a de novo 10;21 balanced translocation. In this work, we cloned both translocation breakpoints from this patient and mapped the ANKRD1 gene, encoding a cardiac transcriptional regulator, 130kb proximally to the breakpoint on chromosome 10. In situ hybridization analysis performed on murine embryos showed ANKRD1 expression in the developing pulmonary veins, suggesting a possible role for this gene in TAPVR pathogenesis. Moreover, ANKRD1 expression levels were found to be highly increased in lymphoblastoid cell lines derived from both the translocation-bearing proband and a second independent sporadic TAPVR patient, suggesting that disruption of the normal ANKRD1 expression pattern is associated with TAPVR. Finally, a nonconservative missense mutation in the ANKRD1 gene was found in a third sporadic TAPVR patient. In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac, specific atrial natriuretic factor (ANF) promoter. Taken together, these results define ANKRD1 as a possible candidate gene for TAPVR pathogenesis.