心房异构患者中NKX2-5和HAND1基因的序列变异。

Sequence variations of NKX2-5 and HAND1 genes in patients with atrial isomerism.

作者信息

Hatemi Ali Can, Güleç Cağrı, Cine Naci, Vural Burçak, Hatırnaz Ozden, Sayitoğlu Müge, Oztunç Funda, Saltık Levent, Kansız Erhan, Erginel Ünaltuna Nihan

机构信息

Department of Cardiovascular Surgery, İstanbul University Cardiology Institute, İstanbul, Turkey.

出版信息

Anadolu Kardiyol Derg. 2011 Jun;11(4):319-28. doi: 10.5152/akd.2011.083. Epub 2011 May 11.

DOI:10.5152/akd.2011.083

PMID:21561848

Abstract

OBJECTIVE

Atrial isomerism is a congenital disorder, which is characterized by lateralization defects in normally asymmetrical developing organs like the heart. Atrial isomerism is supposed to be caused by molecular defects during early development. The NKX2-5 is a cardiac specific transcription factor, which initiates and regulates downstream transcriptional cascades of cardiogenesis. The HAND1 is another transcription factor expressed in the heart, and it is characterized by an asymmetrical pattern of expression. In this study, we aimed to test whether mutations in NKX2-5 and HAND1 genes play a role in the etiology of atrial isomerism.

METHODS

This case-control study consisted of 70 patients who underwent surgical treatment for congenital heart defects including atrial isomerism, 80 healthy subjects (HAND1 gene) and 40 healthy subjects (NKX2-5 gene). All exons and exon-intron boundaries of NKX2-5 and HAND1 genes were analyzed by SSCP, and suspected samples were sequenced for mutation analysis. Digestion with appropriate restriction enzymes was performed for analysis of known mutations and polymorphisms. The frequencies of the alleles and the genotypes were compared among patient and control groups using the Chi-square and the Fisher tests when appropriate.

RESULTS

In intronic region of HAND1 gene, we identified a C>G substitution both in patients and controls. Frequency of mutant allele (11, 42%) was found higher (p=0.046) in patient group than that of the control group (2.5%). Association between atrial isomerism and genotypes with mutant allele was found borderline significant (p=0.054). In NKX2-5 gene, we identified heterozygous Q170X (Gln170ter) mutation in one patient. We did not found any correlation between defined sequence variations and clinical properties of the patients.

CONCLUSION

Our results suggest that mutations or sequence variations in HAND1 or NKX2-5 genes may play role in etiology or pathogenesis of atrial isomerism.

摘要

目的

心房异构是一种先天性疾病，其特征是在心脏等正常不对称发育器官中出现侧向化缺陷。心房异构被认为是由早期发育过程中的分子缺陷引起的。NKX2-5是一种心脏特异性转录因子，它启动并调节心脏发生的下游转录级联反应。HAND1是另一种在心脏中表达的转录因子，其表达模式具有不对称性。在本研究中，我们旨在测试NKX2-5和HAND1基因的突变是否在心房异构的病因中起作用。

方法

本病例对照研究包括70例接受先天性心脏缺陷（包括心房异构）手术治疗的患者、80名健康受试者（HAND1基因）和40名健康受试者（NKX2-5基因）。通过单链构象多态性分析NKX2-5和HAND1基因的所有外显子和外显子-内含子边界，并对疑似样本进行测序以进行突变分析。使用适当的限制性内切酶进行消化以分析已知的突变和多态性。在适当的时候，使用卡方检验和Fisher检验比较患者组和对照组之间的等位基因和基因型频率。

结果

在HAND1基因的内含子区域，我们在患者和对照组中均发现了C>G替换。患者组中突变等位基因的频率（11，42%）高于对照组（2.5%）（p=0.046）。发现心房异构与具有突变等位基因的基因型之间的关联接近显著（p=0.054）。在NKX2-5基因中，我们在一名患者中鉴定出杂合的Q170X（Gln170ter）突变。我们未发现确定的序列变异与患者的临床特征之间存在任何相关性。