Xuan Chao, Jia Ke-Gang, Wang Bin-Bin, Bai Xiao-Yan, Gao Ge, Yang Qin, Wang Xiu-Li, Liu Xiao-Cheng, Ma Xu, He Guo-Wei
TEDA International Cardiovascular Hospital, Medical College, Nankai University, Tianjin, China.
Genet Test Mol Biomarkers. 2013 May;17(5):390-4. doi: 10.1089/gtmb.2012.0435. Epub 2013 Apr 10.
Ventricular septal defect (VSD) is the most common congenital heart disease (CHD). Genome-wide linkage analysis revealed a potential CHD susceptibility locus in the homeodomain leucine zipper-encoding (HOMEZ) gene in a South Indian population. The present study aimed to identify potential pathogenic mutations for HOMEZ and to provide insights into the etiology of isolated VSD in the Chinese population.
Case-control mutational analysis was performed in 400 patients with isolated VSD and 400 healthy controls. Protein-coding exton of HOMEZ and their flanking sequences were amplified by polymerase chain reaction and sequenced on an ABI3730 Automated Sequencer. CLC workbench software was used to compare the conservatism of the HOMEZ protein with other multiple species. The ExPASy-ProtScale online tool was used to predicate the alignment of the hydrophobic features.
Two novel heterozygous missense mutations (c.116 C>T; c. 630T>A) were identified in HOMEZ gene exon-2. The two mutations lead to alanine to valine substitution at position 39 and serine to arginine at position 210, which are highly conserved among many species. The hydropathicity of the valine and arginine residue at the position 39 and 210 were significantly different from the wild type.
We have identified two novel heterozygous missense mutations in HOMEZ gene exon-2 in isolated VSD patients in the Chinese population and have found that these two mutations resulted in alteration of the hydropathicity of the HOMEZ protein. Therefore, the two missense mutations of the HOMEZ gene are directly linked with the etiology of isolated VSD in the Chinese population.
室间隔缺损（VSD）是最常见的先天性心脏病（CHD）。全基因组连锁分析显示，在一个南印度人群中，同源域亮氨酸拉链编码（HOMEZ）基因存在一个潜在的CHD易感位点。本研究旨在鉴定HOMEZ基因的潜在致病突变，并深入了解中国人群中孤立性VSD的病因。
对400例孤立性VSD患者和400例健康对照进行病例对照突变分析。通过聚合酶链反应扩增HOMEZ基因的蛋白质编码外显子及其侧翼序列，并在ABI3730自动测序仪上进行测序。使用CLC工作台软件比较HOMEZ蛋白与其他多个物种的保守性。使用ExPASy-ProtScale在线工具预测疏水特征的比对。
在HOMEZ基因外显子2中鉴定出两个新的杂合错义突变（c.116 C>T；c.630T>A）。这两个突变导致第39位的丙氨酸被缬氨酸取代，第210位的丝氨酸被精氨酸取代，这些在许多物种中高度保守。第39位和第210位的缬氨酸和精氨酸残基的亲水性与野生型有显著差异。
我们在中国人群中孤立性VSD患者的HOMEZ基因外显子2中鉴定出两个新的杂合错义突变，并发现这两个突变导致HOMEZ蛋白亲水性改变。因此，HOMEZ基因的这两个错义突变与中国人群中孤立性VSD的病因直接相关。
