法洛四联症患儿VANGL2、TGFβ2、PAX3基因的序列、甲基化及表达研究
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摘要
圆锥动脉干畸形是一类复杂型先心病,可以导致新生儿时期出现低氧血症和难以纠正的酸中毒,引起患儿早期死亡。先心病是多基因与环境因素相互作用的结果,遗传因素日益受到重视。VANGL2、TGFβ2和PAX3基因敲除实验动物均出现了圆锥动脉干畸形的表现,因而被认为是圆锥动脉干畸形发病的候选基因。然而,在人类圆锥动脉干畸形与VANGL2、TGFβ2和PAX3基因的研究还非常有限。本课题拟研究法洛四联症患儿的VANGL2、TGFβ2和PAX3等三个基因的外显子区及5’非编码区(5’-UTR区)的基因序列、甲基化水平以及其在右室流出道心肌组织中的mRNA和蛋白表达水平,探讨VANGL2、TGFβ2和PAX3基因与法洛四联症的关系,为深入研究以法洛四联症为代表的圆锥动脉干畸形的发生机制提供依据和基础。
第一部分法洛四联症患儿VANGL2、TGFβ2、PAX3基因序列研究
目的：
探讨法洛四联症患儿VANGL2、TGFβ2、PAX3基因的序列变化,观察这些基因是否为法洛四联症发病的候选易感基因。
方法：
应用PCR技术以及测序方法,对100例法洛四联症患儿、200例心脏结构正常的健康儿童,对VANGL2、TGFβ2和PAX3基因编码区外显子和其上游5’-非编码区前1500bp左右的碱基序列进行测序。对VANGL2、TGFβ2和PAX3基因序列变化与圆锥动脉干畸形的关系进行分析。
结果：
1、VANGL2基因序列分析
检测VANGL2基因的全部编码区外显子序列和第一外显子上游1500bp的5’-UTR区域序列,发现3种多态类型,其中第7外显子的33543位点发现等位基因A、G改变,在第8外显子34641位点等位基因G、A改变位于基因编码区内,未造成编码氨基酸的改变,且在病例组和对照组间无明显统计学差异。5’-UTR区的9010位点存在T、G等位基因改变,在两组间基因型差异具有统计学差异(X2=6.865,P=0.032),认为5’-UTR区9010位点的单核苷酸多态性改变可能与法洛四联症的遗传易感性有关。
2、TGF β2基因序列分析
检测TGF β2基因的全部编码区外显子序列和第一外显子上游1500bp的5’-UTR区域序列,在编码区全部8个外显子区未发现基因序列改变,在5’-UTR区域发现3个多态性位点,其中9126位点等位基因A、C改变和9353位点等位基因A、G改变在病例组和对照组中无明显统计学差异。而9040_9043位点在部分病例组合对照组中出现CTTC片段缺失,且两组间差异具有统计学意义(X2=17.469,P<0.001),考虑5’-UTR区9040_9043位点的多态性改变与法洛四联症的遗传易感性有关,推测CTTC片段的表达可能是法洛四联症的危险因素(OR=3.692,95%CI：1.971-6.917)。
3.PAX3基因序列分析
检测PAX3基因的全部编码区外显子序列和第一外显子上游1500bp的5’-UTR区域序列,在编码区第2外显子的95457位点上所有的病例组和对照组均表现为GG纯合子改变,考虑为中国人群的正常碱基序列。在5’-UTR区域发现病例组有2个多态性位点,其中97596位点表现为G、C等位基因单核苷酸多态性改变,且两组间差异具有统计学差异(X2=4.367,P=0.037),推测该位点多态性可能与法洛四联症的遗传易感性有关；在97632_97655位点发现两组均有部分样本出现12个GT重复片段缺失改变,且两组间差异具有统计学差异(X2=72.0,P<0.001),推测5’-UTR区97632_97655位点多态性改变与法洛四联症的遗传易感性有关,且12个GT重复片段的表达可能是法洛四联症的危险因素(OR=16,95%CI：8.002-31.994)。
在PAX3基因5’-UTR区域发现2个突变位点,其中在100例病例组中,有5例法洛四联症患儿表现有97654_97655位点的一个GT片段缺失改变,1例法洛四联症患儿98064位点出现G>GA的改变,认为是中国人群中法洛四联症患儿的突变位点。
小结：
1、VANGL2基因5’-UTR区9010位点T/G单核苷酸的多态性可能与法洛四联症的遗传易感性有关。
2、TGF β2基因5'-UTR区域9040_9043位点CTTC片段缺失改变与法洛四联症的遗传易感性有关,推测CTTC片段的表达可能是法洛四联症的危险因素。
3、PAX3基因5’-UTR区域97596位点G/C单核苷酸多态性可能与法洛四联症的遗传易感性有关,97632_97655位点12个GT重复片段缺失改变与法洛四联症的遗传易感性有关,该位点12个GT片段的表达可能是法洛四联症的危险因素。
4、PAX3基因5’-UTR区域97654_97655位点的单个GT片段缺失和5’-UTR区域98064位点G>GA的改变是中国人群中法洛四联症患儿的突变位点。
第二部分VANGL2、TGFβ2、PAX3基因在法洛四联症患儿心肌组织中甲基化及表达差异的初步研究
目的：
观察VANGL2、TGFβ2、PAX3基因在法洛四联症患儿心肌组织中甲基化及表达差异,探讨这些基因在法洛四联症发病机制中的作用。
方法：
选取5例法洛四联症患儿右室流出道心肌组织作为研究对象,通过MBD柱层析与甲基化敏感性限制性内切酶联用法(COMPARE-MS)观察VANGL2, TGF β2, PAX3基因在法洛四联症患儿心肌组织中甲基化水平变化；应用real-time PCR和免疫组化的方法检测VANGL2、TGFβ2、PAX3基因在法洛四联症患儿心肌组织中的表达差异。
结果：
1、法洛四联症患儿心肌组织VANGL2、TGFβ2和PAX3基因5’-UTR区甲基化水平较对照组均降低。
2、TGFβ2、PAX3基因mRNA在法洛四联症患儿心肌组织中表达明显高于对照组。VANGL2基因mRNA在在法洛四联症患儿心肌组织中表达明显低于对照组。
3、PAX3蛋白表达水平在法洛四联症患儿心肌组织中明显高于对照组。TGFβ2蛋白在心肌细胞中表达水平在病例组和对照组间差异不明显,但在病例组可见心肌细胞周围的间质组织中有TGF β2蛋白的表达。VANGL2蛋白在病例组心肌细胞中表达水平明显低于对照组。
小结：
1、PAX3和TGFβ2基因的表达升高可能与法洛四联症的发生有关。PAX3和TGFβ2基因甲基化水平降低可能与其表达水平升高有关。
2、VANGL2基因在心肌组织中的低表达可能与法洛四联症的发生有关。VANGL2基因mRNA和蛋白水平低表达可能与该基因甲基化降低有关,但可能还受到其他调控因素的影响。
Congenital heart disease (CHD) is one of the most commonly seen congenital malformations in children, which can severely influence mortality and life quality of children. Conotruncal defect (CTD) is a kind of complex congenital heart disease, it can cause hypoxemia and irreversible acidosis during neonatal period, thus, leads to early death. The pathogenesis of CTD has already been more highlighted. Reciprocity of multi-gene and environment are accepted as the cause of CHD. Tetralogy of Fallot (TOF) is the common conotruncal defects. VANGL2, TGFβ2and PAX3gene knockout animals have appeared in the phenotype of conotruncal defects. Thus, these genes were considered as candidate genes for conotruncal development. Our studies were to investigate the DNA sequence changes and examine the methylation and the expression level of VANGL2, TGFβ2and PAX3genes in patients with TOF. The results will help to illustrate the pathogenesis of conotruncal defects.
Part Ⅰ Sequence changes of VANGL2, TGFβ2, PAX3genes in patients with Tetralogy of Fallot
Objective:
To examine the DNA sequence changes of VANGL2, TGFβ2and PAX3genes with Tetralogy of Fallot, and to observe whether these genes are the susceptibility genes for TOF.
Methods:
A cohort of100pediatric patients with Tetralogy of Fallot was recruited in the study,200normal children were used as control. PCR and genotyping were performed for the detections of DNA changes of VANGL2, TGFβ2and PAX3genes.
Results:
1. Sequence changes of VANGL2
Among all TOF patients, only3single nucleotide changes including33543A>AG in exon7,34641G>GA in exon8and9010T>TG in5'-UTR were found, however all of these3heterozygous changes do not alternate the amino acid of the VANGL2protein. There were no significant differences in allelic frequencies and genotypes frequencies of position33543and34641in coding region between the TOF group and the Control. There were significant differences in allelic frequencies (X2=6.865, P=0.032) of position9010in5'-UTR between the TOF group and the Control.
2. Sequence changes of TGFβ2
No mutations were identified in coding region in all TOF patients. However,3single nucleotide changes including9126A>AC,9353A>AG and9040_9043del CTTC in5'-UTR were found. There were no significant differences in allelic frequencies and genotypes frequencies of position9126and9353between the TOF group and the Control. There were significant differences in allelic frequencies (X2=17.469, P<0.001) of position9040_9043in5'-UTR between the TOF group and the Control.
3. Sequence changes of PAX3
A single nucleotide change AA>GG in the position95457in exon2was detected in all examined people. Two single nucleotide changes including97596G>GC and9763297655del GTGTGTGTGTGTGTGTGTGTGTGT in5'-UTR were found in TOF patients. There were significant differences in allelic frequencies and genotypes frequencies (X2=8.711, P=0.013; X2=4.367, P=0.037) of position97596between the TOF group and the Control. There were significant differences in allelic frequencies (X2=72.0, P<0.001) of position97632_97655in5'-UTR between the TOF group and the Control.
There were5patients with97654_97655del GT and1patients with98064G>GA in5'-UTR in all100TOF patient, which were thought as two pathogenic mutations in5'-UTR in TOF patients.
Conclusions:
1. SNPs at position9010T>TG in5'-UTR of VANGL2is associated with the susceptibility of TOF.
2. SNPs at position9040_9043del CTTC in5'-UTR of TGFβ2is associated with the susceptibility of TOF. CTTC allelic may be susceptible allelic to TOF.
3. SNPs at position97596G>GC and97632_97655del GTGTGTGTGTGTGTGTGTGTGTGT in5'-UTR of PAX3is associated with the susceptibility of TOF. GTGTGTGTGTGTGTGTGTGTGTGT allelic in97632_97655may be susceptible allelic to TOF.
4. Two pathogenic mutations in5'-UTR of PAX3were identified in Chinese TOF patients (97654_97655del GT and98064G>GA).
Part II
Methylation at5'-UTR and expression of VANGL2, TGFβ2, PAX3genes in right ventricular outflow tract myocardium in TOF patients
Objective:
To examine the CpG island methylation and expression of VANGL2, TGFβ2, and PAX3genes in the myocardium of patients with TOF, and to illustrate the roles of these genes in the pathogenesis of TOF.
Methods:
Five pediatric patients with Tetralogy of Fallot was recruited in the study. The CpG island methylation status was detected at5'-UTR of VANGL2, TGFβ2and PAX3genes using COMPARE-MS. The mRNA expression of VANGL2, TGFβ2and PAX3was detected in right ventricular outflow tract myocardium using real-time PCR. The protein expression of VANGL2, TGFβ2and PAX3genes was detected using Immunohistochemistry.
Results:
1. The methylation levels of VANGL2, TGFβ2and PAX3at their5'-UTR CpG island in the TOF group were lower than the control.
2. The mRNA expression of TGFβ2and PAX3in myocardium was significantly higher in the TOF group than that in the control, while the mRNA expression of VANGL2was significantly lower in the TOF group than that in the control.
3. The protein expression of PAX3in myocardium was significantly higher in the TOF group than that in the control. The protein expression of TGFβ2was not changed significantly in the TOF group as compared with the control. However, it was expressed obviously in the mesenchymal tissue surrounding the myocardial cells. The protein expression of VANGL2was significantly lower in the TOF group than that in the control.
Conclusions:
1. The increased expression of TGFβ2, PAX3might be related to the development of TOF, which may be regulated by the lower methylation level of TGFβ2, PAX3genes.
2. The decreased expression of VANGL2might also be related to the development of TOF, which may be related to lower methylation level of the gene, interacting with other pathways.
第一部分法洛四联症患儿VANGL2、TGFβ2、PAX3基因序列研究
目的：
探讨法洛四联症患儿VANGL2、TGFβ2、PAX3基因的序列变化,观察这些基因是否为法洛四联症发病的候选易感基因。
方法：
应用PCR技术以及测序方法,对100例法洛四联症患儿、200例心脏结构正常的健康儿童,对VANGL2、TGFβ2和PAX3基因编码区外显子和其上游5’-非编码区前1500bp左右的碱基序列进行测序。对VANGL2、TGFβ2和PAX3基因序列变化与圆锥动脉干畸形的关系进行分析。
结果：
1、VANGL2基因序列分析
检测VANGL2基因的全部编码区外显子序列和第一外显子上游1500bp的5’-UTR区域序列,发现3种多态类型,其中第7外显子的33543位点发现等位基因A、G改变,在第8外显子34641位点等位基因G、A改变位于基因编码区内,未造成编码氨基酸的改变,且在病例组和对照组间无明显统计学差异。5’-UTR区的9010位点存在T、G等位基因改变,在两组间基因型差异具有统计学差异(X2=6.865,P=0.032),认为5’-UTR区9010位点的单核苷酸多态性改变可能与法洛四联症的遗传易感性有关。
2、TGF β2基因序列分析
检测TGF β2基因的全部编码区外显子序列和第一外显子上游1500bp的5’-UTR区域序列,在编码区全部8个外显子区未发现基因序列改变,在5’-UTR区域发现3个多态性位点,其中9126位点等位基因A、C改变和9353位点等位基因A、G改变在病例组和对照组中无明显统计学差异。而9040_9043位点在部分病例组合对照组中出现CTTC片段缺失,且两组间差异具有统计学意义(X2=17.469,P<0.001),考虑5’-UTR区9040_9043位点的多态性改变与法洛四联症的遗传易感性有关,推测CTTC片段的表达可能是法洛四联症的危险因素(OR=3.692,95%CI：1.971-6.917)。
3.PAX3基因序列分析
检测PAX3基因的全部编码区外显子序列和第一外显子上游1500bp的5’-UTR区域序列,在编码区第2外显子的95457位点上所有的病例组和对照组均表现为GG纯合子改变,考虑为中国人群的正常碱基序列。在5’-UTR区域发现病例组有2个多态性位点,其中97596位点表现为G、C等位基因单核苷酸多态性改变,且两组间差异具有统计学差异(X2=4.367,P=0.037),推测该位点多态性可能与法洛四联症的遗传易感性有关；在97632_97655位点发现两组均有部分样本出现12个GT重复片段缺失改变,且两组间差异具有统计学差异(X2=72.0,P<0.001),推测5’-UTR区97632_97655位点多态性改变与法洛四联症的遗传易感性有关,且12个GT重复片段的表达可能是法洛四联症的危险因素(OR=16,95%CI：8.002-31.994)。
在PAX3基因5’-UTR区域发现2个突变位点,其中在100例病例组中,有5例法洛四联症患儿表现有97654_97655位点的一个GT片段缺失改变,1例法洛四联症患儿98064位点出现G>GA的改变,认为是中国人群中法洛四联症患儿的突变位点。
小结：
1、VANGL2基因5’-UTR区9010位点T/G单核苷酸的多态性可能与法洛四联症的遗传易感性有关。
2、TGF β2基因5'-UTR区域9040_9043位点CTTC片段缺失改变与法洛四联症的遗传易感性有关,推测CTTC片段的表达可能是法洛四联症的危险因素。
3、PAX3基因5’-UTR区域97596位点G/C单核苷酸多态性可能与法洛四联症的遗传易感性有关,97632_97655位点12个GT重复片段缺失改变与法洛四联症的遗传易感性有关,该位点12个GT片段的表达可能是法洛四联症的危险因素。
4、PAX3基因5’-UTR区域97654_97655位点的单个GT片段缺失和5’-UTR区域98064位点G>GA的改变是中国人群中法洛四联症患儿的突变位点。
第二部分VANGL2、TGFβ2、PAX3基因在法洛四联症患儿心肌组织中甲基化及表达差异的初步研究
目的：
观察VANGL2、TGFβ2、PAX3基因在法洛四联症患儿心肌组织中甲基化及表达差异,探讨这些基因在法洛四联症发病机制中的作用。
方法：
选取5例法洛四联症患儿右室流出道心肌组织作为研究对象,通过MBD柱层析与甲基化敏感性限制性内切酶联用法(COMPARE-MS)观察VANGL2, TGF β2, PAX3基因在法洛四联症患儿心肌组织中甲基化水平变化；应用real-time PCR和免疫组化的方法检测VANGL2、TGFβ2、PAX3基因在法洛四联症患儿心肌组织中的表达差异。
结果：
1、法洛四联症患儿心肌组织VANGL2、TGFβ2和PAX3基因5’-UTR区甲基化水平较对照组均降低。
2、TGFβ2、PAX3基因mRNA在法洛四联症患儿心肌组织中表达明显高于对照组。VANGL2基因mRNA在在法洛四联症患儿心肌组织中表达明显低于对照组。
3、PAX3蛋白表达水平在法洛四联症患儿心肌组织中明显高于对照组。TGFβ2蛋白在心肌细胞中表达水平在病例组和对照组间差异不明显,但在病例组可见心肌细胞周围的间质组织中有TGF β2蛋白的表达。VANGL2蛋白在病例组心肌细胞中表达水平明显低于对照组。
小结：
1、PAX3和TGFβ2基因的表达升高可能与法洛四联症的发生有关。PAX3和TGFβ2基因甲基化水平降低可能与其表达水平升高有关。
2、VANGL2基因在心肌组织中的低表达可能与法洛四联症的发生有关。VANGL2基因mRNA和蛋白水平低表达可能与该基因甲基化降低有关,但可能还受到其他调控因素的影响。
Congenital heart disease (CHD) is one of the most commonly seen congenital malformations in children, which can severely influence mortality and life quality of children. Conotruncal defect (CTD) is a kind of complex congenital heart disease, it can cause hypoxemia and irreversible acidosis during neonatal period, thus, leads to early death. The pathogenesis of CTD has already been more highlighted. Reciprocity of multi-gene and environment are accepted as the cause of CHD. Tetralogy of Fallot (TOF) is the common conotruncal defects. VANGL2, TGFβ2and PAX3gene knockout animals have appeared in the phenotype of conotruncal defects. Thus, these genes were considered as candidate genes for conotruncal development. Our studies were to investigate the DNA sequence changes and examine the methylation and the expression level of VANGL2, TGFβ2and PAX3genes in patients with TOF. The results will help to illustrate the pathogenesis of conotruncal defects.
Part Ⅰ Sequence changes of VANGL2, TGFβ2, PAX3genes in patients with Tetralogy of Fallot
Objective:
To examine the DNA sequence changes of VANGL2, TGFβ2and PAX3genes with Tetralogy of Fallot, and to observe whether these genes are the susceptibility genes for TOF.
Methods:
A cohort of100pediatric patients with Tetralogy of Fallot was recruited in the study,200normal children were used as control. PCR and genotyping were performed for the detections of DNA changes of VANGL2, TGFβ2and PAX3genes.
Results:
1. Sequence changes of VANGL2
Among all TOF patients, only3single nucleotide changes including33543A>AG in exon7,34641G>GA in exon8and9010T>TG in5'-UTR were found, however all of these3heterozygous changes do not alternate the amino acid of the VANGL2protein. There were no significant differences in allelic frequencies and genotypes frequencies of position33543and34641in coding region between the TOF group and the Control. There were significant differences in allelic frequencies (X2=6.865, P=0.032) of position9010in5'-UTR between the TOF group and the Control.
2. Sequence changes of TGFβ2
No mutations were identified in coding region in all TOF patients. However,3single nucleotide changes including9126A>AC,9353A>AG and9040_9043del CTTC in5'-UTR were found. There were no significant differences in allelic frequencies and genotypes frequencies of position9126and9353between the TOF group and the Control. There were significant differences in allelic frequencies (X2=17.469, P<0.001) of position9040_9043in5'-UTR between the TOF group and the Control.
3. Sequence changes of PAX3
A single nucleotide change AA>GG in the position95457in exon2was detected in all examined people. Two single nucleotide changes including97596G>GC and9763297655del GTGTGTGTGTGTGTGTGTGTGTGT in5'-UTR were found in TOF patients. There were significant differences in allelic frequencies and genotypes frequencies (X2=8.711, P=0.013; X2=4.367, P=0.037) of position97596between the TOF group and the Control. There were significant differences in allelic frequencies (X2=72.0, P<0.001) of position97632_97655in5'-UTR between the TOF group and the Control.
There were5patients with97654_97655del GT and1patients with98064G>GA in5'-UTR in all100TOF patient, which were thought as two pathogenic mutations in5'-UTR in TOF patients.
Conclusions:
1. SNPs at position9010T>TG in5'-UTR of VANGL2is associated with the susceptibility of TOF.
2. SNPs at position9040_9043del CTTC in5'-UTR of TGFβ2is associated with the susceptibility of TOF. CTTC allelic may be susceptible allelic to TOF.
3. SNPs at position97596G>GC and97632_97655del GTGTGTGTGTGTGTGTGTGTGTGT in5'-UTR of PAX3is associated with the susceptibility of TOF. GTGTGTGTGTGTGTGTGTGTGTGT allelic in97632_97655may be susceptible allelic to TOF.
4. Two pathogenic mutations in5'-UTR of PAX3were identified in Chinese TOF patients (97654_97655del GT and98064G>GA).
Part II
Methylation at5'-UTR and expression of VANGL2, TGFβ2, PAX3genes in right ventricular outflow tract myocardium in TOF patients
Objective:
To examine the CpG island methylation and expression of VANGL2, TGFβ2, and PAX3genes in the myocardium of patients with TOF, and to illustrate the roles of these genes in the pathogenesis of TOF.
Methods:
Five pediatric patients with Tetralogy of Fallot was recruited in the study. The CpG island methylation status was detected at5'-UTR of VANGL2, TGFβ2and PAX3genes using COMPARE-MS. The mRNA expression of VANGL2, TGFβ2and PAX3was detected in right ventricular outflow tract myocardium using real-time PCR. The protein expression of VANGL2, TGFβ2and PAX3genes was detected using Immunohistochemistry.
Results:
1. The methylation levels of VANGL2, TGFβ2and PAX3at their5'-UTR CpG island in the TOF group were lower than the control.
2. The mRNA expression of TGFβ2and PAX3in myocardium was significantly higher in the TOF group than that in the control, while the mRNA expression of VANGL2was significantly lower in the TOF group than that in the control.
3. The protein expression of PAX3in myocardium was significantly higher in the TOF group than that in the control. The protein expression of TGFβ2was not changed significantly in the TOF group as compared with the control. However, it was expressed obviously in the mesenchymal tissue surrounding the myocardial cells. The protein expression of VANGL2was significantly lower in the TOF group than that in the control.
Conclusions:
1. The increased expression of TGFβ2, PAX3might be related to the development of TOF, which may be regulated by the lower methylation level of TGFβ2, PAX3genes.
2. The decreased expression of VANGL2might also be related to the development of TOF, which may be related to lower methylation level of the gene, interacting with other pathways.
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