血管功能药理学以及重大心脏疾病的致病基因和蛋白质组学的研究
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摘要
本论文对常见的三种心脏疾病(冠心病、心脏瓣膜病以及先天性心脏病)的不同方面分别进行了研究。论文第一部分对治疗冠心病的冠状动脉旁路移植外科手术中移植血管的功能进行了药理学研究。第二部分对心脏瓣膜病进行了差异蛋白质组学研究,同时对可能与先天性心脏病相关的PLAGL1基因进行了突变分析的研究。
第一部分血管功能药理学与冠状动脉旁路移植术
研究背景及目的：
移植血管痉挛仍然是冠状动脉旁路移植术中的挑战。临床上钙拮抗剂常用于治疗冠心病患者。本部分我们将对新型第三代二氢吡啶类钙拮抗剂阿折地平在人体内乳动脉中对于血管收缩的抑制效应进行研究。
内皮细胞胞内的钙调节依赖于瞬时受体电位通道(TRPs)。标准型瞬时受体电位离子通道(TRPCs)目前被认为是血管内皮细胞中最重要的钙离子透过性阳离子通道而TRPC3通道被报道在动物动脉中与血管的舒张功能相关。然而,TRPCs在人体动脉中的作用尚不明确。因此我们对科研假说,标准型瞬时受体电位离子通道在人体动脉中发挥作用,进行了验证。
实验方法：
离体的内乳动脉环(n=68,来自28个进行冠状动脉旁路移植术的患者)在myograph上进行两方面研究：阿折地平对KC1和U46619预收缩的内乳动脉的舒张作用以及在正常血药浓度时阿折地平对收缩的抑制作用。
人体内乳动脉环(n=42,来自28个进行冠状动脉旁路移植术的患者)按如下方法在myograph上进行研究：分别作出以U46619(-8log M)预收缩后乙酰胆碱的浓度依赖性舒张曲线,记录在加入SKF96365(10μmol/L)或者Pyr3(3μmol/L)孵育前后曲线的变化。同时利用Western Blot和免疫组化对TRPC3蛋白的表达进行鉴定。
实验结果：
阿折地平能够几乎完全舒张KCl(96.5%±0.7%)或U46619(96.5%±1.4%)预收缩的人体内乳动脉(n=8)且对KCl的敏感性相对U46619更高(EC50：-7.49±0.21vs-6.03±0.11log M,p<0.01)；预孵育阿折地平(-6.1log M)可以有效的抑制KCl(最大收缩值从25.8±2.2mN下降至16.0±1.5mN,p<0.01)或U46619(最大收缩值从30.6±4.0mN下降至16.5±2.2mN,p<0.05)引起的人体内乳动脉收缩。
由乙酰胆碱引起的最大舒张值由于非特异性阳离子通道抑制剂SKF96365(48.2±3.7vs.66.0±0.9%in control,p<0.01)或TRPC3通道特异性抑制剂Pyr3(58.4±2.3%vs.67.7±1.1%in control,p<0.01)而明显减小。同时,在人体内乳动脉中检测到TRPC3通道蛋白的表达。
实验结论：
阿折地平对于不同类型的血管收缩剂在人体内乳动脉中引起的收缩均具有有效的抑制作用。因此,阿折地平应用于冠状动脉旁路移植术患者有望可以有效治疗和预防移植血管的痉挛。
TRPC3通道存在于人体内乳动脉中,并且在乙酰胆碱引起的内皮依赖性舒张作用中发挥功能。本部分研究提示TRPC3可能成为在内皮功能障碍疾病如冠心病中潜在的保护内皮功能以改善移植血管远期通畅率的靶点。
第二部分重大心脏疾病的致病基因和蛋白质组学的研究
研究背景及目的：
心脏瓣膜病的遗传基础和蛋白质组学研究能够为诊断和治疗此类疾病提供重要信息。然而,关于心脏瓣膜病(VHD)包括风湿性(RVD)和退行性心脏瓣膜病(DVD)生物标记物的研究尚不明确。本部分实验意在探索血浆中表达量变化与心脏瓣膜病的病理变化相关的蛋白质。
室间隔缺损(VSD)是最常见的先天性心脏病之一。许多遗传学研究提示PLAGL1基因与先天性心脏病的病因学相关。本部分的研究意在鉴别PLAGL1基因中潜在的致病突变,为单纯性室间隔缺损的病因学研究提供参考。
实验方法：。
采用双向电泳联合质谱的方法对RVD.DVD和正常人群对照组的血浆进行差异蛋白质的检测。同时对找出的差异蛋白中可能与VHD病理变化相关的蛋白质进行ELISA验证。
300例单纯性VSD患者和300例健康人群PLAGL1基因中两个编码蛋白的外显子经PCR扩增后,PCR产物采用ABI公司3730自动测序仪测序。应用CLCworkbench software对PLAGL1蛋白进行多物种氨基酸保守性分析。
实验结果：
双向电泳联合质谱共找出差异蛋白点18个,包括14个蛋白质或者多肽。对两个上调的(补体C4A和碳酸酐酶1)和三个下调的(血清铁传递蛋白、alpha-1抗胰凝乳蛋白酶和波连蛋白)可能与VHD病理变化相关的蛋白质进行ELISA验证。补体C4A在RVD病人血浆中含量(715.8±35.6vs.594.7±28.2ng/ml, n=40,P=0.009)以及碳酸酐酶1在DVD病人血浆中含量(237.70±15.7vs.184.7±10.8U/L,n=40,P=0.007)均较正常对照组显著升高。血清铁传递蛋白在RVD病人血浆中含量(2.36±0.20vs.2.93±0.16mg/ml,n=40,P=0.025)以及alpha-1抗胰凝乳蛋白酶在RVD病人血浆中含量(370.0±13.7vs.413.0±116μg/ml,n=40,P=0.019)较正常对照组显著降低。此外,波连蛋白在RVD病人(281.3±11.0vs.323.2±10.0μg/ml,n=40,P=0.006)和DVD病人(283.6±11.4vs.323.2±10.0μg/ml,n=40,P=0.011)血浆中含量均较正常对照组显著降低。
在PLAGL1基因两个编码蛋白的外显子中未检测到任何错义突变或移码突变,只在编码蛋白的外显子2中检测到一个同义突变(c.486A>G,p.E162E).突变位置的密码子翻译的谷氨酸在与其他物种的比对中显示具有保守性。
实验结论：
补体C4A在RVD病人血浆中含量的上升,碳酸酐酶1在DVD病人血浆中含量的上升,血清铁传递蛋白在RVD病人血浆中含量的下降以及alpha-1抗胰凝乳蛋白酶在RVD病人血浆中含量的下降为VHD提供了可能的生物标记物。同时,与瓣膜形成相关的蛋白——波连蛋白在RVD和DVD病人血浆中含量均降低提示在这些病人中可能存在基因缺陷。
我们在单纯性室间隔缺损患者PLAGL1基因编码蛋白的外显子2中检测出一个同义突变,尽管这个突变并未造成氨基酸的变化,但这个突变仍可能与PLAGL1基因的表达调控相关,比如甲基化作用。
Part-I Pharmacology of vasomotion and coronary artery bypass grafting
Background and Objectives:
Graft spasm remains challenging in coronary artery bypass grafting (CABG) surgery. Calcium antagonists are commonly used in patients with coronary artery disease. We investigated the inhibitory effect of a new third-generation dihydropyridine calcium antagonist azelnidipine on the vasoconstriction in human internal mammary artery (IMA) from patients undergoing CABG.
Intracellular calcium regulation in endothelial cells depends on transient receptor potential channels (TRPs). Canonical TRPs (TRPCs) are now recognized as the most important Ca2+-permeable cation channels in vascular endothelium and TRPC3channel is reported to play a role in vasodilation in animal vessels. However, little is known about the role of TRPCs in the human arteries. We therefore tested the hypothesis that TRPCs plays a role in the human arteries.
Methods:
Isolated IMA rings (n=68, taken from28patients) were studied in myograph in two ways:the relaxing effect of azelnidipine on vasoconstrictor-induced precontraction by KCl and U46619and the depressing effect of azelnidipine at plasma concentrations on the contraction.
Cumulative concentration-relaxation curves to acetylcholine (-11to-4.5log M) were established in the human internal mammary artery (IMA) rings (n=42) taken from28patients undergoing coronary artery bypass grafting in pre-contraction induced by U46619(-8log M) in the absence or presence.of SKF96365(10μmol/L) or Pyr3(3μmol/L). Protein expressions of TRPC3were determined by Western Blot and Immunohistochemistry Staining.
Results:
Azelnidipine caused full relaxation in KCl-contracted (96.5%±0.7%) and in U46619-contracted (96.5%±1.4%) IMA rings (n=8) with28.8-fold higher potency to KC1than to U46619(EC50:-7.49±0.21vs-6.03±0.11log M, p<0.01). Pretreatment of IMA with plasma concentrations of azelnidipine (-6.1log M) significantly depressed subsequent contraction to KCl (from25.8±2.2mN to16.0±1.5mN, p<0.01) and U46619(from30.6±4.0mN to16.5±2.2mN, p<0.05).
The maximal relaxation induced by acetylcholine was significantly attenuated by the non-specific cation channels inhibitor, SKF96365(48.2±3.7vs.66.0±0.9%in control, P<0.01) or the selective TRPC3blocker, Pyr3(58.4±2.3%vs.67.7±1.1%in control, P<0.01). The protein expression of TRPC3was detected in human IMA.
Conclusions:
We conclude that in human IMA azelnidipine has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors. Thus, use of azelnidipine in CABG patients is favored in treating and preventing graft spasm.
TRPC3exists and plays a role in the acetylcholine-induced endothelium-dependent relaxation in the human IMA. This study suggests that TRPC3may have the potential to be a new target in endothelial protection in patients with endothelial dysfunction such as in patients with coronary artery disease in order to improve the long term patency of the grafting vessels.
Part-Ⅱ Genetic and proteomic study on heart disease
Background and Objectives:
The genetic basis and proteomics of common valvular heart disease (VHD) are important to provide information for diagnosis and treatment of these diseases. However, little is known about biomarkers in VHD including rheumatic (RVD) and degenerative (DVD) valvular disease. The present proteomic study examined the hypothesis that certain proteins may be related to the pathological changes in the plasma of VHD.
Ventricular septal defect (VSD) is the most common congenital heart disease (CHD). A number of genetic studies have linked the gene oiPLAGLl to the etiology of CHD. The present study aimed to identify potential pathogenic mutations for PLAGL1and to provide insights into the etiology of isolated VSD.
Methods:
Differential protein analysis was performed in the plasma of patients with RVD, DVD and normal controls by using two-dimensional electrophoresis (2-DE) and mass spectrometry. Candidate proteins that might relate to disease processes were further confirmed by enzyme-linked immunosorbent assays (ELISA) in enlarging samples.
Case-control mutational analysis was performed in300patients with isolated VSD and300healthy controls. Two protein-coding extons of PLAGL1and their partial flanking intron sequences were amplified by polymerase chain reaction and sequenced on an ABI3730Automated Sequencer. CLC workbench software was used to compare the conservatism of PLAGL1protein with other multiple species.
Results:
Eighteen differentially expressed protein spots and the14corresponding proteins or polypeptides were identified by two-dimensional electrophoresis (2-DE) and mass spectrometry. Further, two up-regulated (complement C4A and carbonic anhydrase1) and three down-regulated proteins (serotransferrin, alpha-1-antichymotrypsin, and vitronectin) as candidate proteins for validation were measured by ELISA in the above and new samples. The plasma levels (n=40in each group) of complement C4A in RVD (715.8±35.6vs.594.7±28.2ng/ml, P=0.009) and carbonic anhydrase1(237.70±15.7vs.184.7±10.8U/L, P=0.007) in DVD patients were significantly higher than those in normal controls. The plasma levels of serotransferrin (2.36±0.20vs.2.93±0.16mg/ml, P=0.025) and alpha-1-antichymotrypsin (370.0±13.7vs.413.0±11.6μg/ml, P=0.019) in RVD patients were significantly lower than those in normal controls. In addition, the plasma vitronectin level in both RVD (281.3±11.0vs.323.2±10.0μg/ml, P=0.006) and DVD (283.6±11.4vs.323.2±10.0μg/ml, P=0.011) groups were significantly lower than those in normal controls.
Neither missense nor frame-shift mutations were detected in two protein-coding extons of PLAGL1. But a novel synonymous variation (c.486A>G, p. E162E) was detected in protein-coding exon-2. The glutamic that translated with the mutational codon is conservative when compared with other species.
Conclusions:
The elevation of plasma complement C4A in RVD and carbonic anhydrase1in DVD and the decrease of serotransferrin and alpha-1-antichymotrypsin in RVD patients may be useful biomarkers for these valvular diseases. In addition, the decreased plasma level of vitronectin-a protein related to the formation of valvular structure-in both RVD and DVD patients might indicate the possible genetic deficiency in these patients.
We detected a synonymous variation in the protein-coding exon-2of PLAGL1in isolated VSD patients. It is possible that the etiology of isolated VSD might not be directly linked with this mutation, but might be associated with other patterns of gene expression regulation in PLAGL1, such as in the methylation-dependent manner.
第一部分血管功能药理学与冠状动脉旁路移植术
研究背景及目的：
移植血管痉挛仍然是冠状动脉旁路移植术中的挑战。临床上钙拮抗剂常用于治疗冠心病患者。本部分我们将对新型第三代二氢吡啶类钙拮抗剂阿折地平在人体内乳动脉中对于血管收缩的抑制效应进行研究。
内皮细胞胞内的钙调节依赖于瞬时受体电位通道(TRPs)。标准型瞬时受体电位离子通道(TRPCs)目前被认为是血管内皮细胞中最重要的钙离子透过性阳离子通道而TRPC3通道被报道在动物动脉中与血管的舒张功能相关。然而,TRPCs在人体动脉中的作用尚不明确。因此我们对科研假说,标准型瞬时受体电位离子通道在人体动脉中发挥作用,进行了验证。
实验方法：
离体的内乳动脉环(n=68,来自28个进行冠状动脉旁路移植术的患者)在myograph上进行两方面研究：阿折地平对KC1和U46619预收缩的内乳动脉的舒张作用以及在正常血药浓度时阿折地平对收缩的抑制作用。
人体内乳动脉环(n=42,来自28个进行冠状动脉旁路移植术的患者)按如下方法在myograph上进行研究：分别作出以U46619(-8log M)预收缩后乙酰胆碱的浓度依赖性舒张曲线,记录在加入SKF96365(10μmol/L)或者Pyr3(3μmol/L)孵育前后曲线的变化。同时利用Western Blot和免疫组化对TRPC3蛋白的表达进行鉴定。
实验结果：
阿折地平能够几乎完全舒张KCl(96.5%±0.7%)或U46619(96.5%±1.4%)预收缩的人体内乳动脉(n=8)且对KCl的敏感性相对U46619更高(EC50：-7.49±0.21vs-6.03±0.11log M,p<0.01)；预孵育阿折地平(-6.1log M)可以有效的抑制KCl(最大收缩值从25.8±2.2mN下降至16.0±1.5mN,p<0.01)或U46619(最大收缩值从30.6±4.0mN下降至16.5±2.2mN,p<0.05)引起的人体内乳动脉收缩。
由乙酰胆碱引起的最大舒张值由于非特异性阳离子通道抑制剂SKF96365(48.2±3.7vs.66.0±0.9%in control,p<0.01)或TRPC3通道特异性抑制剂Pyr3(58.4±2.3%vs.67.7±1.1%in control,p<0.01)而明显减小。同时,在人体内乳动脉中检测到TRPC3通道蛋白的表达。
实验结论：
阿折地平对于不同类型的血管收缩剂在人体内乳动脉中引起的收缩均具有有效的抑制作用。因此,阿折地平应用于冠状动脉旁路移植术患者有望可以有效治疗和预防移植血管的痉挛。
TRPC3通道存在于人体内乳动脉中,并且在乙酰胆碱引起的内皮依赖性舒张作用中发挥功能。本部分研究提示TRPC3可能成为在内皮功能障碍疾病如冠心病中潜在的保护内皮功能以改善移植血管远期通畅率的靶点。
第二部分重大心脏疾病的致病基因和蛋白质组学的研究
研究背景及目的：
心脏瓣膜病的遗传基础和蛋白质组学研究能够为诊断和治疗此类疾病提供重要信息。然而,关于心脏瓣膜病(VHD)包括风湿性(RVD)和退行性心脏瓣膜病(DVD)生物标记物的研究尚不明确。本部分实验意在探索血浆中表达量变化与心脏瓣膜病的病理变化相关的蛋白质。
室间隔缺损(VSD)是最常见的先天性心脏病之一。许多遗传学研究提示PLAGL1基因与先天性心脏病的病因学相关。本部分的研究意在鉴别PLAGL1基因中潜在的致病突变,为单纯性室间隔缺损的病因学研究提供参考。
实验方法：。
采用双向电泳联合质谱的方法对RVD.DVD和正常人群对照组的血浆进行差异蛋白质的检测。同时对找出的差异蛋白中可能与VHD病理变化相关的蛋白质进行ELISA验证。
300例单纯性VSD患者和300例健康人群PLAGL1基因中两个编码蛋白的外显子经PCR扩增后,PCR产物采用ABI公司3730自动测序仪测序。应用CLCworkbench software对PLAGL1蛋白进行多物种氨基酸保守性分析。
实验结果：
双向电泳联合质谱共找出差异蛋白点18个,包括14个蛋白质或者多肽。对两个上调的(补体C4A和碳酸酐酶1)和三个下调的(血清铁传递蛋白、alpha-1抗胰凝乳蛋白酶和波连蛋白)可能与VHD病理变化相关的蛋白质进行ELISA验证。补体C4A在RVD病人血浆中含量(715.8±35.6vs.594.7±28.2ng/ml, n=40,P=0.009)以及碳酸酐酶1在DVD病人血浆中含量(237.70±15.7vs.184.7±10.8U/L,n=40,P=0.007)均较正常对照组显著升高。血清铁传递蛋白在RVD病人血浆中含量(2.36±0.20vs.2.93±0.16mg/ml,n=40,P=0.025)以及alpha-1抗胰凝乳蛋白酶在RVD病人血浆中含量(370.0±13.7vs.413.0±116μg/ml,n=40,P=0.019)较正常对照组显著降低。此外,波连蛋白在RVD病人(281.3±11.0vs.323.2±10.0μg/ml,n=40,P=0.006)和DVD病人(283.6±11.4vs.323.2±10.0μg/ml,n=40,P=0.011)血浆中含量均较正常对照组显著降低。
在PLAGL1基因两个编码蛋白的外显子中未检测到任何错义突变或移码突变,只在编码蛋白的外显子2中检测到一个同义突变(c.486A>G,p.E162E).突变位置的密码子翻译的谷氨酸在与其他物种的比对中显示具有保守性。
实验结论：
补体C4A在RVD病人血浆中含量的上升,碳酸酐酶1在DVD病人血浆中含量的上升,血清铁传递蛋白在RVD病人血浆中含量的下降以及alpha-1抗胰凝乳蛋白酶在RVD病人血浆中含量的下降为VHD提供了可能的生物标记物。同时,与瓣膜形成相关的蛋白——波连蛋白在RVD和DVD病人血浆中含量均降低提示在这些病人中可能存在基因缺陷。
我们在单纯性室间隔缺损患者PLAGL1基因编码蛋白的外显子2中检测出一个同义突变,尽管这个突变并未造成氨基酸的变化,但这个突变仍可能与PLAGL1基因的表达调控相关,比如甲基化作用。
Part-I Pharmacology of vasomotion and coronary artery bypass grafting
Background and Objectives:
Graft spasm remains challenging in coronary artery bypass grafting (CABG) surgery. Calcium antagonists are commonly used in patients with coronary artery disease. We investigated the inhibitory effect of a new third-generation dihydropyridine calcium antagonist azelnidipine on the vasoconstriction in human internal mammary artery (IMA) from patients undergoing CABG.
Intracellular calcium regulation in endothelial cells depends on transient receptor potential channels (TRPs). Canonical TRPs (TRPCs) are now recognized as the most important Ca2+-permeable cation channels in vascular endothelium and TRPC3channel is reported to play a role in vasodilation in animal vessels. However, little is known about the role of TRPCs in the human arteries. We therefore tested the hypothesis that TRPCs plays a role in the human arteries.
Methods:
Isolated IMA rings (n=68, taken from28patients) were studied in myograph in two ways:the relaxing effect of azelnidipine on vasoconstrictor-induced precontraction by KCl and U46619and the depressing effect of azelnidipine at plasma concentrations on the contraction.
Cumulative concentration-relaxation curves to acetylcholine (-11to-4.5log M) were established in the human internal mammary artery (IMA) rings (n=42) taken from28patients undergoing coronary artery bypass grafting in pre-contraction induced by U46619(-8log M) in the absence or presence.of SKF96365(10μmol/L) or Pyr3(3μmol/L). Protein expressions of TRPC3were determined by Western Blot and Immunohistochemistry Staining.
Results:
Azelnidipine caused full relaxation in KCl-contracted (96.5%±0.7%) and in U46619-contracted (96.5%±1.4%) IMA rings (n=8) with28.8-fold higher potency to KC1than to U46619(EC50:-7.49±0.21vs-6.03±0.11log M, p<0.01). Pretreatment of IMA with plasma concentrations of azelnidipine (-6.1log M) significantly depressed subsequent contraction to KCl (from25.8±2.2mN to16.0±1.5mN, p<0.01) and U46619(from30.6±4.0mN to16.5±2.2mN, p<0.05).
The maximal relaxation induced by acetylcholine was significantly attenuated by the non-specific cation channels inhibitor, SKF96365(48.2±3.7vs.66.0±0.9%in control, P<0.01) or the selective TRPC3blocker, Pyr3(58.4±2.3%vs.67.7±1.1%in control, P<0.01). The protein expression of TRPC3was detected in human IMA.
Conclusions:
We conclude that in human IMA azelnidipine has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors. Thus, use of azelnidipine in CABG patients is favored in treating and preventing graft spasm.
TRPC3exists and plays a role in the acetylcholine-induced endothelium-dependent relaxation in the human IMA. This study suggests that TRPC3may have the potential to be a new target in endothelial protection in patients with endothelial dysfunction such as in patients with coronary artery disease in order to improve the long term patency of the grafting vessels.
Part-Ⅱ Genetic and proteomic study on heart disease
Background and Objectives:
The genetic basis and proteomics of common valvular heart disease (VHD) are important to provide information for diagnosis and treatment of these diseases. However, little is known about biomarkers in VHD including rheumatic (RVD) and degenerative (DVD) valvular disease. The present proteomic study examined the hypothesis that certain proteins may be related to the pathological changes in the plasma of VHD.
Ventricular septal defect (VSD) is the most common congenital heart disease (CHD). A number of genetic studies have linked the gene oiPLAGLl to the etiology of CHD. The present study aimed to identify potential pathogenic mutations for PLAGL1and to provide insights into the etiology of isolated VSD.
Methods:
Differential protein analysis was performed in the plasma of patients with RVD, DVD and normal controls by using two-dimensional electrophoresis (2-DE) and mass spectrometry. Candidate proteins that might relate to disease processes were further confirmed by enzyme-linked immunosorbent assays (ELISA) in enlarging samples.
Case-control mutational analysis was performed in300patients with isolated VSD and300healthy controls. Two protein-coding extons of PLAGL1and their partial flanking intron sequences were amplified by polymerase chain reaction and sequenced on an ABI3730Automated Sequencer. CLC workbench software was used to compare the conservatism of PLAGL1protein with other multiple species.
Results:
Eighteen differentially expressed protein spots and the14corresponding proteins or polypeptides were identified by two-dimensional electrophoresis (2-DE) and mass spectrometry. Further, two up-regulated (complement C4A and carbonic anhydrase1) and three down-regulated proteins (serotransferrin, alpha-1-antichymotrypsin, and vitronectin) as candidate proteins for validation were measured by ELISA in the above and new samples. The plasma levels (n=40in each group) of complement C4A in RVD (715.8±35.6vs.594.7±28.2ng/ml, P=0.009) and carbonic anhydrase1(237.70±15.7vs.184.7±10.8U/L, P=0.007) in DVD patients were significantly higher than those in normal controls. The plasma levels of serotransferrin (2.36±0.20vs.2.93±0.16mg/ml, P=0.025) and alpha-1-antichymotrypsin (370.0±13.7vs.413.0±11.6μg/ml, P=0.019) in RVD patients were significantly lower than those in normal controls. In addition, the plasma vitronectin level in both RVD (281.3±11.0vs.323.2±10.0μg/ml, P=0.006) and DVD (283.6±11.4vs.323.2±10.0μg/ml, P=0.011) groups were significantly lower than those in normal controls.
Neither missense nor frame-shift mutations were detected in two protein-coding extons of PLAGL1. But a novel synonymous variation (c.486A>G, p. E162E) was detected in protein-coding exon-2. The glutamic that translated with the mutational codon is conservative when compared with other species.
Conclusions:
The elevation of plasma complement C4A in RVD and carbonic anhydrase1in DVD and the decrease of serotransferrin and alpha-1-antichymotrypsin in RVD patients may be useful biomarkers for these valvular diseases. In addition, the decreased plasma level of vitronectin-a protein related to the formation of valvular structure-in both RVD and DVD patients might indicate the possible genetic deficiency in these patients.
We detected a synonymous variation in the protein-coding exon-2of PLAGL1in isolated VSD patients. It is possible that the etiology of isolated VSD might not be directly linked with this mutation, but might be associated with other patterns of gene expression regulation in PLAGL1, such as in the methylation-dependent manner.
引文
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