PDF(Pubmed)
Abstract：
OBJECTIVE: Aggregating evidence highlights the strong genetic basis underpinning congenital heart disease (CHD). Here BMP4 was chosen as a prime candidate gene causative of human CHD predominantly because BMP4 was amply expressed in the embryonic hearts and knockout of Bmp4 in mice led to embryonic demise mainly from multiple cardiovascular developmental malformations. The aim of this retrospective investigation was to discover a novel BMP4 mutation underlying human CHD and explore its functional impact.
METHODS: A sequencing examination of BMP4 was implemented in 212 index patients suffering from CHD and 236 unrelated non-CHD individuals as well as the family members available from the proband carrying a discovered BMP4 mutation. The impacts of the discovered CHD-causing mutation on the expression of NKX2-5 and TBX20 induced by BMP4 were measured by employing a dual-luciferase analysis system.
RESULTS: A new heterozygous BMP4 mutation, NM_001202.6:c.318T>G;p.(Tyr106*), was found in a female proband affected with familial CHD. Genetic research of the mutation carrier\'s relatives unveiled that the truncating mutation was in co-segregation with CHD in the pedigree. The nonsense mutation was absent from 236 unrelated non-CHD control persons. Quantitative biologic measurement revealed that Tyr106*-mutant BMP4 failed to induce the expression of NKX2-5 and TBX20, two genes whose expression is lost in CHD.
CONCLUSIONS: The current findings indicate BMP4 as a new gene predisposing to human CHD, allowing for improved prenatal genetic counseling along with personalized treatment of CHD patients.
METHODS: A sequencing examination of BMP4 was implemented in 212 index patients suffering from CHD and 236 unrelated non-CHD individuals as well as the family members available from the proband carrying a discovered BMP4 mutation. The impacts of the discovered CHD-causing mutation on the expression of NKX2-5 and TBX20 induced by BMP4 were measured by employing a dual-luciferase analysis system.
RESULTS: A new heterozygous BMP4 mutation, NM_001202.6:c.318T>G;p.(Tyr106*), was found in a female proband affected with familial CHD. Genetic research of the mutation carrier\'s relatives unveiled that the truncating mutation was in co-segregation with CHD in the pedigree. The nonsense mutation was absent from 236 unrelated non-CHD control persons. Quantitative biologic measurement revealed that Tyr106*-mutant BMP4 failed to induce the expression of NKX2-5 and TBX20, two genes whose expression is lost in CHD.
CONCLUSIONS: The current findings indicate BMP4 as a new gene predisposing to human CHD, allowing for improved prenatal genetic counseling along with personalized treatment of CHD patients.
摘要：
目的：聚集的证据强调了先天性心脏病（CHD）的强大遗传基础。这里选择BMP4作为人类CHD的主要候选基因，主要是因为BMP4在胚胎心脏中充分表达，而在小鼠中敲除Bmp4导致胚胎死亡，主要来自多种心血管发育畸形。这项回顾性研究的目的是发现人类CHD潜在的新型BMP4突变并探索其功能影响。
方法：对212名冠心病患者和236名无关的非冠心病个体以及从先证者获得的携带发现的BMP4突变的家庭成员进行了BMP4测序检查。通过使用双荧光素酶分析系统测量发现的CHD引起的突变对BMP4诱导的NKX2-5和TBX20表达的影响。
结果：一个新的杂合BMP4突变，NM_001202.6:c.318T>G；p.(Tyr106*),在患有家族性CHD的女性先证者中发现。对突变携带者亲属的遗传研究表明，在系谱中，截断突变与CHD共分离。236名无关的非CHD对照者不存在无义突变。定量生物学测量显示，Tyr106*-突变体BMP4未能诱导NKX2-5和TBX20的表达，这两个基因在CHD中表达丢失。
结论：目前的研究结果表明BMP4是人类冠心病易感的新基因，允许改善产前遗传咨询以及CHD患者的个性化治疗。
方法：对212名冠心病患者和236名无关的非冠心病个体以及从先证者获得的携带发现的BMP4突变的家庭成员进行了BMP4测序检查。通过使用双荧光素酶分析系统测量发现的CHD引起的突变对BMP4诱导的NKX2-5和TBX20表达的影响。
结果：一个新的杂合BMP4突变，NM_001202.6:c.318T>G；p.(Tyr106*),在患有家族性CHD的女性先证者中发现。对突变携带者亲属的遗传研究表明，在系谱中，截断突变与CHD共分离。236名无关的非CHD对照者不存在无义突变。定量生物学测量显示，Tyr106*-突变体BMP4未能诱导NKX2-5和TBX20的表达，这两个基因在CHD中表达丢失。
结论：目前的研究结果表明BMP4是人类冠心病易感的新基因，允许改善产前遗传咨询以及CHD患者的个性化治疗。
