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.
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。