FBN1新生突变引起的马凡综合征及其基因型-表型的关联研究

发布时间：2018-03-15 02:34

  本文选题：马凡综合征　切入点：FBN基因　出处：《中国病理生理杂志》2016年03期 　论文类型：期刊论文

【摘要】：目的:本研究对2个不同马凡综合征(Marfan syndrome)的小家系进行致病基因FBN1的编码区和剪切位点突变检测,以寻找致病的突变,并初步探索马凡综合征基因型-表型的关联。方法:通过临床检查、实验室检查及心脏超声检查确诊2个无血缘关系的家庭中原疑似为马凡综合征的3例患者。运用新一代测序对家系1的疑似患者行FBN1基因的全外显子组测序,并对检出的致病性遗传变异进行Sanger验证及在所有家系成员中验证;对于家系2的存活成员,本研究直接进行PCR扩增FBN1基因的所有编码区及剪切位点,对产物进行直接Sanger测序。另外在50个正常对照中对新发现的突变位点进行基于PCR产物的测序分析,以排除多态性;并对实验结果行生物信息学分析。结果:所有存活的疑似患者均确诊为马凡综合征。在家系1中,我们检测到了一个FBN1基因数据库中尚未报道的新突变c.4685GA(p.Cys1562Tyr),并且患者父母和同胞姐姐均未检测到此变异,故此突变为一个新生突变。该错义突变使第1 562位上极性中性的含硫的半胱氨酸被极性中性的含羟苯基的酪氨酸所替代,影响了fibrillin-1蛋白一个TGF-β结合结构域,导致蛋白质的二级结构发生改变。家系2含父母及一对同卵双胎患者,其中一患者已去世。我们在存活患者检测到1个FBN1基因的已报道致病突变c.3706TC(p.Cys1236Arg),该突变在患者父母中不存在,故也为新生突变。结论:本文报道了一例FBN1基因的新突变及另一例由FBN1基因已知突变引起的马凡综合征,二者皆为新生突变,并在家系中进行了基因型-表型的比较,表明家系1的新突变可能与经典马凡综合征的表型相关,而家系2的已知突变确和新生儿重症马凡综合征表型相关。
[Abstract]:Objective: to detect the coding region and shear site mutation of the FBN1 gene in two different Marfan syndrome lines, in order to search for the pathogenic mutation. And to explore the relationship between genotype and phenotype of Marfan syndrome. Laboratory examination and echocardiography confirmed 3 cases of suspected Marfan syndrome in 2 unrelated families. The whole exon group of FBN1 gene was sequenced by a new generation of sequencing. The pathogenicity genetic variation was verified by Sanger and among all the family members. For the surviving members of family 2, all coding regions and splicing sites of FBN1 gene were directly amplified by PCR. In addition, the new mutation sites were sequenced based on PCR products in 50 normal controls to exclude polymorphism. Bioinformatics analysis was performed on the results of the experiment. Results: all the suspected survivors were diagnosed with Marfan syndrome. We detected a new mutation, c.4685GAp.Cys1562TyrN, which has not been reported in a FBN1 gene database, and neither the patient's parents nor sibling sisters have detected this mutation. The missense mutation resulted in the substitution of the polar neutral cysteine containing sulfur with the polar neutral tyrosine containing hydroxyphenyl, which affected a TGF- 尾 binding domain of the fibrillin-1 protein. Family 2 contains parents and a pair of identical twins, one of whom is dead. We detected a reported FBN1 gene mutation in surviving patients, c. 3706 TCU p.Cys1236 Arg.com, which is not present in patients' parents. Conclusion: a new mutation of FBN1 gene and another case of Marfan syndrome caused by known mutation of FBN1 gene are reported. It was suggested that the new mutation of family 1 might be related to the phenotype of classical Marfan syndrome, while the known mutation of family 2 was related to the phenotype of neonatal severe Marfan syndrome.
【作者单位】： 中山大学中山医学院医学遗传学教研室;中山大学疾病基因组研究所;广州市妇女儿童医疗中心 心脏中心;广州市公安局白云区分局刑警大队技术中队;广州市公安局黄埔区分局;中山大学新华学院;华大基因;
【基金】：国家自然科学基金资助项目(No.31471193)
【分类号】：R725.9
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本文编号：1614070