纯合子Thr359Met导致的遗传性凝血因子Ⅶ缺乏症家系分析

Analysis of an inherited FⅦ deficiency pedigree caused by homozygosity of Thr359Met

目的 探讨一个遗传性FⅦ缺乏症家系的基因突变类型。方法 检测FⅦ∶Ag、FⅦ∶C、FⅦa,并对缺陷进行分型 ;用DNA直接测序法对先证者及其家庭成员FⅦ基因的全部外显子及其侧翼进行分析 ;用蛋白质分子模型模拟软件对基因突变的生物结构病理学进行分析。结果 先证者FⅦ基因外显子 8的 115 14位为纯合子C→T导致氨基酸Thr35 9Met;父母及其子均为杂合子Thr35 9Met;Thr35 9Met导致CRM 型缺陷 ;蛋白质空间构型模拟分析发现 ,Thr35 9Met导致蛋白质空间构型发生改变 ,有较大侧链的Met置换了Thr后引起空间位阻 ,同时氢键数目也发生改变。结论 该遗传性FⅦ缺乏症家系为纯合子错义突变Thr35 9Met;推测此突变影响了蛋白质分子的空间构型 ,从而产生异常FⅦ蛋白的功能。

Objective To explore the gene mutation type of an inherited coagulation factor Ⅶ deficiency pedigree. Methods FⅦ∶Ag, FⅦ∶C, FⅦa were detected to classify deficiency type. FⅦ gene mutations were analysed in the proband and her family members by DNA directly sequencing. Biostructural pathology of the identified mutation was analysed by molecular modeling. Results Homozygosity of C→T transition at position 11514 in exon 8 resulting in Thr359Met was identified in the proband, and heterozygosity for Thr359Met was confirmed in her parents, her son and some other family members. Thr359Met induces CRM deficiency. It is found by computer simulated molecular model that the replacement of Thr by Met which has a larger and longer side chain might cause steric hindrance, and change the number of H bonds. Conclusions Homozygous missense mutation Thr359Met was found in a pedigree of hereditary FⅦ deficiency. This mutation might change the configuration of protein molecule and result in severe FⅦ deficiency.