纯合子His348G1n导致的遗传性凝血因子Ⅶ缺乏症家系分析

目的 对1个姨表近亲结婚的遗传性凝血因子Ⅷ(coagulation factorⅦ,FⅦ)缺乏症家系进行基因突变检测,探讨其分子发病机制.方法 检测凝血酶原时间(prothrombin time,PT)、活化部分凝血活酶时间、纤维蛋白原、血浆凝血因子活性等指标以明确诊断;用DNA直接测序法对先证者及家系成员FⅦ基因的全部外显子及侧翼、5'和3'非翻译区进行分析,寻找基因突变,用反向测序证实所发生的突变.结果 先证者PT(30.9 s)和FⅦ活性(3%)明显异常,女儿、父亲和母亲的PT(分别为21.2 s、16.3 s和16.1 s)稍延长和FⅦ活性(分别为22%、25%和35%)减低,胞弟各指标均在正常范围内;先证者FⅦ基因第8外显子的11482位为纯合T→G导致氨基酸His348Gln;女儿、父亲和母亲为His348Gln杂合子,胞弟为正常野生型.结论 该遗传性FⅦ缺乏症家系为纯合子错义突变His348Gln,推测此突变遗传自近亲结婚具有该杂合子的父母.

Abstract：

Obiective To investigate the gene mutation and the molecular pathogenesis of an inherited coagulation factor Ⅶ (F Ⅶ ) deficiency pedigree with consanguineous marriage. Methods The diagnosis was validated by coagulant parameter assay on the prothrombin time (PT), activated partial thromboplastin time, fibrinogen and coagulation factor activity. F Ⅶ gene mutations were analyzed in the proband and other family members by direct DNA sequencing of the PCR products of all exons, exon-intron boundaries and 5' and 3' untranslated sequences. The mutations were confirmed by reverse sequencing.Results The values of PT and FⅦ activity in the proband were significantly abnormal, they were 30. 9 s and 3% respectively. The PT of her daughter, father and mother was slightly extended to 21.2 s, 16.3 s and 16. 1 s respectively, and the FⅦ activity was reduced to 22%, 25% and 35% respectively. The coagulant parameters of her younger brother were within normal range. Homozygous T→G transition at position 11482 in exon 8 was identified in the proband resulting in His348Gln, and heterozygosity for His348Gln was confirmed in her daughter and her parents, and the normal wild-type was observed in her younger brother. Conclusion Homozygous missense mutation of His348Gln was found in a pedigree of hereditary FⅦ deficiency. The mutation was inherited from her heterozygote parents.