一个遗传性凝血因子Ⅺ缺陷症家系的基因分析

The gene analysis of a Chinese pedigree with congenital blood coagulation factor XI deficiency

目的：对一个遗传性凝血因子Ⅺ（FⅪ）缺陷症家系进行FⅪ基因突变的分析和家系调查,探讨其分子发病机制。方法：检测先证者及其家系成员活化部分凝血活酶时间（APTT）、凝血酶原时间（PT）、凝血因子Ⅷ活性（FⅧ：C）、凝血因子Ⅸ活性（FⅨ：C）、凝血因子Ⅻ活性（FⅫ：C）、FⅪ活性（FⅪ：C）和FⅪ抗原（FⅪ：Ag）含量等进行表型诊断;用DNA直接测序法分析先证者FⅪ基因所有15个外显子、侧翼、5’和3’非翻译区及家系成员相应的突变位点区域,用反向测序证实所发生的突变。结果：先证者APTT延长为50.0 s（正常为27.0~41.0 s）,先证者弟弟与儿子APTT同样延长,分别为53.7 s和51.8 s,家系其他成员APTT无明显延长;先证者及其弟弟、儿子、父亲的FⅪ：C明显减低,分别为22.5%、22.3%、35.5%和42.0%,FⅪ：Ag含量分别为29.0%、18.0%、29.0%和40.0%,表现为交叉反应物质（CRM）阴性;先证者母亲凝血指标均在参考范围内。基因测序发现先证者及其父亲、弟弟、儿子FⅪ基因第8号外显子存在C16642T杂合无义突变,导致编码第263位氨基酸谷氨酰胺提前出现终止密码（Gln263stop）。结论：FⅪ基因第8号外显子C16642T杂合无义突变是导致该遗传性FⅪ缺陷症家系FⅪ水平降低的主要原因。

Objective： To analyze genetic mutation and explore its molecular pathogenesis for a Chinese pedigree with congenital blood coagulation factor XI deficiency. Methods： Activated partial thromboplastin time（APTT）, Prothrombin time（PT）, FXI activity（FXI：C）, FXI antigen（FXI：Ag） and other coagulant parameters were assayed. Exons 1-15, exon-intron boundaries and 5＇, 3＇ untranslated sequences of FXI gene of the proband and other family members were analyzed by direct sequencing. The detected mutations were confirmed by sequencing the complementary strand. Results： The proband had prolonged APTT（50.0 s）. The APTT results of her brother and son were prolonged too, which were 53.7 second and 51.8 second respectively. Other members＇ APTT were in normal range. The activity and antigen of proband＇s FXI was 22.5% and 29.0%, while her brother was 22.3% and 18.0%, her son was 35.5% and 29.0%, her father was 42.0% and 40% separately, which were called cross-reactivity material negative. The mother of proband had normal results above-mentioned. After the amplification and sequencing of 15 extrons in FXI, an exon 8 C16642→T mutation in proband as well as in her father, brother and son was found, which led to an amino acid change of Gln→Term at residue 263. Conclusion： The mutation of C16642→T on exon 8 is the main reason for the congenital FXI deficiency in this Chinese pedigree.