新的无义突变p.Lys327X和移码突变p.Leu424CysfsX8导致的遗传性凝血因子Ⅺ缺陷症

Novel mutations p. Lys327X and p. Leu424CysfsX8 underlying congenital factor Ⅺ deficiency

目的对1个遗传性凝血因子Ⅺ(coagulation factor Ⅺ,FⅪ)缺陷症家系进行凝血指标检测和基因突变分析,探讨其分子发病机制。方法检测先证者及其家系成员血浆活化部分凝血活酶时间(activated partial thromboplastin time,APTT)、FⅪ活性(FⅪ activity,FⅪ∶C)和FⅪ抗原(FⅪ antigen,FⅪ∶Ag)等凝血指标;对先证者FⅪ基因所有的外显子及其侧翼序列进行PCR扩增和DNA直接测序,针对先证者的突变位点,对该家系成员进行相应的基因突变检测;采用Mutation Taster软件对突变氨基酸的致病性进行预测。结果先证者APTT延长为82.4 s,FⅪ∶C为0.8%,FⅪ∶Ag<1%,基因测序发现其FⅪ基因第10外显子c.1033A>T(p.Lys327X)及第12外显子c.1325delT (p.Leu424CysfsX8)复合杂合突变;家系分析表明先证者二姐、儿子、女儿、大孙女、二孙女和孙子FⅪ基因存在c.1033A>T杂合突变,大姐及弟弟FⅪ基因存在c.1325delT杂合缺失突变;Mutation Taster软件分析结果表明该2种突变可能对蛋白质功能产生影响,能够引起相应疾病。结论FⅪ基因p.Lys327X无义突变和p.Leu424CysfsX8移码突变是导致先证者遗传性FⅪ缺陷症的分子发病机制,c.1033A>T(p.Lys327X)突变尚未见报道。

Objective To analyze the phenotype and genetic mutations in a pedigree affected with factor Ⅺ(FⅪ) deficiency. Methods Activated partial thromboplastin time (APTT), FⅪ activity (FⅪ∶C) and FⅪ antigen (FⅪ∶Ag) were determined for the proband and his family members. All exons and exon-intron boundaries of the FⅪ gene of the proband were analyzed by direct sequencing. Suspected mutation was verified in his family members. Results The proband had APTT of 82.4 s, FⅪ∶C of 0.8%, and FⅪ∶Ag of <1%. DNA sequencing showed that he has carried c. 1033A>T (Lys327X) mutation in exon 10 and c. 1325delT (Leu424CysfsX8) mutation in exon 12 of the FⅪ gene. His elder sister, son, daughter, two granddaughters and one grandson were heterozygous carriers of the c. 1033A>T mutation, while his older sister and younger brother were heteozygous carriers of the c. 1325delT mutation. Analysis using Mutation Taster software showed that both p. Lys327X and p. Leu424CysfsX8 may affect the function of protein and lead to the corresponding disease. Conclusion The novel mutations of Lys327X and Leu424CysfsX8 of the the FⅪ gene probably underlie the pathogenesis of congenital coagulation factor Ⅺ deficiency in this pedigree.