摘要
目的 通过表型及基因分析,探讨1例非近亲婚配的遗传性凝血因子Ⅶ(FⅦ)缺陷症家系的分子发病机制。方法 检测整个家系(共4人)的凝血指标来明确诊断包括凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)、血浆FⅦ活性(FⅦ:C)等。PCR扩增先证者F7基因所有外显子包括侧翼序列、5’和3’非翻译区及其他家系成员相应的突变位点区域,测序后寻找突变位点,以反向测序验证突变位点;使用生物信息学软件(PolyPhen-2和MutationTaster)预测突变位点的致病性。结果 先证者PT(61.4 s)和FⅦ:C(8%)明显异常,家系中其余3位成员PT值均正常,FⅦ:C均略低于正常对照组;基因分析显示先证者F7基因1号外显子存在c.27_28delCT杂合无义突变,8号外显子存在Cys254Arg的错义突变,先证者父亲及哥哥的F7基因分析显示有Cys254Arg杂合型突变,先证者母亲的F7基因分析显示有c.27_28delCT杂合无义突变;生物信息学分析提示提示Cys254Arg突变有致病性。结论 该家系F7基因存在c.27_28delCT、Cys254Arg两种突变,复合杂合突变的存在是引起先证者FⅦ:C低水平的主要分子机制,也是引起先证者颅内出血的主要原因,先证者两种杂合突变基因分别遗传自杂合子父母。
Objective To explore the gene mutation and the molecular pathogenesis of inherited coagulation factor VII(FVII)deficiency in a pedigree with non consanguineous marriage.Methods PT,APTT,FIB and FVII:C were assayed to make a definite diagnosis.All exons,exon-intron boundaries and 5'and 3'untranslated sequences of F7 were screened by PCR and direct sequencing.Suspected mutations were confirmed by sequencing the opposite strand.Two bioinformatics online software(PolyPhen-2 and Mutation Taster)was used to predict the possible impact of the mutation on the protein function.Results The PT and FVIl:C of proband were obvious abnormal which were 61.4 s and 8%separately.Two mutation was found in the proband,one was found in exon 1 of F7 which results in c.27_28delCT heterozygous nonsense mutation and another was found in exon 8 of F7 which result in Cys254Arg missense mutation.Her father and brother were found c.27_28delCT mutation,her mother carried the mutation of Cys254Arg.But the PT of these three members was normal and the FVII activity were slightly lower than the normal control group.Both results of two bioinformatics software show that mutation of Cys254Arg was pathogenic.Conclusion Two mutations of Cys254Arg and c.27_28delCT were discovered in a pedigree of hereditary FVIl deficiency.The compound heterozygous mutations were inherited from his heterozygote parents.
作者
苏正仙
金先富
蔡昀达
姜俊宇
应潇颖
陈超超
毕晓洁
SU Zhengxian;JIN Xianfu;CAI Yunda;JIANG Junyu;YING Xiaoying;CHEN Chaochao;BI Xiaojie(Department of Clinical Laboratory,Taizhou Hospital of Zhejiang Province,Linhai,Zhejiang 317000,China)
出处
《中国优生与遗传杂志》
2023年第5期1059-1062,共4页
Chinese Journal of Birth Health & Heredity
基金
台州市科技计划(1902ky17)。
关键词
遗传性凝血因子Ⅶ缺乏症
基因突变
复合杂合突变
颅内出血
hereditary coagulation factor VII deficiency
gene mutation
compound heterozygous mutations
intracranial hemorrhage
