[两个因错义变异导致遗传性低纤维蛋白血症的中国家系的基因分析]
[Genetic analysis of two Chinese pedigrees affected with Hereditary hypofibrinemia due to missense variants].
作者信息
Zheng Xiaoyong, Chen Yi, Wen Mengzhen, Jin Yanhui, Zeng Manlin, Jia Kaiqi, Chen Yuan, Wang Mingshan, Yang Lihong
机构信息
Center of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, China.
出版信息
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Mar 10;40(3):276-281. doi: 10.3760/cma.j.cn511374-20211014-00813.
OBJECTIVE
To retrospectively analyze the clinical phenotypes and genetic variants in two Chinese pedigrees affected with Hereditary hypofibrinemia (IFD) and explore their molecular pathogenesis.
METHODS
Two probands and their pedigree members were admitted to the First Affiliated Hospital of Wenzhou Medical University on March 30, 2021 and May 27, 2021, respectively. Clinical phenotypes of the probands were collected, and blood clotting indexes of the probands and their pedigree members were determined. Variants of the FGA, FGB and FGG genes were analyzed by Sanger sequencing, and candidate variants were verified by sequence comparison. Bioinformatic software was used to analyze the conservation of the amino acids and pathogenicity of the proteins. Alteration in protein structure and intermolecular force before and after the variant was analyzed by simulating the protein model.
RESULTS
Proband 1, a 18-year-old male, had significantly low plasma fibrinogen activity (Fg:C) and plasma fibrinogen antigen (Fg:Ag), respectively at 0.80 g/L and 1.00 g/L. Proband 2, a 43-year-old male, had slightly low Fg:C and Fg:Ag at 1.35 g/L and 1.30 g/L, respectively. The Fg:C and Fg:Ag of proband 1's father, proband 2's father and son were also below the normal level. Genetic testing showed that proband 1 had harbored a heterozygous missense variant of c.688T>G (p.Phe230Val) in exon 7 of the FGG gene, which was inherited from his father. Proband 2, his father and son all had harbored a heterozygous variant of c.2516A>C (p.Asn839Thr) in exon 6 of the FGA gene. Homology analysis showed that the Phe230 and Asn839 residues were highly conserved among homologous species. Bioinformatic analysis predicted that both p.Phe230Val and p.Asn839Thr were pathogenic variants.
CONCLUSION
Analysis of protein simulation model showed that the p.Asn839Thr variant has changed the hydrogen bo`nd between the amino acids, thus affecting the stability of the protein structure. The heterozygous missense variants of p.Phe230Val and p.Asn839Thr probably underlay the IFD in the two pedigrees.
目的
回顾性分析两个遗传性低纤维蛋白原血症（IFD）中国家系的临床表型和基因变异，探讨其分子发病机制。
方法
两名先证者及其家系成员分别于2021年3月30日和2021年5月27日入住温州医科大学附属第一医院。收集先证者的临床表型，测定先证者及其家系成员的凝血指标。采用Sanger测序法分析FGA、FGB和FGG基因的变异，并通过序列比对验证候选变异。使用生物信息学软件分析氨基酸的保守性和蛋白质的致病性。通过模拟蛋白质模型分析变异前后蛋白质结构和分子间力的变化。
结果
先证者1为18岁男性，血浆纤维蛋白原活性（Fg:C）和血浆纤维蛋白原抗原（Fg:Ag）显著降低，分别为0.80g/L和1.00g/L。先证者2为43岁男性，Fg:C和Fg:Ag略低，分别为1.35g/L和1.30g/L。先证者1的父亲、先证者2的父亲和儿子的Fg:C和Fg:Ag也低于正常水平。基因检测显示，先证者1在FGG基因第7外显子中存在杂合错义变异c.688T>G（p.Phe230Val），该变异遗传自他的父亲。先证者2及其父亲和儿子在FGA基因第6外显子中均存在杂合变异c.2516A>C（p.Asn839Thr）。同源性分析表明，Phe230和Asn839残基在同源物种中高度保守。生物信息学分析预测p.Phe230Val和p.Asn839Thr均为致病变异。
结论
蛋白质模拟模型分析显示，p.Asn839Thr变异改变了氨基酸之间的氢键，从而影响了蛋白质结构的稳定性。p.Phe230Val和p.Asn839Thr的杂合错义变异可能是这两个家系中IFD的发病原因。
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