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Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S

复合杂合度 生物 分子生物学 蛋白质C 蛋白质S缺乏症 突变 突变蛋白 蛋白质S 突变体 野生型 基因突变 基因 遗传学 生物化学
作者
Jingyi Zhou,Wenyan Shen,Yi Gu,Min Li,Wei Feng Shen
出处
期刊:Journal of Clinical Pathology [BMJ]
卷期号:73 (1): 7-13 被引量:5
标识
DOI:10.1136/jclinpath-2019-205956
摘要

Hereditary protein S (PS) deficiency is one of the natural anticoagulant deficiencies causing thrombophilia. We herein described a young male with recurrent deep venous thrombosis, who was diagnosed as type I PS deficiency with compound heterozygous mutations of PROS1 gene. We aimed to analyse the relationship between the genotype and phenotype detection and investigate the pathological mechanisms of PROS1 mutations causing PS deficiency.Genetic analysis of PROS1 gene was carried out by direct sequencing. Thrombin generation potential and the inhibition function of thrombin generation by plasma PS were detected by thrombin generation test (TGT). The mRNA transcription level of mutant PS in vitro was measured by real-time PCR, while the protein level was evaluated by western blot and ELISA. Cellular distribution of the protein was further analysed by immunofluorescence.Compound heterozygous mutations (PROS1 c.1551_1552delinsG, p.Thr518Argfs*39 and PROS1 c.1681C>T, p.Arg561Trp) were identified in the propositus, and the former one was a novel small indel mutation. TGT results showed impaired inhibition of thrombin generation with the addition of activated protein C in his parents with certain heterozygous mutations. In vitro expression study, p.Thr518Argfs*39 mutant produced truncated protein retained in the cytoplasm, while p.Arg561Trp mutant partially affected the secretion of PS. Both mutations are located in C-terminal sex hormone-binding globulin (SHBG)-like domain of PS.Compound heterozygous mutations identified in the study have strong detrimental effect, causing severe type I PS deficiency in the propositus. SHBG-like domain of PS might play an important role in PS secretion system.
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