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

Abstract

<jats:sec><jats:title>Aims</jats:title><jats:p>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 <jats:italic>PROS1</jats:italic> gene. We aimed to analyse the relationship between the genotype and phenotype detection and investigate the pathological mechanisms of <jats:italic>PROS1</jats:italic> mutations causing PS deficiency.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Genetic analysis of <jats:italic>PROS1</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Compound heterozygous mutations (<jats:italic>PROS1</jats:italic> c.1551_1552delinsG, p.Thr518Argfs*39 and <jats:italic>PROS1</jats:italic> c.1681C&gt;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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>

Rapid identification of a pathogenic variant of PROS1 in a thrombophilic family by whole exome sequencing

“… [7] Other variants in the SHBG domain have also been shown to affect the secretion of PS, causing severe type I PS deficiency. [8] The above robust evidence verified the pathogenic role of the mutation, which was responsible for the multiple venous thrombotic events in this family.…”

Clinical and genetic characterization of a protein S deficient patient with multiple thrombotic events

“…Notably, around half of individuals with PS deficiency are asymptomatic. 11 Therefore, routine screening for PS level is crucial for Asian VTE patients and their families. However, most functional PS assays focus on measuring the ability of PS to prolong the coagulation time of plasma as a cofactor of APC rather than TFPI.…”