A phenotypically neutral dimorphism of protein S: The substitution of Lys155 by Glu in the second EGF domain predicted by an A to G base exchange in the gene

Yamazaki, Tomio; Sugiura, Isamu; Matsushita, Tadashi; Kojima, Tetsuhito; Kagami, Kazuo; Takamatsu, Junki; Saito, Hidehiko

doi:10.1016/0049-3848(93)90081-x

Cited by 55 publications

(47 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As for the population-specific prevalent mutations, frequent Lys196Glu (K196E) of PROS1 in Japan results in PS deficiency being most frequent in both VTE patients and the general population (Table 3). [26][27][28] Although the sensitivity of coagulation tests for detecting heterozygous Lys196Glu mutation is limited, 27,29,30 earlier studies involving only coagulation tests also demonstrated a high frequency of PS deficiency in the Japan population.14,15,31 Lys196Glu was not observed in our study or in other previous studies, indicating that it is a unique mutation in Japan. In China, two recent studies found two predominant mutations of PROC, Lys173del and Arg189Trp, both in VTE patients and in the general population (Table 3).…”

contrasting

confidence: 47%

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

et al. 2013

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o nIn this regard, we investigated the molecular genetic defects of natural anticoagulant deficiencies (PC, PS, and AT) in a large number of consecutive VTE patients and in the general population in Korea screened by coagulation tests. The results revealed unique frequencies and mutation spectrums of natural anticoagulant deficiencies in the group of VTE patients and in the general population. These frequencies and the mutation spectrums in Korea were not only distinct from those in Caucasian populations but also from those in other Asian countries. Methods Patients and populationThe group of patients consisted of consecutive VTE patients screened for thrombophilia including PC, PS, and AT deficiencies at Samsung Medical Center, Seoul, Korea, from January 2005 to December 2012. For the population group, at least 3,000 individuals visiting the institution for routine check-ups were screened from September 2005 to January 2006 using the same coagulation tests for natural anticoagulant deficiency as those used in the patients. In each group, those suspected of having a natural anticoagulant deficiency underwent molecular genetic tests to confirm the deficiency. In both groups, we excluded those with low levels of multiple (2 or more) natural anticoagulants, especially in association with underlying liver disease or other extrinsic factors. Written informed consent was obtained from the patients in the study, which was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, Korea. Coagulation testsThe thrombophilia profile tests for VTE patients included screening for genetic thrombophilia: PC activity (Stachrom ® Protein C, Diagnostica Stago, Asnieres-Sur-Seine, France), PS free antigen (Liatest ® Free Protein S, Diagnostica Stago), and AT activity (Stachrom ® ATIII, Diagnostica Stago). All coagulation tests were performed on the STA ® coagulation analyzer (Diagnostica Stago). The local reference intervals were determined according to the guidelines from the Clinical and Laboratory Standards Institute (http://www.clsi.org/) as the 2.5-97.5 percentiles (PC activity, PS free antigen,.2% for males and 56.0-132.6% for females; and AT activity, 81.5-119.3%). 10 Tests for PC antigen, PS total antigen and activity, and AT antigen were additionally performed when indicated. Natural anticoagulant deficiency was suspected in VTE patients when the result was below the lower limit of the reference interval (2.5 percentile). Screening for natural anticoagulant deficiency in the population group was performed using the same coagulation tests as those used in the VTE patients. Individuals with levels of PC, PS, or AT below the 1 st percentile were selected for molecular genetic tests. Molecular genetic analysesGenomic DNA was extracted from peripheral blood leukocytes using the Wizard Genomic DNA Purification kit following the standard protocols (Promega, Madison, WI, USA). Molecular genetic diagnosis of natural anticoagulant deficiency was performed by...

show abstract

contrasting

confidence: 47%

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

et al. 2013

View full text Add to dashboard Cite

show abstract

“…For example, the presence of EGF4 increases the calcium affinities of EGF2 and EGF3 22 and the fragment EGF1-4 is 10-fold more active than EGF1-3 in inhibiting of the interaction between PS and APC, suggesting either a significant interaction between EGF4 and APC or an effect of EGF4 on the conformation of EGF1. A natural variant within EGF2 (Lys155Glu) has variously been reported to be phenotypically neutral 23 or to have no ability to enhance APC activity. 24 Our results confirm that EGF2 has an important role in PS anticoagulant function.…”

Section: Resultsmentioning

confidence: 99%

Deletion or replacement of the second EGF-like domain of protein S results in loss of APC cofactor activity

Mille-Baker

Rezende

Simmonds

et al. 2003

Blood

View full text Add to dashboard Cite

Human protein S (PS), a cofactor of anticoagulant-activated protein C (APC), is a modular protein containing 4 epidermal growth factor (EGF)-like domains. EGF1 appears to mediate PS interaction with APC, but the roles of EGFs 2, 3, and 4 are less clear. We synthesized PS variants lacking single EGF domains (EGF2, 3, or 4) and assessed their APC cofactor activity in a factor Va inactivation assay. The variant lacking EGF2 (variant 134) showed the most dramatic loss of activity (ϳ10% of recombinant wild-type PS activity). Replacement of EGF2 by an additional EGF3 (variant 1334) resulted in a comparable loss of activity, suggesting that the loss of a specific rather than "spacer" function of EGF2 was responsible. We confirmed that the variant 134 had a functional ␥-carboxyglutamic acid (Gla) domain and that EGF1 was correctly folded. This is the first clear evidence that EGF2 is required for the expression of PS activity. (Blood.

show abstract

“…The plasminogen-A620T mutation, formerly referred to as plasminogen-Tochigi, and the protein S-K196E mutation, formerly referred to as protein S-Tokushima, exhibited decreased activities of plasminogen and protein S despite normal antigen levels. [2][3][4] The ADAMTS13-P475S mutation exhibited low von Willebrand factorcleaving activity in vitro. 5 The factor XII-4CϾT substitution in the 5Ј-untranslated region, formerly referred to as 46CϾT, showed decreased plasma levels of both antigen and activity.…”

Section: Protein S-k196e Mutation As a Genetic Risk Factor For Deep Vmentioning

confidence: 99%

Protein S–K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients

Kimura¹,

Honda²,

Kawasaki³

et al. 2006

Blood

Self Cite

View full text Add to dashboard Cite

Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patientsDeep vein thrombosis (DVT) is a multifactorial disease caused by interactions between acquired risk factors and coagulation abnormalities. 1 In whites, the factor V-Leiden and the prothrombin-20210GϾA are widely recognized as genetic risk factors for DVT. However, these 2 mutations are not present in Japanese populations, and little is known about the genetic risk factors for DVT in these populations. In this study, we evaluated the genetic contributions of 5 polymorphisms in Japanese DVT patients. The plasminogen-A620T mutation, formerly referred to as plasminogen-Tochigi, and the protein S-K196E mutation, formerly referred to as protein S-Tokushima, exhibited decreased activities of plasminogen and protein S despite normal antigen levels. 2-4 The ADAMTS13-P475S mutation exhibited low von Willebrand factorcleaving activity in vitro. 5 The factor XII-4CϾT substitution in the 5Ј-untranslated region, formerly referred to as 46CϾT, showed decreased plasma levels of both antigen and activity. 6 The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism is related to in vitro differences in transcription activity. 7 We genotyped subjects for these 5 polymorphisms and compared their genotypic frequencies between 161 DVT patients and 3655 population-based controls. The protocol for this study was approved by the ethical review committee, and only those subjects who provided written informed consent for genetic analyses were included in this study. All participants of this study were Japanese. The controls were from a general population randomly selected from the residents of Suita City located in the second largest urban area in Japan (the Suita Study). 8 One hundred sixty-one DVT patients, 78 men and 83 women, were registered by the Study Group of Research on Measures for Intractable Diseases, working under the auspices of the Ministry of Health, Labor, and Welfare of Japan. Six centers (Tochigi, Tokyo, Nagoya, Kyoto, and 2 in Osaka) participated in this study. The patients' mean age was 49.5 years (range, 12-87 years) and their mean body mass index was 23.6 Ϯ 3.3. Thirteen percent of patients had a family history of thrombosis, and 16% of the patients had recurrent thrombosis.Of all the polymorphisms tested, only the frequency of protein S-K196E was statistically different between the 2 groups ( 2 ϭ 38.3, P Ͻ .001) ( Table 1). No other frequency differences were statistically significant. Two DVT patients were homozygous for the protein S-196E allele; however, no homozygotes were identified in the control group. One patient with the 196EE genotype first developed DVT following surgery at age 47, while the other patient developed DVT during pregnancy at age 32.The mutant protein S with the E allele has already been intensively studied as protein S-Tokushima. 11 The protein S mutant showed the reduced activated protein C cofactor activity compared with wild-type protein S, suggesting a direct link between the protein S-...

show abstract

A phenotypically neutral dimorphism of protein S: The substitution of Lys155 by Glu in the second EGF domain predicted by an A to G base exchange in the gene

Cited by 55 publications

References 23 publications

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

Deletion or replacement of the second EGF-like domain of protein S results in loss of APC cofactor activity

Protein S–K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients

Contact Info

Product

Resources

About