SERPINC1 Human
Description
Definition and Biological Role of SERPINC1
The SERPINC1 gene encodes antithrombin (previously called antithrombin III), a critical glycoprotein in the serpin family that regulates blood coagulation. It inhibits thrombin and other activated serine proteases (e.g., Factor IXa, Xa, and XIa) to prevent excessive clot formation . Antithrombin binds to heparin, enhancing its inhibitory activity by altering its conformation, which accelerates the neutralization of clotting factors .
Key Features of SERPINC1
Gene Structure
Hereditary Antithrombin Deficiency (HAD)
HAD is classified into two main types based on genetic mutations:
Novel Mutations and Case Studies
Recent studies highlight emerging mutations:
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Case 1: A Chinese patient with a novel SERPINC1 mutation (c.50A>G, p.Y17C) presented with thrombotic microangiopathy (TMA) and recurrent gastrointestinal bleeding .
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Case 2: Families with SERPINC1 mutations showed 86% penetrance, with 44% classified as Type I and 56% as Type II deficiencies .
Therapeutic Challenges
Patients with HAD often face anticoagulant-related bleeding risks. In severe cases (e.g., TMA), antithrombin replacement therapy may be required, though outcomes remain variable .
Genetic Testing
Prevalence and Mutation Distribution
| Population | HAD Prevalence | Common Mutation Types |
|---|---|---|
| General Population | 0.02%–0.20% | Type I (44%), Type II (56%) |
| Thrombosis Patients | 0.5%–5% | Type IIa (reactive site mutations) |
Pathophysiological Mechanisms
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Heparin Dependency: Type IIb mutations (heparin-binding defects) show reduced thrombotic risk due to residual antithrombin activity without heparin .
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Polymerization: Missense mutations may cause antithrombin misfolding, leading to polymerization and functional loss .
Gaps in Research
Product Specs
Belonging to the serpin superfamily, Serpin Peptidase Inhibitor, Clade C Member 1 (SERPINC1) functions as a plasma protease inhibitor. SERPINC1 plays a crucial role in regulating the blood coagulation cascade by inhibiting thrombin, along with other activated serine proteases involved in this pathway. Specifically, SERPINC1 inhibits Thrombin and Factors IXa, Xa, and XIa. Deficiencies in SERPINC1 can lead to antithrombin III (ATIII) deficiency, an autosomal dominant disorder that may result in hereditary thrombophilia, a condition characterized by an increased tendency for blood clotting.
Q&A
What is the SERPINC1 gene and what protein does it encode?
SERPINC1 encodes antithrombin (AT), a serine protease inhibitor (SERPIN) family member with critical anticoagulant functions. Structurally, SERPINs consist of a globular domain with central beta sheets and a reactive center loop (RCL) that protrudes from the main body . This structural arrangement is essential for antithrombin's inhibitory function in the coagulation cascade. The SERPINC1 gene contains 7 exons and regulatory regions that collectively encode the functional protein . Mutations in this gene can lead to antithrombin deficiency, resulting in hypercoagulability and increased thrombotic risk.
What are the classification systems for SERPINC1-related antithrombin deficiency?
Antithrombin deficiency is classified into distinct types based on molecular and functional characteristics:
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Type I deficiency: Characterized by proportionally reduced antithrombin activity and antigen levels (approximately 44% of SERPINC1 mutations) . This typically results from mutations affecting protein synthesis, stability, or secretion.
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Type II deficiency: Characterized by normal antithrombin antigen levels but reduced functional activity, further subclassified into:
This classification system helps researchers correlate genotype with clinical phenotype and guides appropriate diagnostic approaches.
How can researchers distinguish between inherited and acquired antithrombin deficiency?
Distinguishing between these forms requires a methodological approach:
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Laboratory assessment:
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Clinical context evaluation:
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Exclude acquired causes (liver disease, nephrotic syndrome, disseminated intravascular coagulation)
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Assess family history of thrombosis
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Consider age at first thrombotic event (earlier onset suggests hereditary forms)
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Genetic confirmation:
What is the relationship between SERPINC1 mutation type and thrombotic phenotype?
Research demonstrates significant correlations between mutation types and clinical manifestations:
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Null mutations vs. missense mutations:
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Pediatric carriers of null mutations show significantly more severe thrombotic phenotypes than carriers of missense mutations
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5-year VTE-free survival is significantly higher for missense mutation carriers (92.0%, 95% CI: 71.6%-97.9%) compared to null mutation carriers (66.7%, 95% CI: 19.5%-90.4%; p=0.0012)
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Arterial vs. venous thrombosis:
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Ischemic stroke correlation:
How do SERPINC1 mutations specifically impact ischemic stroke risk?
The relationship between SERPINC1 mutations and ischemic stroke is particularly noteworthy:
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Detection rates:
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Clinical profiles:
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Detection methodology:
What are the clinical manifestations of SERPINC1 mutations in pediatric populations?
Pediatric presentations have distinct characteristics:
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Age at diagnosis:
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Laboratory parameters:
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Thrombotic events:
What genetic testing methods should researchers employ to detect SERPINC1 mutations?
A comprehensive genetic testing approach includes:
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Direct Sanger sequencing:
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Multiplex ligation-dependent probe amplification (MLPA):
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Promoter region analysis:
This combined approach has demonstrated high detection rates in symptomatic individuals, with one study showing 86% of families with antithrombin deficiency had a detrimental SERPINC1 gene mutation that segregated in the family .
What in silico tools are most effective for analyzing SERPINC1 variants?
Several prediction tools have demonstrated utility in evaluating SERPINC1 variants:
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MutPred:
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PhD-SNP:
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PolyPhen-2 HumDiv:
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MutationTaster:
Researchers should use multiple prediction tools to increase confidence in variant classification, as discrepancies between tools can occur.
What diagnostic algorithm should researchers follow for suspected SERPINC1-related thrombosis?
Based on current evidence, a systematic approach includes:
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Initial screening:
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Measure AT activity in patients with:
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Young-onset thrombosis (<45 years)
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Recurrent thrombosis despite treatment
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Thrombosis without evident provoking factors
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Family history of thrombotic events
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Secondary testing for decreased AT activity (<80%):
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Measure AT antigen levels to determine deficiency type
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Perform SERPINC1 gene testing using both sequencing and MLPA methods
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Confirmation and family testing:
How should researchers design studies to characterize novel SERPINC1 variants?
A comprehensive approach includes:
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Genetic analysis:
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Complete sequencing of all exons, intron-exon boundaries, and regulatory regions
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MLPA analysis for large deletions/duplications
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Family segregation studies
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In silico assessment:
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Multiple prediction tools (MutPred, PhD-SNP, PolyPhen-2, MutationTaster)
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Conservation analysis across species
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Structural modeling to predict conformational changes
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Functional characterization:
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Expression systems to assess synthesis, secretion, and stability
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Enzyme inhibition assays to measure impact on function
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Heparin binding assays for type II variants
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Population data:
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Frequency assessment in control populations
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Presence in population databases (gnomAD, 1000 Genomes)
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What experimental models are most appropriate for studying SERPINC1 function?
Several experimental systems can be employed:
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Cell-based models:
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Expression of wild-type and mutant SERPINC1 in mammalian cell lines
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Analysis of protein production, secretion, and stability
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Co-culture systems to study interactions with target proteases
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Biochemical assays:
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Structural biology approaches:
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X-ray crystallography to determine how mutations affect protein structure
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Molecular dynamics simulations to predict impact on protein folding
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What methodological challenges exist in conducting family studies for SERPINC1 mutations?
Family studies face several research challenges:
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Variable penetrance:
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Not all individuals with pathogenic mutations develop thrombotic events
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Additional genetic or environmental modifiers likely influence phenotype
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Sample size limitations:
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Variant interpretation:
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Novel variants require multiple lines of evidence for classification
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Discrepancies between in silico prediction tools can complicate analysis
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Detection rates of pathogenic SERPINC1 variants by thrombosis type
| Thrombosis Type | Patients (n) | Pathogenic Variant Detection Rate | p-value |
|---|---|---|---|
| Ischemic stroke | 7 | 100% | 0.044 |
| Any arterial thrombosis | 8 | 87.5% | 0.177 |
| Venous thrombosis only | 11 | 54.5% | Reference |
Data derived from retrospective observational study (2009-2021)
Distribution of SERPINC1 mutation types in antithrombin deficiency
| Deficiency Type | Mutation Type | Percentage |
|---|---|---|
| Type I | Various | 44% |
| Type II HBS | Heparin binding site mutations | 11% |
| Type II PE | Pleiotropic effect mutations | 33% |
| Type II RS | Reactive site mutations | 6% |
| AT Cambridge II | Specific variant | 6% |
Data compiled from familial antithrombin deficiency cohort
VTE-free survival in pediatric SERPINC1 mutation carriers
| Mutation Type | 5-year VTE-free Survival | 95% Confidence Interval | p-value |
|---|---|---|---|
| Missense mutations | 92.0% | 71.6%-97.9% | 0.0012 |
| Null mutations | 66.7% | 19.5%-90.4% | Reference |
Data from pediatric cohort study (n=43) with median age 14.8 years (range 1-21)
Product Science Overview
Serpin Peptidase Inhibitor, Clade C Member 1, also known as Antithrombin III (ATIII), is a crucial protein in the regulation of blood coagulation. It belongs to the serine protease inhibitor (serpin) superfamily, which includes proteins that inhibit proteases by trapping them in a stable complex. This article delves into the background, structure, function, and clinical significance of this important protein.
The gene encoding Serpin Peptidase Inhibitor, Clade C Member 1, is located on chromosome 1q25.1 . The protein is synthesized in the liver and secreted into the bloodstream. It consists of 432 amino acids, including six cysteines that form three disulfide bonds . The protein has four glycosylation sites, which are crucial for its stability and function .
The protein contains two important functional domains:
Antithrombin III is the most important inhibitor of thrombin and other coagulation proteinases . It regulates clot formation by inhibiting thrombin activity directly and interfering with earlier stages of the clotting cascade . The heparin-antithrombin mechanism is one of the principal natural anticoagulant systems that exert damping effects on various steps of the coagulation cascade .
Inherited antithrombin III deficiency is a risk factor for the early development of venous thromboembolism . This condition, known as Thrombophilia 7, can lead to severe complications if not managed properly . Additionally, recent studies have shown that Serpin Peptidase Inhibitor, Clade C Member 1, acts as a tumor suppressor in hepatocellular carcinoma by inducing apoptosis and blocking macrophage polarization .
Human recombinant Antithrombin III is produced using recombinant DNA technology. This involves inserting the gene encoding the protein into a suitable expression system, such as bacteria or mammalian cells, to produce the protein in large quantities. Recombinant Antithrombin III is used in clinical settings to treat patients with hereditary antithrombin deficiency and to prevent thromboembolic events during surgeries and childbirth.
