Cis-Segregation of c.1171C&gt;T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G&gt;A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Gemmati, Donato; Longo, Giovanna; Franchini, Eugenia; Silva, Juliana Araujo; Gallo, Ines; Lunghi, Barbara; Moratelli, S.; Maestri, Iva; Serino, Maria Luisa; Tisato, Veronica

doi:10.3390/genes12060934

Cited by 10 publications

(8 citation statements)

References 66 publications

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“…This is why we did not include this polymorphism in our meta-analysis. Moreover, there are new candidate genes identified by Genome-Wide Association Studies (GWAS), such as factors XI and XII [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

Factor V Leiden, Factor II, Protein C, Protein S, and Antithrombin and Ischemic Strokes in Young Adults: A Meta-Analysis

Tsalta-Mladenov

Levkova

Andonova

2022

Genes

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Ischemic strokes are one of the leading causes of death worldwide. The aim of this meta-analysis is to elaborate on the role of inherited predisposition to thrombophilia in the etiology of ischemic strokes in young adults. The keywords factor V Leiden (FVL), factor II, prothrombin (PT), protein C (PC), protein S (PS), antithrombin (AT), ischemic stroke, and young were used to search different databases. We selected studies with participants who were between 18 and 65 years. A total of 104 studies were eligible for inclusion in the meta-analysis. All the studied genetic markers were risk factors for ischemic stroke according to our results (FVL OR = 1.74; PT OR = 1.95; PC OR = 10.20; PS OR = 1.74; AT OR = 3.47; p < 0.05). There was moderate heterogeneity for most of the results, and subgroup analyses were conducted by dividing the studies according to the geographic location, gender ratio, and selection criteria of the performed study. There were no significant differences between the groups, but different geographic location was a probable source of heterogeneity. All of the studied markers—FVL, prothrombin, PC, PS, and AT—were significantly associated with increased risk of ischemic stroke in young adults and, if tested, could improve the quality of care.

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Section: Discussionmentioning

confidence: 99%

Factor V Leiden, Factor II, Protein C, Protein S, and Antithrombin and Ischemic Strokes in Young Adults: A Meta-Analysis

Tsalta-Mladenov

Levkova

Andonova

2022

Genes

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“…Total RNA was isolated from HEK293T cells using the TRIPURE ISOLATION REAGENT kit (11,667,165,001; Roche, Switzerland). Reverse transcription and qRT-PCR were used to detect differences in the transcript levels of SERPINC1.…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

“…SERPINC1 is located on chromosome 1 q23.1–25, is 13.5 kb in length, and consists of seven exons and six introns [ 10 ]. Furthermore, SERPINC1 is highly susceptible to alterations, and even small changes in its nucleotide sequence can cause severe structural and functional changes promoting thrombosis [ 11 ]. Most clinical cases are heterozygous because it is difficult for homozygotes to survive, and most die during embryonic development.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency

Wang

Ruan

et al. 2023

Thrombosis J

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Background Antithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated. Methods Candidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses. Results The proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discovered variant is not currently included in the ClinVar and HGMD databases. p.Arg229* resulted in a premature stop codon in exon 4, and bioinformatics analysis suggests that the truncated protein structure lost its domain of interaction with factor IX (Ala414 site) after the deletion of nonsense mutations. However, considering the AT truncation protein resulting from the p.Arg229* variant loss a great proportion of the molecule, we speculate the variant may affect two functional domains HBS and RCL and lack of the corresponding function. The thrombophilia and decreased-AT-activity phenotypes of the two pedigrees were separated from their genetic variants. After lentiviral plasmid transfection into HEK293T cells, the expression level of AT protein decreased in the constructed c.1377delC mutant cells compared to that in the wild-type, which was not only reduced in c.685C > T mutant cells but also showed a significant band at 35 kDa, suggesting a truncated protein. Immunofluorescence localization showed no significant differences in protein localization before and after the mutation. Conclusions The p.Asn460Thrfs*20 and p.Arg229* variants of SERPINC1 were responsible for the two hereditary AT deficiency pedigrees, which led to AT deficiency by different mechanisms. The p.Asn460Thrfs*20 variant is reported for the first time.

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“…Combined defects have been described, such as the SERPINC1 variant and F5 Leiden cis-segregation, and are associated with a higher risk of thrombosis [18]. Common selected gene variants may also strongly synergize with less common mutations, leading to potential life-threatening conditions when combined with rare severest mutations [19].…”

Section: Inherited Thrombophiliamentioning

confidence: 99%

Inherited Thrombophilia in the Era of Direct Oral Anticoagulants

Khider

Gendron

Mauge

2022

IJMS

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Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and FII G20210A variants. They are associated with a high thrombosis risk and can impact the duration of anticoagulation therapy for patients with a venous thromboembolism (VTE) event. Therefore, it is important to diagnose thrombophilia and to use adapted anticoagulant therapy. The widespread use of direct anticoagulants (DOACs) for VTE has raised new issues concerning inherited thrombophilia. Concerning inherited thrombophilia diagnosis, DOACs are directed toward either FIIa or FXa and can therefore interfere with coagulation assays. This paper reports DOAC interference in several thrombophilia tests, including the assessment of antithrombin, protein S, and protein C activities. Antithrombin activity and clot-based assays used for proteins C and S can be overestimated, with a risk of missing a deficiency. The use of a device to remove DOACs should be considered to minimize the risk of false-negative results. The place of DOACs in the treatment of VTE in thrombophilia patients is also discussed. Available data are encouraging, but given the variability in thrombosis risk within natural anticoagulant deficiencies, evidence in patients with well-characterized thrombophilia would be useful.

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Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Cited by 10 publications

References 66 publications

Factor V Leiden, Factor II, Protein C, Protein S, and Antithrombin and Ischemic Strokes in Young Adults: A Meta-Analysis

Factor V Leiden, Factor II, Protein C, Protein S, and Antithrombin and Ischemic Strokes in Young Adults: A Meta-Analysis

Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency

Inherited Thrombophilia in the Era of Direct Oral Anticoagulants

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