New genetic variant in the SERPINC1 gene: hereditary Antithrombin deficiency case report, familial thrombosis and considerations on genetic counseling

Polyak, Margarita; Zaklyazminskaya, Elena

doi:10.1186/s12881-020-01001-5

Cited by 5 publications

(7 citation statements)

References 20 publications

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“…As outlined in the previous section, tumor cell heterogeneity and especially the existence of CSCs in tumors is a major problem in the failure of cancer treatment. Since µ g delivers an exceptional environment for cell culture and has been shown to stimulate cellular changes and processes that could not be achieved under normal gravitational conditions [ 59 ], the investigation of how CSCs act under µ g is an interesting topic. Even though, to our knowledge, the number of published studies on CSCs exposed to µ g conditions is limited, researchers have initiated work in this essential field during recent years [ 59 , 60 ].…”

Section: Cancer Research In Microgravitymentioning

confidence: 99%

“…Since µ g delivers an exceptional environment for cell culture and has been shown to stimulate cellular changes and processes that could not be achieved under normal gravitational conditions [ 59 ], the investigation of how CSCs act under µ g is an interesting topic. Even though, to our knowledge, the number of published studies on CSCs exposed to µ g conditions is limited, researchers have initiated work in this essential field during recent years [ 59 , 60 ]. Most knowledge has been obtained from thyroid, breast, and prostate cancer cells studies.…”

Section: Cancer Research In Microgravitymentioning

confidence: 99%

“…Notably, these cancer cells are able to differentiate into two distinct phenotypes under µ g conditions; one population being maintained as adherently cells located on the bottom of the cultivation flask, and another population aggregating into three-dimensional (3D), multicellular spheroids (MCS) [ 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. Such µ g -engineered MCS may thus delineate a model of intermediate metastasis by mimicking the diverse interplay between monolayer culture and the in vivo tumor [ 59 ]. As these MCS have similar features as the primary tumor and exhibit stem-like features simultaneously, MCS of various cancer types obtained under reduced gravitational conditions may thus represent a unique model for the study of CSC biology.…”

Section: Cancer Research In Microgravitymentioning

confidence: 99%

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The Fight against Cancer by Microgravity: The Multicellular Spheroid as a Metastasis Model

Grimm

Schulz

Krüger

et al. 2022

IJMS

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Cancer is a disease exhibiting uncontrollable cell growth and spreading to other parts of the organism. It is a heavy, worldwide burden for mankind with high morbidity and mortality. Therefore, groundbreaking research and innovations are necessary. Research in space under microgravity (µg) conditions is a novel approach with the potential to fight cancer and develop future cancer therapies. Space travel is accompanied by adverse effects on our health, and there is a need to counteract these health problems. On the cellular level, studies have shown that real (r-) and simulated (s-) µg impact survival, apoptosis, proliferation, migration, and adhesion as well as the cytoskeleton, the extracellular matrix, focal adhesion, and growth factors in cancer cells. Moreover, the µg-environment induces in vitro 3D tumor models (multicellular spheroids and organoids) with a high potential for preclinical drug targeting, cancer drug development, and studying the processes of cancer progression and metastasis on a molecular level. This review focuses on the effects of r- and s-µg on different types of cells deriving from thyroid, breast, lung, skin, and prostate cancer, as well as tumors of the gastrointestinal tract. In addition, we summarize the current knowledge of the impact of µg on cancerous stem cells. The information demonstrates that µg has become an important new technology for increasing current knowledge of cancer biology.

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Section: Cancer Research In Microgravitymentioning

confidence: 99%

Section: Cancer Research In Microgravitymentioning

confidence: 99%

Section: Cancer Research In Microgravitymentioning

confidence: 99%

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The Fight against Cancer by Microgravity: The Multicellular Spheroid as a Metastasis Model

Grimm

Schulz

Krüger

et al. 2022

IJMS

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“…In high-risk settings, the use of AT replacement therapy reduces this risk [ 85 ]. Paradoxically, according to guidelines issued in 2012 by the American College of Chest Physicians, special antithrombotic agents should not be used prophylactically in women with a history of hereditary thrombophilia and pregnancy complications (grade 2C) [ 86 ]. Low-molecular-weight heparin (LMWH) has been widely recognized in the literature as a safe and effective alternative to oral anticoagulant therapy (e.g., warfarin) in early and late pregnancy.…”

Section: Discussionmentioning

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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“…Furthermore, studies have found that antithrombin deficiency plays an important role in the pathogenesis of VTE. Antithrombin is an important inhibitor of blood coagulation proteases; individuals with hereditary AT deficiency have elevated thrombotic risk (29)(30)(31). Studies have revealed that the mutation profile of the AT gene (SERPINC1) is heterogeneous (32)(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

The Higher Prevalence of Venous Thromboembolism in the Hungarian Roma Population Could Be Due to Elevated Genetic Risk and Stronger Gene-Environmental Interactions

Natae

Kósa

Sándor

et al. 2021

Front. Cardiovasc. Med.

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Background: Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures.Objective: To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations.Methods: The study was based on data extracted from a database consisting of results previously obtained from a complex health survey with three pillars (questionnaire-based, physical, and laboratory examinations) involving 406 general Hungarian and 395 Roma subjects. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. After allele frequency comparisons, the odds ratio (OR) was calculated for individual SNPs. Furthermore, genetic risk scores (weighted GRS, unweighted GRS) were computed to estimate the joint effect of the genetic factors. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk after interaction terms were created between genetic and VTE risk factors [diabetes mellitus (DM), cancer, chronic kidney diseases (CKD), coronary artery diseases (CAD), migraine, depression, obesity, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), and smoking].Results: Interestingly, the rs121909567 (SERPINC1, ATBp3 mutation) SNP was not present in the general population at all. However, the risk allele frequency was 1% among the Roma population, which might suggest a founder effect in this minority. This polymorphism multiplicatively interacted with CAD, CKD, cancer, DM, depression, migraine, and obesity. Even though interactions were not statistically significant, the trend of interaction showed the probability of an incremental VTE risk among the Roma population. The risk of VTE was 4.7 times higher (p > 0.05) for Roma subjects who had ≥3 wGRS (median value) compared with individuals having lower wGRS values but lower for the general subjects (OR = 3.1 × 10−8). Additionally, the risk of VTE was 6.6 times higher in the Roma population that had ≥3 risk alleles (median value) than in individuals with the 0–1 risk allele, and the overall risk was much higher for the Roma population (OR = 6.6; p > 0.05) than for the general Hungarian population (OR = 1.5; p > 0.05). Five positive and significant GxE interactions were identified in the Roma population. The risk of VTE was higher among depressive Roma subjects who carried the risk variant rs2036914 (β = 0.819, p = 0.02); however, this interaction was not significant for the general subjects. The joint presence of high levels of LDL-C and rs2066865 (FGG) increased the VTE risk only among Roma individuals (β = 0.389, p = 0.002). The possibility of VTE risk increment, as a result of a multiplicative interaction between rs8176719 (ABO) and cancer, was identified, which was higher for the Roma population (β = 0.370, p < 0.001) than for the general population (β = −0.042, p = 0.6). The VTE risk increased in the Roma population (β = 0.280, p = 0.001), but was higher in the general population (β = 0.423, p = 0.001) as a result of the multiplicative interaction between CAD and rs2036914 (F11). The presence of a multiplicative interaction between rs2066865 (FGG) and CAD increased the VTE risk for the Roma population (β = 0.143, p = 0.046) but not for the general population (β = −0.329, p < 0.001).Conclusions: rs121909567 (SERPINC1, ATBp3) was confirmed as a founder mutation in the Roma population. Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE, although the finding is highly subjected to the selection and observational biases due to the very small number of VTE cases and the observational nature of the study design, respectively. As a result of higher genetic load and GxE interactions, this minority Roma population is at higher risk of VTE than the general Hungarian population. Thus, our results suggest the need for an intensive search for the rs121909567 (SERPINC1; ATBp3) founder mutation, which might be an important factor for the assessment of thrombotic disease susceptibility among the Roma population. In addition, we strongly recommend further studies among a large number of VTE cases to explore the more precise impact of genetic and environmental risk factors on VTE in the study populations.

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New genetic variant in the SERPINC1 gene: hereditary Antithrombin deficiency case report, familial thrombosis and considerations on genetic counseling

Cited by 5 publications

References 20 publications

The Fight against Cancer by Microgravity: The Multicellular Spheroid as a Metastasis Model

The Fight against Cancer by Microgravity: The Multicellular Spheroid as a Metastasis Model

Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency

The Higher Prevalence of Venous Thromboembolism in the Hungarian Roma Population Could Be Due to Elevated Genetic Risk and Stronger Gene-Environmental Interactions

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