The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor
Само за регистроване кориснике
2020
Аутори
Pruner, IvaFarm, Maria
Tomić, Branko
Gvozdenov, Maja
Kovač, Mirjana
Miljić, Predrag
Soutari, Nida Mahmoud Hourani
Antović, Aleksandra
Radojković, Dragica
Antović, Jovan P.
Đorđević, Valentina
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
BACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C gt T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C gt T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C gt T variant. Scanning electron mi- croscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C gt T variant was significantly increased in patients w...ith venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824C gt T transfected cells. Our ex vivo study of FII c.1824C gt T carriers showed that the presence of this variant was associated with hyperprothrom-binemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C gt T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C gt T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests.
Извор:
Clinical Chemistry, 2020, 66, 2, 379-389Издавач:
- Oxford Univ Press Inc, Cary
Финансирање / пројекти:
- Комплексне болести као модел систем за проучавање модулације фенотипа-структурна и функционална анализа молекуларних биомаркера (RS-MESTD-Basic Research (BR or ON)-173008)
Повезане информације:
- Друга верзија
https://doi.org/10.1093/clinchem/hvz015
DOI: 10.1093/clinchem/hvz015
ISSN: 0009-9147
PubMed: 32040579
WoS: 000514385400016
Scopus: 2-s2.0-85079233913
Колекције
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Pruner, Iva AU - Farm, Maria AU - Tomić, Branko AU - Gvozdenov, Maja AU - Kovač, Mirjana AU - Miljić, Predrag AU - Soutari, Nida Mahmoud Hourani AU - Antović, Aleksandra AU - Radojković, Dragica AU - Antović, Jovan P. AU - Đorđević, Valentina PY - 2020 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1375 AB - BACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C gt T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C gt T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C gt T variant. Scanning electron mi- croscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C gt T variant was significantly increased in patients with venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824C gt T transfected cells. Our ex vivo study of FII c.1824C gt T carriers showed that the presence of this variant was associated with hyperprothrom-binemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C gt T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C gt T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests. PB - Oxford Univ Press Inc, Cary T2 - Clinical Chemistry T1 - The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor EP - 389 IS - 2 SP - 379 VL - 66 DO - 10.1093/clinchem/hvz015 ER -
@article{ author = "Pruner, Iva and Farm, Maria and Tomić, Branko and Gvozdenov, Maja and Kovač, Mirjana and Miljić, Predrag and Soutari, Nida Mahmoud Hourani and Antović, Aleksandra and Radojković, Dragica and Antović, Jovan P. and Đorđević, Valentina", year = "2020", abstract = "BACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C gt T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C gt T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C gt T variant. Scanning electron mi- croscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C gt T variant was significantly increased in patients with venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824C gt T transfected cells. Our ex vivo study of FII c.1824C gt T carriers showed that the presence of this variant was associated with hyperprothrom-binemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C gt T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C gt T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests.", publisher = "Oxford Univ Press Inc, Cary", journal = "Clinical Chemistry", title = "The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor", pages = "389-379", number = "2", volume = "66", doi = "10.1093/clinchem/hvz015" }
Pruner, I., Farm, M., Tomić, B., Gvozdenov, M., Kovač, M., Miljić, P., Soutari, N. M. H., Antović, A., Radojković, D., Antović, J. P.,& Đorđević, V.. (2020). The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor. in Clinical Chemistry Oxford Univ Press Inc, Cary., 66(2), 379-389. https://doi.org/10.1093/clinchem/hvz015
Pruner I, Farm M, Tomić B, Gvozdenov M, Kovač M, Miljić P, Soutari NMH, Antović A, Radojković D, Antović JP, Đorđević V. The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor. in Clinical Chemistry. 2020;66(2):379-389. doi:10.1093/clinchem/hvz015 .
Pruner, Iva, Farm, Maria, Tomić, Branko, Gvozdenov, Maja, Kovač, Mirjana, Miljić, Predrag, Soutari, Nida Mahmoud Hourani, Antović, Aleksandra, Radojković, Dragica, Antović, Jovan P., Đorđević, Valentina, "The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor" in Clinical Chemistry, 66, no. 2 (2020):379-389, https://doi.org/10.1093/clinchem/hvz015 . .