Budd–Chiari syndrome in a patient heterozygous for the point mutation C20221T of the prothrombin gene

Balim, Zuhal; Kosova, Buket; Falzon, K.; Wettinger, Stephanie Bezzina; Çolak, Yusuf Ziya

doi:10.1046/j.1538-7836.2003.t01-2-00115.x

Cited by 18 publications

(23 citation statements)

References 5 publications

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“…The mutation was also subsequently found in a South-east Asian female and in her newborn [4]; this woman had a family history of thrombosis and individual history of late pregnancy losses and pre-eclampsia. The mutation was also found in a Turkish man with Budd-Chiari syndrome and in two of his siblings [7]. All nine cases thus far documented with the 20221C !…”

Section: Discussionmentioning

confidence: 76%

Abnormal melt curve profile during prothrombin 20210G → A analysis due to the 20209C → T variant

Dunn

Allen

Bates

et al. 2006

Blood Coagulation &Amp; Fibrinolysis

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The common factor II 20210G --> A mutation, located in the 3'-untranslated region, is an important risk factor for the development of thromboembolic disorders, especially in Caucasians. A number of methods are employed for clinical laboratory diagnosis of this mutation, some of which are capable of detecting adjacent 3'-end sequence variations. We present results from an African deep vein thrombosis patient tested for the 20210G --> A mutation by real-time polymerase chain reaction and melt-curve analysis using hybridization probes that incidentally detected an adjacent 3'-untranslated region variant. The patient sample was tested using the Factor II (Prothromobin) G20210A Kit (Roche Diagnostics, Indianapolis, Indiana, USA), in conjunction with the Roche LightCycler. A polymerase chain reaction fragment from the 3'-end of the F2 gene was subsequently sequenced for identification of the variant. Melt-curve analysis revealed a normal 20210*G peak and an unknown aberrant allelic peak. Following sequence analysis, the patient was determined to be heterozygous for 20209C --> T. The presence of the 20209C --> T variant in the current patient and in eight other reported individuals of African descent, most with thrombosis-associated complaints, suggests that this rare variant poses a potential increased risk for thromboembolic disease in this ethnic group.

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Section: Discussionmentioning

confidence: 76%

Abnormal melt curve profile during prothrombin 20210G → A analysis due to the 20209C → T variant

Dunn

Allen

Bates

et al. 2006

Blood Coagulation &Amp; Fibrinolysis

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“…RAS or DCPAS mutations that could affect mRNA 3¢ end formation F2: C20221T is probably a pathological mutation in a CstF binding site but the functional consequences of A20218G are less clear A C20221T mutation in the F2 gene was identified in a 9-year-old child with acute vascular rejection and intrarenal segmental arterial thrombosis of an allogeneic kidney transplant (Wylenzek et al 2001), a 28-year-old man with Budd-Chiari syndrome (Balim et al 2003), and a 40-year-old women with pregnancy complications (Schrijver et al 2003), respectively. The clinical phenotypes of these patients are consistent with a gain-offunction mutation.…”

Section: ¢ Fr Variantsmentioning

confidence: 99%

A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes I: general principles and overview

2006

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The 3' regulatory regions (3' RRs) of human genes play an important role in regulating mRNA 3' end formation, stability/degradation, nuclear export, subcellular localization and translation and are consequently rich in regulatory elements. Although 3' RRs contain only approximately 0.2% of known disease-associated mutations, this is likely to represent a rather conservative estimate of their actual prevalence. In an attempt to catalogue 3' RR-mediated disease and also to gain a greater understanding of the functional role of regulatory elements within 3' RRs, we have performed a systematic analysis of disease-associated 3' RR variants; 121 3' RR variants in 94 human genes were collated. These included 17 mutations in the upstream core polyadenylation signal sequence (UCPAS), 81 in the upstream sequence (USS) between the translational termination codon and the UCPAS, 6 in the left arm of the 'spacer' sequence (LAS) between the UCPAS and the pre-mRNA cleavage site (CS), 3 in the right arm of the 'spacer' sequence (RAS) or downstream core polyadenylation signal sequence (DCPAS) and 7 in the downstream sequence (DSS) of the 3'-flanking region, with 7 further mutations being treated as isolated examples. All the UCPAS mutations and the rather unusual cases of the DMPK, SCA8, FCMD and GLA mutations exert a significant effect on the mRNA phenotype and are usually associated with monogenic disease. By contrast, most of the remaining variants are polymorphisms that exert a comparatively minor influence on mRNA expression, but which may nevertheless predispose to or otherwise modify complex clinical phenotypes. Considerable efforts have been made to validate/elucidate the mechanisms through which the 3' untranslated region (3' UTR) variants affect gene expression. It is hoped that the integrative approach employed here in the study of naturally occurring variants of actual or potential pathological significance will serve to complement ongoing efforts to identify all functional regulatory elements in the human genome.

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“…This novel C→T mutation at position 20221 (F2 20221*T) has been identified in a 9-year-old patient with an acute vascular rejection and intrarenal segmental arterial thrombosis of an allogeneic kidney transplant [41], in a 28-year-old man with Budd-Chiari syndrome [42], and has also been found to be associated with recurrent fetal loss and intrauterine growth retardation in a 40-year-old South Asian female with a family history of thrombosis [43]. Although this rare mutation has only been found in a small number of patients, the location in the F2 3′ end processing signal and the observed clinical phenotypes suggest that the F2 20221 mutation may be thrombosis related by increasing 3′ end processing efficiency.…”

Section: ′ End Processing and Prothrombin Mutations In Thrombophiliamentioning

confidence: 99%

3′ End Processing of the Prothrombin mRNA in Thrombophilia

Danckwardt¹,

Hartmann²,

Gehring³

et al. 2006

Acta Haematol

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Clinical and genetic studies have led to the discovery of specific genotypes that predispose to thromboembolism in adults and children. The exploration of the underlying pathologies has revealed a broad variety of affected molecular mechanisms. Most recently, the functional analysis of the prothrombin (F2) 20210*A variant revealed increased efficiency of 3′ end processing as a novel genetic mechanism predisposing to human disease. Here, we review the 3′ end processing of the human F2 mRNA and demonstrate how clinically relevant mutations in the F2 gene contribute to thrombophilia by interfering with a tightly balanced architecture of noncanonical 3′ end formation signals.

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Budd–Chiari syndrome in a patient heterozygous for the point mutation C20221T of the prothrombin gene

Cited by 18 publications

References 5 publications

Abnormal melt curve profile during prothrombin 20210G → A analysis due to the 20209C → T variant

Abnormal melt curve profile during prothrombin 20210G → A analysis due to the 20209C → T variant

A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes I: general principles and overview

3′ End Processing of the Prothrombin mRNA in Thrombophilia

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