Combined cis-regulator elements as important mechanism affecting FXII plasma levels

Sabater‐Lleal, Maria; Chillón, Miguel; Mordillo, Carolina; Martínez, Ángel; Gil-Guiñón, Estel; Mateo, José; Blangero, John; Almasy, Laura; Fontcuberta, Jordi; Soria, José Manuel Nieto

doi:10.1016/j.thromres.2009.08.019

Cited by 9 publications

(6 citation statements)

References 32 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard, genotyping the c.-4T>C status may provide important information in order to help predict the severity of HAE, and moreover, it could be readily included in next generation sequencing platforms intended for HAE diagnosis. With regard to the F12 gene, the c.-4T>C polymorphism is recognized as the only common variation accounting for the variability in the plasma levels of FXII ( Calafell et al, 2010 ; Sabater-Lleal et al, 2010 ). Carriers of the T allele showed a significant reduction in the plasma levels of FXII that reach in TT homozygous half of the values observed in CC homozygous ( Kanaji et al, 1998 ; Corral et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

et al. 2020

View full text Add to dashboard Cite

Background Hereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency. Objectives To assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients. Methods The c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate. Results The c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) ( p = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) ( p = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; p = 0.006) but not the degree of estrogen dependence or time until remission. Conclusion The c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease.

show abstract

Section: Discussionmentioning

confidence: 99%

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

et al. 2020

View full text Add to dashboard Cite

show abstract

“…HNF-4 null mice exhibit reduced expression of factor XII (22). In the present report of Thrombosis Research , Sabater-Lleal et al contribute to our understanding on what regulates factor XII plasma levels (23). These authors describe two new mutations, a C/G substitution at position -8 and a C/T substitution at position -13 of the factor XII gene that result in decreased expression levels.…”

mentioning

confidence: 82%

Why do we want to know how factor XII levels are modulated?

Schmaier

2010

Thrombosis Research

View full text Add to dashboard Cite

New interest in factor XII has been found due to the fact that its murine knockout animal is protected from arterial thrombosis in several models (1,2). The mechanism(s) for these observations have not been precisely described. However, several investigators have shown that factor XII converting to factor XIIa presumably by autoactivation on surfaces such as platelet polysomes, expressed RNA, exposed vascular collagen, and/or aggregated protein contributes to developing thrombus (3-6). Since factor XII participates in the size of an induced-clot formation it has a role in thrombosis. This activity describes for the first time an in vivo pathophysiologic event contributed to by factor XII/XIIa.It is known from the observations of Ratnoff and others that factor XII is essential for surface activated blood coagulation reactions (7). Recognition that factor XII initiates test-tube blood coagulations was the basis for the waterfall hypothesis for the blood coagulation system (8). However, factor XII deficient patients do not have a bleeding defect even though their surfaceactivated blood coagulation tests are prolonged. Thus, factor XII is not a hemostatic protein.The dichotomy of factor XII being needed for normal blood coagulation tests, but not hemostasis has confused this field for decades. Now that it is generally agreed that tissue factor is the physiologic initiator of blood coagulation leading to hemostasis, the contact activation system needs to be redefined (9,10). Contact activation mechanisms explain how common blood coagulations tests like the activated partial thromboplastin time (APTT) or activated coagulation time (ACT) which are performed on millions of patients annually work. The molecular mechanism for factor XII autoactivation still is not known. Factor XII autoactivation at the molecular level occurs by imposing specific orientation and ordering on the adsorbed protein molecules on sum frequency generation vibrational spectroscopy (11). Alternatively, factor XII in vivo may be activated by contact as described above with various biologic substances in developing thrombus or secondary to formed plasma kallikrein, its only known enzyme activator.The kinetics of factor XII activation by plasma kallikrein (K m =11 µM) is similar to factor XIIa activation of prekallikrein (K m =2.4 µM). However, the K m of prekallikrein activation in vivo by its endothelial cell membrane expressed serine protease, prolylcarboxypeptidase, is 9 nM (12). These latter kinetic data suggest that physiologic factor XII activation is secondary to plasma kallikrein formation. However, it has yet to be shown if prolylcarboxypeptidase is important for in vivo prekallikrein activation for factor XII activation. Although C1 inhibitor deficient mice have angioedema, indicating higher constitutive bradykinin formation from

show abstract

“…Hepatocyte nuclear factor‐4 (HNF4) is a transcription factor that can both inhibit and enhance FXII expression . HNF4 knockout mice had decreased expression of FXII , and mutations in the putative HNF4 binding site in humans also had reduced FXII expression . Additional studies are needed to determine how expression of FXII in liver disease affects thrombotic risk.…”

Section: Regulation Of Fxii In Hepatocytesmentioning

confidence: 99%

Contact system revisited: an interface between inflammation, coagulation, and innate immunity

Long

Kenne

Jung

et al. 2016

Journal of Thrombosis and Haemostasis

262

286

View full text Add to dashboard Cite

Summary. The contact system is a plasma protease cascade initiated by factor XII (FXII) that activates the proinflammatory kallikrein-kinin system and the procoagulant intrinsic coagulation pathway. Anionic surfaces induce FXII zymogen activation to form proteolytically active FXIIa. Bacterial surfaces also have the ability to activate contact system proteins, indicating an important role for host defense using the cooperation of the inflammatory and coagulation pathways. Recent research has shown that inorganic polyphosphate found in platelets activates FXII in vivo and can induce coagulation in pathological thrombus formation. Experimental studies have shown that interference with FXII provides thromboprotection without a therapy-associated increase in bleeding, renewing interest in the FXIIa-driven intrinsic pathway of coagulation as a therapeutic target. This review summarizes how the contact system acts as the cross-road of inflammation, coagulation, and innate immunity.

show abstract

Combined cis-regulator elements as important mechanism affecting FXII plasma levels

Abstract: Introduction-Factor XII (FXII) deficiency is a recessive Mendelian trait due to mutations in the F12 gene. There is no bleeding associated with FXII deficiency, but FXII deficiency has been reported to be associated with risk of thrombosis in some studies.

Cited by 9 publications

References 32 publications

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

Why do we want to know how factor XII levels are modulated?

Contact system revisited: an interface between inflammation, coagulation, and innate immunity

Contact Info

Product

Resources

About