Compound heterozygous mutations Glu502Lys and Met527Thr of the FXII gene in a patient with factor XII deficiency

Liu, Siqi; Lin, Chanchan; Luo, Shasha; Yang, Lizhu; Jin, Yanhui; Zhu, Li; Wang, Mingshan

doi:10.1080/16078454.2019.1598679

Cited by 11 publications

(7 citation statements)

References 19 publications

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“…The substitution may impair intracellular protein processing and eventually lead to a CRM-negative FXII deficiency. Zhang et al had previously shown Met527Thr mutation to be the cause of FXII deficiency in a family, which is the same site but different mutant amino acid from our study [21].…”

Section: Discussionsupporting

confidence: 44%

A novel homozygous missense mutation (Met527Ile) in a consanguineous marriage family with inherited factor XII deficiency

et al. 2020

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Objective: To identify potential mutations of the FXII gene (F12) in a consanguineous marriage family with hereditary coagulation factor XII (FXII) deficiency, and it will improve the understanding of the pathogenesis involved in the disease. Clinical presentation: The proband was a 58-year-old male who had chronic gastritis. He was found to have a significantly prolonged activated partial thromboplastin time (APTT) at 101.0s (reference range, 29.0-43.0 s) before stomachendoscopy. Techniques: The coagulation factor XII activity (FXII:C) and FXII antigen (FXII:Ag) were measured by one-stage clotting assay and enzyme-linked immunosorbent assay, respectively. The F12 gene was amplified by polymerase chain reaction and sequenced. Mutation sites were further confirmed by reverse sequencing. The conservatism and possible impact of the amino acid substitution were analyzed by multiple bioinformatics tools, as well as 3D protein model analysis. Results: The proband had a prolonged APTT (101.0 s), whose FXII:C and FXII:Ag were obviously reduced, both at 1.0% (normal range, 72-113%). Gene sequencing revealed that he carried a homozygous missense mutation of Met527Ile. Family study showed that his mother, son and daughter carried a heterozygous Met527Ile. Bioinformatics and model analysis of the mutation indicated that Met527Ile may be detrimental and potentially alters the structure and the function of the protein. Conclusion:The novel mutation Met527Ile could potentially account for the reduced activity of FXII in this family.

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Section: Discussionsupporting

confidence: 44%

A novel homozygous missense mutation (Met527Ile) in a consanguineous marriage family with inherited factor XII deficiency

et al. 2020

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“…Since its discovery, it has become clear that the contact system is a driving force behind thrombosis and hemoincompatibility (4). Remarkably, deficiency in contact factors does not translate into bleeding disorders (5–7), suggesting that a function beyond hemostasis justifies the existence of this enzyme system.…”

Section: Introductionmentioning

confidence: 99%

Plasminflammation—An Emerging Pathway to Bradykinin Production

Maas

2019

Front. Immunol.

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Plasminogen activation is essential for fibrinolysis—the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.

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“…Different range genetic testing was performed to test genetic variations of SERPING1. Firstly, Sanger sequencing of the gene coding part (using primers from published manuscript with Big Dye Terminator kit 3.0 following manufacturer protocol) was conducted [17][18][19]. For two cases, exome sequencing (performed using Twist Bioscience reagents at CeGaT medical laboratory) analysis of the single nucleotide variation and copy number variation (CNV) in SERPING1 were done.…”

Section: Genetic Testingmentioning

confidence: 99%

National survey on clinical and genetic characteristics of patients with hereditary angioedema in Latvia

Kanepa

Nartisa

Rots

et al. 2023

Allergy Asthma Clin Immunol

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Background Hereditary angioedema (HAE) is a rare and life-threatening inborn error of immunity. HAE is mostly caused by pathogenic variations in the serine protease inhibitor gene 1 (SERPING1), leading to deficient or dysfunctional C1-inhibitor (C1-INH), overproduction of bradykinin, and development of recurrent subcutaneous and/or submucosal oedema. The prevalence of HAE is 1 in 50,000 − 100000 people worldwide. We aimed to describe the clinical features and genetic spectrum of hereditary angioedema with C1-INH deficiency (C1-INH-HAE) in Latvia. Methods All patients from Latvia diagnosed with HAE (types I/II) from 2006 to March 2022 were included in the study. Laboratory tests and clinical data were analysed, and genetic tests with Sanger sequencing and whole genome sequencing were performed. Results The study identified 10 C1-INH-HAE patients (nine females, one male) from eight families. The point prevalence of HAE in Latvia is 0.53 per 100 000 inhabitants. Of all patients, seven (70%) had HAE type I and three (30%) had HAE type II. The median age of patients was 54 years and the median age at onset of symptoms was 15 years. A significant delay (median 20.5 years) until diagnosis was observed, and 60% of patients had a positive family history of angioedema. All HAE patients have been hospitalised a median two times during their lifetime. Skin (100%), abdominal (80%), and airway (80%) oedema were the most frequent symptoms. Triggering factors (60%) and prodromal symptoms (90%) were referred. Attacks were severe in 50% of patients, moderate in 10%, and mild in 40%. Pathogenic variations of SERPING1 were identified in eight patients (six families), confirming the diagnosis molecularly. In two patients (two families), no pathogenic variations in the genes were found even after whole genome sequencing. Conclusions Current data shows a significant delay and clear underdiagnosis of HAE in Latvia. Higher awareness and better information and communication between doctors would improve the diagnosis and management of HAE; as would screening of family members, patients with recurrent angioedema unresponsive to antihistamines and glucocorticoids, and patients with recurrent episodes of severe, unexplained abdominal pain.

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Compound heterozygous mutations Glu502Lys and Met527Thr of the FXII gene in a patient with factor XII deficiency

Cited by 11 publications

References 19 publications

A novel homozygous missense mutation (Met527Ile) in a consanguineous marriage family with inherited factor XII deficiency

A novel homozygous missense mutation (Met527Ile) in a consanguineous marriage family with inherited factor XII deficiency

Plasminflammation—An Emerging Pathway to Bradykinin Production

National survey on clinical and genetic characteristics of patients with hereditary angioedema in Latvia

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