Dataset Information

C.259A>C in the fibrinogen gene of alpha chain (FGA) is a fibrinogen with thrombotic phenotype.

ABSTRACT: Introduction:Dysfibrinogenemia is a rare inherited disease that results from mutation in one of the three fibrinogen genes. Diagnosis can be misleading since it may present as a bleeding tendency or thrombosis and a specific coagulation test for diagnosis is not routinely available. Aim:To search for a new candidate gene of thrombophilia in a family with three generations of arterial and venous thrombosis. Methods:Whole exome sequencing followed by Sanger validation and segregation analysis was carried out. In addition, structural modeling was performed. Screening for thrombophilia along with blood counts, prothrombin time, activated partial thromboplastin, thrombin, reptilase time, and fibrinogen was done in each patient. Results and discussion:A missense c.259A>C, p.K87Q (g.chr4: 155510050A-C) (rs764281241) in FGA gene was found in all three siblings without any other known thrombophilia marker to explain thrombosis in all three siblings. It is expected to be damaging by six out of seven prediction programs and is very rare in the entire population with Exac=0.000008. Conclusion:The occurrence of the c.259A>C mutation in FGA may well explain the thrombosis phenotype of the affected family and is suggested as a new marker for thrombophilia phenotype.

SUBMITTER: Salomon O

PROVIDER: S-EPMC6400116 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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c.259A>C in the fibrinogen gene of alpha chain (<i>FGA</i>) is a fibrinogen with thrombotic phenotype.

Salomon Ophira O Barel Ortal O Eyal Eran E Ganor Reut Shnerb RS Kleinbaum Yeroham Y Shohat Mordechai M

The application of clinical genetics 20190228

<h4>Introduction</h4>Dysfibrinogenemia is a rare inherited disease that results from mutation in one of the three fibrinogen genes. Diagnosis can be misleading since it may present as a bleeding tendency or thrombosis and a specific coagulation test for diagnosis is not routinely available.<h4>Aim</h4>To search for a new candidate gene of thrombophilia in a family with three generations of arterial and venous thrombosis.<h4>Methods</h4>Whole exome sequencing followed by Sanger validation and seg ...[more]

PMID: 30881084

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Project description:p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen ?. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB-lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.

Dataset Information

C.259A>C in the fibrinogen gene of alpha chain (FGA) is a fibrinogen with thrombotic phenotype.

Publications

c.259A>C in the fibrinogen gene of alpha chain (<i>FGA</i>) is a fibrinogen with thrombotic phenotype.

Similar Datasets

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