Hypofibrinogenaemia associated with a novel heterozygous γ289 Ala→Val substitution (fibrinogen Dorfen)

Dear, Amy; Brennan, Stephen O.; Dempfle, Carl-Erik; Kirschstein, W.; George, Peter M.

doi:10.1160/th04-07-0409

Cited by 7 publications

(3 citation statements)

References 16 publications

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“…Accordingly, the coagulatory impairment of this disease was simply explained as hypofibrinogemia. 4 In contrast, the present study suggested that the variant fibrinogen was slightly secreted into the blood and showed lower function of fibrin polymerization.…”

Section: Discussioncontrasting

confidence: 82%

“…Moreover, there was also no such episode in the Dorfen report. 4 Therefore, it seems that replacement therapy was not necessary during the first trimester for this patient. Therapy appropriate to the phenotype must be provided, considering the exact period and dosing duration in order to reduce the risk of adverse events.…”

Section: Discussionmentioning

confidence: 90%

“…However, with fibrinogen Dorfen, the patient had normal fibrinogen function and the mutated type of fibrinogen protein was not detected in the blood circulation. 4 Based on these findings, the authors speculated that the mutated protein could not be secreted from hepatocytes. However, in our case, impairment of the fibrinogen function in the plasma was observed.…”

Section: Discussionmentioning

confidence: 99%

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Familial discrepancy of clinical outcomes associated with fibrinogen Dorfen: A case of huge genital hematoma after episiotomy

Kagami

Yamazaki

Minami

et al. 2016

J of Obstet and Gynaecol

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This study demonstrates a case of a huge genital hematoma after delivery, associated with fibrinogen Dorfen. Fibrinogen Dorfen is the mutation of a fibrinogen-coded exon gene, which has a single heterozygous GCC → GTC transition at codon 289 of the γ gene, predicting an Ala → Val substitution. Because Ala289 plays a crucial role in maintaining the structure of the polymerization site of hole 'a' via a hydrogen bond, it is speculated that the γ 289Ala → Val substitution can change not only the fibrinogen structure, but also the function of polymerization. In our case, although the patient's gene mutation was the same as that of her mother, there was a discrepancy in the clinical outcomes. Although the precise mechanism regarding this discrepancy remains unknown, it may cause different perinatal outcomes in terms of vaginal delivery, such as the severe bleeding in this patient and the absence of clinical symptoms in her mother. This is the first report suggesting the heterogeneity of fibrinogen functions of fibrinogen Dorfen, which may be critical to the clinical outcome.

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Section: Discussioncontrasting

confidence: 82%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Familial discrepancy of clinical outcomes associated with fibrinogen Dorfen: A case of huge genital hematoma after episiotomy

Kagami

Yamazaki

Minami

et al. 2016

J of Obstet and Gynaecol

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Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Neerman-Arbez

Moerloose

2007

Hum. Mutat.

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Communicated by Arupa GangulyFibrinogen is synthesized in hepatocytes in the form of a hexamer composed of two sets of three polypeptides (Aa, Bb, and c). Each polypeptide is encoded by a distinct gene, FGA, FGB, and FGG, all three clustered in a region of 50 kb on 4q31. Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Although the disease was first described in 1920, the genetic defect responsible for this disorder long remained unknown. We identified the gene and the first causative mutations for this disease in a nonconsanguineous Swiss family in 1999. Since this first report, 61 additional mutations, the majority in FGA, have been identified in patients with afibrinogenemia (in homozygosity or in compound heterozygosity) or in heterozygosity in hypofibrinogenemia, since many of these patients are in fact asymptomatic carriers of afibrinogenemia mutations. Mutations in the fibrinogen genes may lead to deficiency of fibrinogen by several mechanisms: these can act at the DNA level, at the RNA level by affecting mRNA splicing or stability, or at the protein level by affecting protein synthesis, assembly, or secretion. The expression of selected mutations has shown that mechanisms acting at all three levels play a role in the molecular basis of this disease. We report here the identification of 10 novel mutations, of which eight are localized in FGA, thus increasing the total number of causative mutations identified to 72 and confirming the relative importance of FGA in the molecular basis of fibrinogen deficiency. Hum Mutat 28(6), [540][541][542][543][544][545][546][547][548][549][550][551][552][553] 2007. r r 2007 Wiley-Liss, Inc.

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Congenital hypodysfibrinogenemia associated with a novel deletion of three residues (γAla289_Asp291del) in fibrinogen

Zhu

Zhao

Wang

et al. 2018

J Thromb Thrombolysis

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Hypodysfibrinogenemia is the least frequently reported congenital fibrinogen disorder, characterized by both quantity and quality defects of fibrinogen. In this study, we investigated the molecular basis of hypodysfibrinogenemia in a Chinese family. Functional fibrinogen was measured by Clauss method, and the antigenic fibrinogen was measured by immunoturbidimetry assay. All the exons and exon-intron boundaries of fibrinogen genes (FGA, FGB and FGG) were analysed by direct DNA sequencing. To further evaluate its molecular and functional characterizations, fibrinogen was purified from the plasma of propositus, then SDS-PAGE, fibrin polymerization, clot lysis, and electron microscopy scanning were all performed. The propositus showed a slight decrease of immunologic fibrinogen (1.52 g/L) but dramatically reduced functional fibrinogen (0.3 g/L). DNA sequencing revealed a novel heterozygous CCTTTGATG deletion in the exon 8 of FGG, leading to the deletion of Ala289, Phe290, and Asp291 in fibrinogen γ-chain. The polymerization of the fibrinogen from the propositus was markedly impaired, with prolonged lag period and decreased final turbidity. The fibrinogen clottability showed a reduced fraction of participating clot formation. While the clot lysis showed normal. Scanning electron microscopy revealed that the fibers of the propositus were thicker than normal, with larger pores and curlier meshworks. We conclude that γAla289_Asp291del is responsible for the hypodysfibrinogenemia in this case.

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Hypofibrinogenaemia associated with a novel heterozygous γ289 Ala→Val substitution (fibrinogen Dorfen)

Cited by 7 publications

References 16 publications

Familial discrepancy of clinical outcomes associated with fibrinogen Dorfen: A case of huge genital hematoma after episiotomy

Familial discrepancy of clinical outcomes associated with fibrinogen Dorfen: A case of huge genital hematoma after episiotomy

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Congenital hypodysfibrinogenemia associated with a novel deletion of three residues (γAla289_Asp291del) in fibrinogen

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