Genetic analyses of novel compound heterozygous hypodysfibrinogenemia, Tsukuba I: FGG c.1129+62_65 del AATA and FGG c.1299+4 del A

Mukai, Saki; Nagata, Kazuhiro; Ikeda, Minami; Arai, Shinpei; Sugano, Mitsutoshi; Honda, Takayuki; Okumura, Nobuo

doi:10.1016/j.thromres.2016.11.002

Cited by 10 publications

(6 citation statements)

References 31 publications

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“…deep intronic mutations or high clinical suspicion despite normal laboratory tests). 21,22 Second, the number of hypodysfibrinogenaemic probands was too low to assess the genetic epidemiology of this subtype of CFD. Even though most of the reported fibrinogen variants have been widely investigated, the pathogenic role of some new mutations has not been completely validated.…”

Section: Discussionmentioning

confidence: 99%

Mutational Epidemiology of Congenital Fibrinogen Disorders

et al. 2018

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Background Numerous mutations in FGA, FGB or FGG lead to congenital fibrinogen disorders (CFDs), but their epidemiology is not well characterized. The aim of this study was to evaluate the molecular epidemiology of CFD and to develop a genotyping strategy. Methods Genetic data from 266 unrelated CFD patients genotyped at our laboratory and from a CFD open access database (n = 1,142) were evaluated. We developed a step-wise screening strategy for the molecular diagnosis of CFD and prospectively tested this strategy on 32 consecutive CFD probands. Results We identified 345 mutated alleles overall, among 187 heterozygous, 63 homozygous and 16 compound heterozygous individuals. Afibrinogenemia was almost always caused by null mutations (98.6%), mainly in FGA (85%). Hypofibrinogenemia was mainly caused by missense mutations of FGB or FGG (54.2%). Dysfibrinogenemia was almost always caused by heterozygous missense mutations (99.3%) in FGA and FGG. Hotspot mutations were prevalent among quantitative (33.1%) and qualitative fibrinogen disorders (71.1%). The mutational cluster at our laboratory was similar with that reported in the CFD open access database. The proposed step-wise genetic screening strategy proved efficient in both the development and validation samples for CFD: the screening of FGA exons 2, 4, 5 and FGG exon 8 and search for the 11 kb deletion of FGA led to the identification of approximately 80% of mutated alleles, including 15 new mutations. Conclusion The described molecular epidemiology of CFD is complex. The proposed step-wise genetic screening strategy may provide an efficient way to identify causative mutations analysing a minimal number of exons.

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Section: Discussionmentioning

confidence: 99%

Mutational Epidemiology of Congenital Fibrinogen Disorders

et al. 2018

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“…The expression vectors Bβ-wt and Bβ-mt were introduced into CHO cell lines using lipofection, as described previously [ 19 , 20 ]. Transfected CHO cell lines were cultured in 5% CO 2 at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

A Novel Mutation in the Fibrinogen Bβ Chain (c.490G>A; End of Exon 3) Causes a Splicing Abnormality and Ultimately Leads to Congenital Hypofibrinogenemia

Taira

Matsuda

Arai

et al. 2017

IJMS

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We found a novel heterozygous mutation in the fibrinogen Bβ chain (c.490G>A) of a 3-year-old girl with congenital hypofibrinogenemia. To clarify the complex genetic mechanism, we made a mini-gene including a FGB c.490G>A mutation region, transfected it into a Chinese Hamster Ovary (CHO) cell line, and analyzed reverse transcription (RT) products. The assembly process and secretion were examined using recombinant mutant fibrinogen. Direct sequencing demonstrated that the mutant RT product was 99 bp longer than the wild-type product, and an extra 99 bases were derived from intron 3. In recombinant expression, a mutant Bβ-chain was weakly detected in the transfected CHO cell line, and aberrant fibrinogen was secreted into culture media; however, an aberrant Bβ-chain was not detected in plasma. Since the aberrant Bβ-chain was catabolized faster in cells, the aberrant Bβ-chain in a small amount of secreted fibrinogen may catabolize in the bloodstream. FGB c.490G>A indicated the activation of a cryptic splice site causing the insertion of 99 bp in intron 3. This splicing abnormality led to the production of a Bβ-chain possessing 33 aberrant amino acids, including two Cys residues in the coiled-coil domain. Therefore, a splicing abnormality may cause impaired fibrinogen assembly and secretion.

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“…The immunological fibrinogen level was determined using anti-fibrinogen antibody-coated latex particles (Q-May Co., Ohita, Japan). The thrombin clotting time for plasma was also measured as described previously [23].…”

Section: Coagulation Testsmentioning

confidence: 99%

Acquired dysfibrinogenemia: monoclonal λ-type IgA binding to fibrinogen caused lower functional plasma fibrinogen level and abnormal clot formation

et al. 2020

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Background: We reported a case of acquired dysfibrinogenemia with monoclonal gammopathy of undetermined significance presenting λ-type IgA M protein. The patient showed lower functional (0.38 g/dL) and normal immunological fibrinogen (3.24 g/dL).To examine the cause of the false lower value of fibrinogen, we performed experiments using the patient's purified fibrinogen and IgA. Methods: Fibrinogen was purified from the patient's plasma, and IgA was purified from patient's plasma or serum by immunoaffinity chromatography. We performed thrombincatalyzed fibrin polymerization, scanning electron microscopy (SEM), immunoblotting analysis, and enzyme-linked immunosorbent assays (ELISAs).Results: Fibrin polymerization in the patient's plasma was markedly reduced, and SEM showed no fiber bundles or sponge-like structures. Purified IgA did not influence polymerization, whereas immunoprecipitated plasma with an anti-IgA (α-chain) antibody indicated normalization of polymerization and clot structure. Western blotting analysis revealed the presence of monoclonal λ-type IgA-bound fibrinogen, and the proportion was significantly higher than normal control plasma using ELISA. Conclusion: Our results suggested that IgA M protein-bound fibrinogen is not normally converted into fibrin, and instead finally forms an aberrantly structured fragile clot. The 3 patient's reduced plasma fibrinogen level was caused by the presence of IgA M proteinbound fibrinogen and not by IgA M protein alone.

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Genetic analyses of novel compound heterozygous hypodysfibrinogenemia, Tsukuba I: FGG c.1129+62_65 del AATA and FGG c.1299+4 del A

Abstract: Introduction: We found a novel hypodysfibrinogenemia designated Tsukuba I caused by

Cited by 10 publications

References 31 publications

Mutational Epidemiology of Congenital Fibrinogen Disorders

Mutational Epidemiology of Congenital Fibrinogen Disorders

A Novel Mutation in the Fibrinogen Bβ Chain (c.490G>A; End of Exon 3) Causes a Splicing Abnormality and Ultimately Leads to Congenital Hypofibrinogenemia

Acquired dysfibrinogenemia: monoclonal λ-type IgA binding to fibrinogen caused lower functional plasma fibrinogen level and abnormal clot formation

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