Recombinant variant fibrinogens substituted at residues γ326Cys and γ339Cys demonstrated markedly impaired secretion of assembled fibrinogen

Haneishi, Ayumi; Terasawa, Fumiko; Fujihara, Noriko; Yamauchi, Kazuyoshi; Okumura, Nobuo; Katsuyama, Tsutomu

doi:10.1016/j.thromres.2009.03.011

Cited by 9 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the effects of the mutations on the human body are more complex. When combined with naturally occurring heterozygous cases of γCys326Tyr and γCys326Ser and their results, Haneishi et al suggested that small amounts of variants might be secreted into plasma (24). So far, 2 heterozygous cases of 2 fibrinogen variants at γCys365 substituted by Ser or Asp have been reported, and these caused hypofibrinogenemia and hypodysfibrinogenemia, respectively (25,26).…”

Section: Discussionmentioning

confidence: 99%

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

et al. 2021

View full text Add to dashboard Cite

Background: Congenital hypofibrinogenemia is a rare bleeding disease that is classified as the quantitative deficient type. In the present study, investigated the relationship between the genotype and phenotype in a family with hypofibrinogenemia. Methods:The proband was aware of a predisposition to bleeding. Functional analysis was performed for her all family members, including coagulation function tests, thrombus molecular markers, thromboelastography, scanning electron microscopy, DNA sequencing, and high-performance liquid chromatography-mass spectrometry (HPLC-MS). Pathogenicity analysis and protein modeling of mutant amino acids were also performed.Results: A novel heterozygous mutation in c.1094delG was detected in FGG exon 8, which resulted in p.Cys365Phefs*41 (containing the signal peptide) in the proband and her mother, who showed a corresponding decrease in fibrinogen function and levels. Thromboelastography indicated that the strength of their blood clots decreased and they had an increased risk of bleeding. The proband fibrin network structure was looser than healthy controls, with large pores in the network, which increased the permeability of lytic enzymes.Results of HPLC-MS showed a lack of mutant peptide chain expression in their plasma, indicating that the family had congenital hypofibrinogenemia, with a clinical phenotype that is related to the degree of fibrinogen deficiency. The mutation truncated the γ-peptide chain and destroyed the functional structure of fibrinogen, including the γ352Cys-γ365Cys disulfide bond. The truncated peptide chains may also lead to nonsense-mediated decay. Conclusions:The mutation induced a structural change at the carboxyl-terminal of the fibrinogen molecule, leading to fibrinogen secretion dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

et al. 2021

View full text Add to dashboard Cite

show abstract

“…On one hand, mutations can lead to a decreased assembly and/or secretion of an abnormal fibrinogen chain. Pulse‐chase analysis of recombinant Suhl (Frostburg) and Cordoba Fibrinogen in CHO or COS‐1 cells showed that the rate of both assembly and secretion were lower than that of normal fibrinogen . On the other hand, Fibrinogen Otsu I (Vlissingen, Frankfurt IV) and Okayama II were normally synthetized and assembled but only partially secreted .…”

Section: Discussionmentioning

confidence: 99%

“…Seven additional hypodysfibrinogenemia cases were a result of compound heterozygosity for mutations on the same or different fibrinogen genes [4,8,[14][15][16][17][18]. Expression of recombinant fibrinogens was performed for seven fibrinogen variants [5][6][7][18][19][20][21].…”

Section: Molecular Anomaliesmentioning

confidence: 99%

“…On one hand, mutations can lead to a decreased assembly and/or secretion of an abnormal fibrinogen chain. Pulse-chase analysis of recombinant Suhl (Frostburg) and Cordoba Fibrinogen in CHO or COS-1 cells showed that the rate of both assembly and secretion were lower than that of normal fibrinogen [21,39].…”

Section: Diagnosis Of Hypodysfibrinogenemia: Hypo-vs Hypodysfibrinogmentioning

confidence: 99%

See 1 more Smart Citation

Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation

Casini

Brungs

Lavenu‐Bombled

et al. 2017

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Background Hypodysfibrinogenemia is a rare disease characterized by decreased levels of a dysfunctional fibrinogen. It shares features with both hypo- and dysfibrinogenemia, although with specific molecular patterns and clinical phenotypes. Objectives To better define the genetics, the diagnosis and the clinical features of hypodysfibrinogenemia. Patients/Methods A systematic literature search led to 167 records. After removal of duplicates, abstract screening and full-text reviewing, 56 molecular and/or clinical studies were analyzed, including a novel FGB missense mutation in a woman with a mild bleeding phenotype. Results A total of 32 single causative mutations were reported, mainly in the COOH-terminal region of the γ or Aα chains at heterozygous or homozygous state. Seven additional hypodysfibrinogenemias were due to compound heterozygosity. The hypofibrinogenemic phenotypes were a result of an impaired assembly or secretion or an increased clearance of the fibrinogen variant, whereas the dysfibrinogenemic phenotype was mainly a result of a defective fibrin polymerization and an abnormal calcium or tPA binding. Among 51 identified index cases, a functional/antigenic fibrinogen ratio < 0.7 had a sensitivity of 86% for the diagnosis of hypodysfibrinogenemia. Eleven patients (22%) were asymptomatic at time of diagnosis, 23 (45%) had a mild bleeding phenotype with mainly obstetrical or gynecologic-related hemorrhage and 22 (43%) had experienced at least one thrombotic event, including 23 venous and eight arterial thromboses. Conclusions This first systematic review on hypodysfibrinogenemia shows the heterogeneity of causative mutations and that misdiagnosis could occur in relation to the functional and antigenic fibrinogen levels. Family studies reveal an incomplete segregation of the mutation with the clinical phenotype.

show abstract

“…We have already established eight variant fibrinogen-synthesizing CHO cells, all showing reduced secretion of variant fibrinogen into the media [18,19]. In addition, these cells showed elevated levels of cytoplasmic fibrinogen.…”

Section: Introductionmentioning

confidence: 99%

γ375W fibrinogen-synthesizing CHO cells indicate the accumulation of variant fibrinogen within endoplasmic reticulum

Tamaki

Arai

Ogiwara

et al. 2014

Thrombosis Research

Self Cite

View full text Add to dashboard Cite

show abstract

Recombinant variant fibrinogens substituted at residues γ326Cys and γ339Cys demonstrated markedly impaired secretion of assembled fibrinogen

Cited by 9 publications

References 22 publications

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

A novel fibrinogen γ-chain frameshift mutation, p. Cys365Phefs*41, causing hypofibrinogenemia with bleeding phenotype in a Chinese family

Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation

γ375W fibrinogen-synthesizing CHO cells indicate the accumulation of variant fibrinogen within endoplasmic reticulum

Contact Info

Product

Resources

About