Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion.

Kant, Jeffrey A.; Fornace, Albert J.; Saxe, Debra; Simon, M; McBride, O W; Crabtree, Gerald R.

doi:10.1073/pnas.82.8.2344

Cited by 256 publications

(174 citation statements)

References 38 publications

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“…Clinical presentation is highly variable13 and approximately 50% of CD patients are diagnosed incidentally 14, 15. Hypodysfibrinogenemia is defined by disproportionately decreased fibrinogen antigen and decreased function 5. Patients with hypodysfibrinogenemia patients can be asymptomatic or have bleeding and/or clotting events.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

Smith

Bornikova

Noetzli

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Fibrinogen Disorders are characterized by variable expressivity.Patients with fibrinogen disorders can present with bleeding, thrombosis, or both.As previously reported, genotype‐phenotype correlations are difficult to establish.Molecular modeling may help to further understand the effects of mutations on the mature fibrinogen protein. IntroductionFibrinogen is a complex molecule comprised of two sets of Aα, Bβ, and γ chains. Fibrinogen deficiencies can lead to the development of bleeding or thromboembolic events. The objective of this study was to perform DNA sequence analysis of patients with clinical fibrinogen abnormalities, and to perform genotype‐phenotype correlations.Materials and Methods DNA from 31 patients was sequenced to evaluate disease‐causing mutations in the three fibrinogen genes: FGA,FGB, and FGG. Clinical data were extracted from medical records or from consultation with referring hematologists. Fibrinogen antigen and functional (Clauss method) assays, as well as reptilase time (RT) and thrombin time (TT) were obtained for each patient. Molecular modeling was used to simulate the functional impact of specific missense variants on the overall protein structure.ResultsSeventeen mutations, including six novel mutations, were identified in the three fibrinogen genes. There was little correlation between genotype and phenotype. Molecular modeling predicted a substantial conformational change for a novel variant, FGG p.Ala289Asp, leading to a more rigid molecule in a region critical for polymerization and alignment of the fibrin monomers. This mutation is associated with both bleeding and clotting in the two affected individuals.ConclusionsRobust genotype‐phenotype correlations are difficult to establish for fibrinogen disorders. Molecular modeling might represent a valuable tool for understanding the function of certain missense fibrinogen mutations but those should be followed by functional studies. It is likely that genetic and environmental modifiers account for the incomplete penetrance and variable expressivity that characterize fibrinogen disorders.

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Section: Introductionmentioning

confidence: 99%

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

Smith

Bornikova

Noetzli

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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“…Three chains are coded by FGA, FGB, and FGG (located as a cluster on chromosome 4q31), respectively [2], and synthesized, assembled into a six-chain molecule in hepatocytes, secreted into blood, and circulated at 1.8-3.5 g/l. [3].…”

Section: Introductionmentioning

confidence: 99%

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

Mukai

Nagata

Ikeda

et al. 2016

Thrombosis Research

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“…Fibrinogen is a 340 kDa plasma glycoprotein that is composed of two sets of three different polypeptide chains: Aα, Bβ, and γ, which are stabilized by 29 disulfide bonds, including intrachain and interchain connections and represented as (Aα-Bβ-γ) 2 [1]. The fibrinogen molecule has a trinodular structure in which the central E region contains the N-termini of all six chains and the external D regions contain the C-termini of the Bβ-and γ-chains and a short segment of the Aα-chains.…”

Section: Introductionmentioning

confidence: 99%

“…The C-termini of the Aα-chains (αC domains) extend briefly through the D regions and fold back into coiled-coil connectors [1]. Three chains are coded by FGA, FGB, and FGG [2], and synthesized, assembled into a six-chain molecule in hepatocytes, and secreted into blood.…”

Section: Introductionmentioning

confidence: 99%

Differences in the function and secretion of congenital aberrant fibrinogenemia between heterozygous γD320G (Okayama II) and γΔN319-ΔD320 (Otsu I)

Mukai

Ikeda

Takezawa

et al. 2015

Thrombosis Research

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Background:We encountered two patients with hypodysfibrinogenemia and designated them as Okayama II and Otsu I. Although the affected residue(s) in Okayama II and Otsu I overlapped, functionally determined fibrinogen levels and the ratio of functionally to immunologically determined plasma fibrinogen levels were markedly different. Methods: DNA sequence and functional analyses were performed for purified plasma fibrinogen. A recombinant protein was synthesized in Chinese hamster ovary (CHO) cells to determine the secretion of variant fibrinogens. Results: A heterozygous ANG in FGG, resulting in γ320AspNGly for Okayama II, and a heterozygous deletion of AATGAT in FGG, resulting in the deletion of γAsn319 and γAsp320 (γΔN319-ΔD320) for Otsu I, were obtained. SDS-PAGE and Coomassie staining revealed that the variant γ-chain was not clear in Okayama II, but was clearly present in Otsu I. The lag period for the fibrin polymerization of Okayama II was slightly slower than that of the normal control, whereas Otsu I fibrinogen indicated no polymerization within 30 min. Both variant γ-chains were synthesized in CHO cells and assembled into fibrinogen; however, the fibrinogen concentration ratio of the medium/cell lysate of γ320Gly was six-fold lower than that of γΔN319-ΔD320. Conclusions: We concluded that the plasma fibrinogen of Okayama II, constituted by a lower ratio of the variant γ-chain, led to the almost normal functioning of fibrin polymerization. However, the plasma fibrinogen of Otsu I, with a higher ratio of the variant γ-chain, led to marked reductions in fibrin polymerization.

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Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion.

Abstract: Human fibrinogen cDNA probes for the a-,

Cited by 256 publications

References 38 publications

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

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

Differences in the function and secretion of congenital aberrant fibrinogenemia between heterozygous γD320G (Okayama II) and γΔN319-ΔD320 (Otsu I)

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