Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins

@article{V2007MolecularMA,
  title={Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins},
  author={Dũng Ch{\'i} Vũ and Marguerite Neerman-Arbez},
  journal={Journal of Thrombosis and Haemostasis},
  year={2007},
  volume={5}
}
Summary.  Fibrinogen, the soluble precursor of fibrin, which is the main protein constituent of the blood clot, is synthesized in hepatocytes in the form of a hexamer composed of two sets of three polypeptides (Aα, Bβ, and γ). Each polypeptide is encoded by a distinct gene, FGA, FGB and FGG, all three clustered in a region of 50 kb on 4q32. Congenital afibrinogenemia is characterized by the complete absence of fibrinogen. The first causative mutation for this disease was identified in Geneva in… 
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TLDR
The continuous characterization of novel molecular defects responsible for fibrinogen deficiency combined with modelling of mutant proteins will continue to provide a better comprehension of the complexity of fibr inogen synthesis and physiology.
Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation.
TLDR
The genetic basis of dys- and hypo-dysfibrinogenemia in seven unrelated patients was investigated, revealing six different variants, two of which novel (FGB-p.Asp185Asn and FGG- p.Asn230Lys) and the second gain-of-glycosylation mutation involving the FGB gene.
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The identification of a novel missense mutation in FGA exon 1 affecting the translation initiation codon is reported, identified in a young boy from Madagascar in compound heterozygosity with a second mutation in C>T (CGA>TGA) R129X.
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TLDR
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TLDR
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TLDR
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Fibrinogen is an abundant protein synthesized in the liver, present in human blood plasma at concentrations ranging from 1.5-4 g/L in healthy individuals with a normal half-life of 3-5 days. With
Congenital fibrinogen disorders: an update.
TLDR
Determination of the molecular defects is important because it gives the possibility to confirm the diagnosis, to elaborate a diagnostic strategy, to distinguish in some cases that the patient is at risk of thrombosis rather than bleeding, and to enable prenatal diagnosis.
Fibrinogen residue γAla341 is necessary for calcium binding and 'A-a' interactions.
TLDR
Fibrinogen residue γAla341 is important for the proper conformation of the γ-module, maintaining calcium-binding site and 'A-a' interactions, and is shown to be dependent on the calcium concentration.
A novel mutation in the FGB: c.1105C>T turns the codon for amino acid Bβ Q339 into a stop codon causing hypofibrinogenemia.
TLDR
Function analysis and sequencing of the three fibrinogen genes revealed a novel heterozygous nonsense mutation in the FGB gene c.1105C>T, which converts the codon for residue Bβ 339Q to stop, causing deletion of Bβ chain residues 339-461.
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References

SHOWING 1-10 OF 68 REFERENCES
Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia.
TLDR
Exercise of additional mutants and structural modelling suggests that neither the last six residues nor R455 is crucial per se for secretion, but prevent protein misfolding by protecting hydrophobic residues in the betaC core, and provides new insight into the mechanisms accounting for the quality control of fibrinogen secretion.
Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations
TLDR
The identification of 10 novel mutations are reported, 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.
Fibrinogen Mumbai: intracellular retention due to a novel G434D mutation in the Bbeta-chain gene.
TLDR
expression data confirm the importance of Bbeta-chain D domain folding in the intracellular processing of fibrinogen, and cause severe hypofibrinogensemia by impairing fibr inogen secretion.
Novel fibrinogen truncation with deletion of Bbeta chain residues 440-461 causes hypofibrinogenaemia.
TLDR
DNA sequencing of all exons, exon-intron boundaries and promoter regions of the fibrinogen Aalpha, Bbeta, and gamma genes revealed a single heterozygous g-->a mutation at nucleotide 8035 of the Bbeta gene, which creates a premature stop at the Trp 440 codon and results in a 22-residue truncation ofthe Bbeta chain.
Congenital afibrinogenemia: intracellular retention of fibrinogen due to a novel W437G mutation in the fibrinogen Bbeta-chain gene.
TLDR
Results of both pulse-chase experiments and enzyme-linked immunosorbent assays demonstrated intracellular retention of the mutant W437G fibrinogen and marked reduction of its secretion, underline the importance of the Bbeta-chain D domain in fibr inogen folding and secretion.
Deletion of the fibrogen alpha-chain gene (FGA) causes congenital afibrogenemia
TLDR
The identification of causative mutations in a nonconsanguineous Swiss family with congenital afibrinogenemia is reported and it is demonstrated that humans, like mice, may be born without the capacity to synthesize functional fibr inogen.
Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion.
TLDR
Transient transfection experiments with plasmids expressing wild-type and mutant fibrinogens demonstrated that the presence of either mutation was sufficient to abolish fibrInogen secretion, demonstrating that missense mutations in the Bbeta fibr inogen gene could cause congenital afibrinogenemia by impairing fibrine secretion.
Studies on the assembly and secretion of fibrinogen.
TLDR
A mechanism of assembly is proposed based on the assumption that all these complexes are precursors of complete fibrinogen, and the conditioned media of hepatocytes and of transfected COS cells contained free A alpha, free gamma, and two of the above-mentioned complexes.
A detailed consideration of a principal domain of vertebrate fibrinogen and its relatives
  • R. Doolittle
  • Biology, Medicine
    Protein science : a publication of the Protein Society
  • 1992
TLDR
Constraints imposed by the locations of cystines, carbohydrate attachment residues, and proteinase‐sensitive points provided further insights into the general organization of the postulated secondary structures of vertebrate fibrinogen.
Afibrinogenemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation.
TLDR
This is the first report of a mutation in the fibr inogen gamma-chain gene causing afibrinogenemia and indicates that, in addition to the Aalpha and Bbeta-chain genes, the gamma- chain gene must also be considered in mutation screening for afibrInogenemia.
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