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PMID:18676163

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Citation

Platè, M, Asselta, R, Spena, S, Spreafico, M, Fagoonee, S, Peyvandi, F, Tenchini, ML and Duga, S Congenital hypofibrinogenemia: characterization of two missense mutations affecting fibrinogen assembly and secretion. Blood Cells Mol. Dis. 41:292-7

Abstract

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by abnormally low levels of fibrinogen in plasma, generally due to heterozygous mutations in one of the three fibrinogen genes (FGA, FGB, and FGG, coding for Aalpha, Bbeta, and gamma chain, respectively). Hypofibrinogenemic patients are usually asymptomatic, whereas individuals bearing similar mutations in the homozygous or compound heterozygous state develop a severe bleeding disorder: afibrinogenemia. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations affecting fibrinogen assembly or secretion, distributed throughout the 50-kb fibrinogen gene cluster. In this study, we report the mutational screening of two unrelated hypofibrinogenemic patients leading to the identification of two missense mutations, one hitherto unknown (alphaCys45Phe), and one previously described (gammaAsn345Ser). The involvement of alphaCys45Phe and gammaAsn345Ser in the pathogenesis of hypofibrinogenemia was investigated by in-vitro expression experiments. Both mutations were demonstrated to cause a severe impairment of intracellular fibrinogen processing, either by affecting half-molecule dimerization (alphaCys45Phe) or by hampering hexamer secretion (gammaAsn345Ser).

Links

PubMed Online version:10.1016/j.bcmd.2008.06.004

Keywords

Adult; Afibrinogenemia/congenital; Afibrinogenemia/diagnosis; Afibrinogenemia/genetics; Animals; COS Cells; Cercopithecus aethiops; DNA Mutational Analysis; Fibrinogen/genetics; Fibrinogen/metabolism; Fibrinogen/secretion; Humans; Male; Mutagenesis, Site-Directed; Mutation, Missense; Point Mutation; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FIBA

involved_in

GO:0065003: protein-containing complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBG

involved_in

GO:0009306: protein secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBG

part_of

GO:0005577: fibrinogen complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FIBG

involved_in

GO:0009306: protein secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_direct_input:(GO:0005577)

Seeded From UniProt

complete

HUMAN:FIBA

part_of

GO:0005577: fibrinogen complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FIBA

involved_in

GO:0065003: protein-containing complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_direct_input:(GO:0005577)

Seeded From UniProt

complete

HUMAN:FIBB

part_of

GO:0005577: fibrinogen complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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