Hypodysfibrinogenaemia due to production of mutant fibrinogen alpha-chains lacking fibrinopeptide A and polymerisation knob ‘A’

Autor: Christine Biron-Andréani, Lionel Reyftmann, Richard J. Fish, Philippe de Moerloose, Chandrasekaran Nagaswami, Pierre Boulot, John W. Weisel, Silja Vorjohann, Marguerite Neerman-Arbez
Rok vydání: 2010
Předmět:
Male
Fibrinogen/*genetics/metabolism
DNA Mutational Analysis
medicine.disease_cause
Fibrinogen
Compound heterozygosity
Exon
Fibrinogens
Abnormal/*genetics/metabolism
Fibrinopeptide A/*genetics/metabolism
Chlorocebus aethiops
ddc:576.5
Blood coagulation test
ddc:616
Genetics
Mutation
biology
Fibrinogens
Abnormal
Blood Coagulation/*genetics
Hematology
Afibrinogenemia
Pedigree
Phenotype
COS Cells
Female
Blood Coagulation Tests
medicine.drug
Adult
Heterozygote
Adolescent
RNA Splicing
Blotting
Western
Transfection
Article
Fibrin
Cercopithecus aethiops
Young Adult
Thrombin
medicine
Animals
Humans
Genetic Predisposition to Disease
Blood Coagulation
Fibrinopeptide A
Afibrinogenemia/blood/*genetics
Molecular biology
Introns
Microscopy
Electron
Scanning
biology.protein
Protein Multimerization
Minigene
Zdroj: Thrombosis and Haemostasis, Vol. 104, No 5 (2010) pp. 990-997
ISSN: 2567-689X
0340-6245
DOI: 10.1160/th10-03-0161
Popis: SummaryInherited disorders of fibrinogen are rare and affect either the quantity (hypofibrinogenaemia and afibrinogenaemia) or the quality of the circulating fibrinogen (dysfibrinogenaemia) or both (hypodysfibrinogenaemia). Extensive allelic heterogeneity has been found for all these disorders: in congenital afibrinogenaemia for example more than 40 mutations, the majority in FGA, have been identified in homozygosity or in compound heterozygosity. Numerous mutations have also been identified in patients with hypofibrinogenaemia, many of these patients are in fact heterozygous carriers of afibrinogenaemia mutations. Despite the number of genetic analyses performed, the study of additional patients still allows the identification of novel mutations. Here we describe the characterization of a novel FGA intron 2 donor splice-site mutation (Fibrinogen Montpellier II) identified in three siblings with hypodysfibrinogenaemia. Functional analysis of RNA produced by the mutant minigene in COS-7 cells revealed that the mutation led to the in-frame skipping of exon 2. Western blot analysis of COS-7 cells expressing an exon 2 deleted FGA cDNA revealed that an alpha-chain lacking exon 2, which codes in particular for fibrinopeptide A and polymerisation knob ‘A’, has the potential to be assembled into a hexamer and secreted. Analysis of precipitated fibrinogen from patient plasma showed that the defect leads to the presence in the circulation of alpha-chains lacking knob ‘A’ which is essential for the early stages of fibrin polymerisation. Fibrin made from purified patient fibrinogen clotted with thrombin displayed thinner fibers with frequent ends and large pores.
Databáze: OpenAIRE
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