期刊
THROMBOSIS AND HAEMOSTASIS
卷 104, 期 5, 页码 990-997出版社
GEORG THIEME VERLAG KG
DOI: 10.1160/TH10-03-0161
关键词
Hypodysfibrinogenaemia; fibrinogen assembly; fibrinogen secretion; mutation identification and expression
资金
- NHLBI NIH HHS [R01 HL090774, R01 HL030954] Funding Source: Medline
Inherited 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 additonal 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 ex pressing 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
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