Thromb Haemost 2010; 104(05): 990-997
DOI: 10.1160/TH10-03-0161
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Silja Vorjohann
1  Department of Genetic Medicine and Development, University of Geneva Medical Centre, Geneva, Switzerland
,
Richard J. Fish
1  Department of Genetic Medicine and Development, University of Geneva Medical Centre, Geneva, Switzerland
,
Christine Biron-Andreani
2  Hematology Laboratory, University Hospital, Montpellier, France
,
Chandrasekaran Nagaswami
3  Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
,
John W. Weisel
3  Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
,
Pierre Boulot
4  Department of Gynecology and Obstetrics, University Hospital, Montpellier, France
,
Lionel Reyftmann
4  Department of Gynecology and Obstetrics, University Hospital, Montpellier, France
,
Philippe de Moerloose
5  Division of Angiology and Hemostasis, University Hospital and Faculty of Medecine, Geneva, Switzerland
,
Marguerite Neerman-Arbez
1  Department of Genetic Medicine and Development, University of Geneva Medical Centre, Geneva, Switzerland
5  Division of Angiology and Hemostasis, University Hospital and Faculty of Medecine, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

Received: 08 March 2010

Accepted after major revision: 14 July 2010

Publication Date:
24 November 2017 (online)

Summary

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 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.