A Deletion Located in the 3′ Non Translated Part of the Factor IX Gene Responsible for Mild Haemophilia B

Jl, Charmantier; Mj, Baas; Schwartz, Agnès; Ml, Wiesel; Grunebaum, Lélia; Jp, Cazenave

doi:10.1055/s-0038-1649582

Cited by 7 publications

(4 citation statements)

References 3 publications

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“…DNA was extracted from peripheral blood lymphocytes as previously described (39). In brief, the mononuclear cells from 5 ml of EDTA-anticoagulated blood were isolated using Lymphoprep (Nycomed, Oslo, Norway).…”

Section: Methodsmentioning

confidence: 99%

A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation.

Lanza¹,

Stierlé²,

Fournier³

et al. 1992

J. Clin. Invest.

134

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We describe a new variant of Glanzmann's thrombasthenia (variant Strasbourg I). The patient (M.S.) showed an absence of platelet aggregation to ADP, thrombin, and collagen, and a decreased clot retraction. Platelet fibrinogen was -20% of normal levels. ADP-stimulated platelets bound markedly reduced amounts of soluble fibrinogen and platelet adhesion to surface-bound fibrinogen was defective. Normal to subnormal amounts of glycoprotein (GP) Ilb-Illa (am,83) complexes, the platelet fibrinogen receptor, were revealed by SDS-PAGE, crossed immunoelectrophoresis, and antibody binding. However, the complexes were unusually sensitive to dissociation with EDTA at room temperature. Furthermore, flow cytometry showed that the platelets failed to bind the activation-dependent monoclonal antibody, PAC-1, after stimulation. In contrast, an RGDS-containing peptide induced significant binding of the anti-ligand-induced binding site antibody, D3GP3, suggesting the presence ofa functional RGD binding domain on the patient's GPIIb-IIIa complex. Sequence analysis was performed after polymerase chain reaction amplification of selected patient's GPIIIa exons, and of the patient's platelet GPIIb and GPIIIa mRNAs. A point mutation (C to T) was localized in exon D (iv) of GPIIIa that resulted in an 214Arg to 214Trp amino acid substitution. The defect has been inherited from the parents who are heterozygous for the same mutation. This substitution points to an essential amino acid in a region of GPIIIa involved in the binding of fibrinogen and influencing the Ca2+-dependent stability of the GPIIb-IIIa complex. (J. Clin.

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Section: Methodsmentioning

confidence: 99%

A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation.

Lanza¹,

Stierlé²,

Fournier³

et al. 1992

J. Clin. Invest.

134

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“…Indeed, a novel SNP C.8899G > A was found at the 3¢UTR region of exon 26 in two Korean patients with AHA (Hwang et al, 2011). While this has not been reported by other groups in the case of AHA as yet, a similar correlation between a SNP in the 3¢UTR of F9 and levels of circulating factor IX in haemophilia B has been proposed (de la Salle et al, 1993). More recently, several polymorphisms have been reported in the coding sequence of F8, which are differently distributed between patients of different ethnic origins.…”

Section: Polymorphisms In the F8 Gene In Aha Patientsmentioning

confidence: 73%

Do proteolytic antibodies complete the panoply of the autoimmune response in acquired haemophilia A?

et al. 2011

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SummaryAcquired haemophilia A (AHA) is a rare bleeding disorder characterized by the sudden generation of autoantibodies against factor VIII (FVIII) in individuals with no previous history of abnormal haemostasis. Understanding the pathogenesis of this disease has been hampered by the rarity of the patients and the difficulty in obtaining biological material from untreated patients. Still, progress has been made recently in understanding the pathogenesis of AHA. In particular, the importance of CD4 + T cells in AHA development has been documented and the epitopes targeted by T cells on FVIII have been delineated. Accordingly, a polymorphism in the cytotoxic T-lymphocyteassociated protein 4 gene (CTLA4), known to participate in the regulation of CD4 + T-cell responses, and a preferential usage of certain human leukocyte antigen class II haplotypes, have been associated with the disease. Recent findings have documented the presence of immunoglobulin G (IgG) with proteolytic activity against FVIII and factor IX (FIX) in patients with AHA. While FVIII-hydrolysing IgG has been shown to inactivate FVIII, FIX-hydrolysing IgG from AHA patients activate FIX in vitro. Here, we describe the latest findings on the immunopathogenesis of AHA, with a special focus on the potential role played by antibodies endowed with proteolytic properties.

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“…In 5 families with hemophilia B (HB), a point mutation in the 3'-UTR of the F9 gene greatly reduced plasma FIX concentration to less than 3% of the normal level [ 14 ]. In addition, a 653-bp deletion located in the 3'-UTR of the F9 gene was found to be responsible for mild HB [ 15 ]. Although these reports concern the F9 gene, we suggest that the novel mutation in the 3'-UTR of the F8 gene discovered in cases of acquired HA may also be related to F8 mRNA stability or translational capacity.…”

Section: Discussionmentioning

confidence: 99%

Identification of a sharedF8mutation in the Korean patients with acquired hemophilia A

et al. 2011

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Although uncommon, acquired hemophilia A (HA) is associated with a high rate of mortality due to severe bleeding. In spite of many hypotheses regarding the cause of acquired HA, there is as yet no established theory. In this study, we investigated the possibility that mutation(s) in the F8 gene may be correlated with the development of inhibitory autoantibodies. Direct sequencing analysis was performed on all 26 exons of the F8 gene of 2 patients exhibiting acquired HA. Both patients were found to share a common point mutation (c.8899G>A) in the 3'-untranslated region (3'-UTR) of exon 26. This is the first report on the genotyping of F8 in the context of acquired HA.

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A Deletion Located in the 3′ Non Translated Part of the Factor IX Gene Responsible for Mild Haemophilia B

Cited by 7 publications

References 3 publications

A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation.

A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation.

Do proteolytic antibodies complete the panoply of the autoimmune response in acquired haemophilia A?

Identification of a sharedF8mutation in the Korean patients with acquired hemophilia A

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