Heterogeneity of factor IX BM difference of cleavage sites by factor XIa and Ca2+in factor IX Kashihara, Factor IX Nagoya and Factor IX Niigata

Yoshioka, Akira; Ohkubo, Y. Zenmei; Nishimura, Takuya; Tanaka, Ichiro; Fukui, Hiromu; Ogata, Kanji; Kamiya, Tadashi; Takahashi, Hiroyuki

doi:10.1016/0049-3848(86)90338-5

Cited by 11 publications

(4 citation statements)

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“…We have reported here a simple method for analysis of activation mechanisms of FIX using partially purified material from a small amount of the patient's plasma. The findings shown are identical to those previously observed for the respective FIX in a purified system (10). Although this analytic method is insufficient for quantitative studies, it is quite useful for screening of defective activation mechanisms of abnormal FIX.…”

Section: Discussionsupporting

confidence: 86%

“…To our knowledge, a total of eleven FIX variant proteins have been isolated and investigated. The first six of the variants [FIX Alabama (7), FIX Eindhoven (8), FIX Bm Lake Elsinore (9), FIX Long Beach (9), FIX Los Angeles (9) and FIX Niigata (10)] reported in the literature undergo a similar pattern of cleavage by FXIa/Ca2+ and by FVIIa/TF/Ca2+, and are activated at a rate similar to that observed for normal FIX. Only two out of six variants, FIX Bm Lake Elsinore and FIX Niigata, have markedly prolonged ox brain prothrombin time (PT).…”

Section: Introductionmentioning

confidence: 62%

“…Later the defect in FIX Alabama was described to be a substitution of a glycine for an aspartic acid at position 47 (11). The second two of the variants [FIX Deventer (12) and FIX Kashihara (10,13)] are cleaved at the Arg-Ala bond by FXIa. The former was isolated from plasma with a markedly prolonged ox brain PT and the latter with a moderately prolonged PT.…”

Section: Introductionmentioning

confidence: 99%

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A Simple Method for Analyzing Factor IX Activation in the Patients with Hemophilia B Variants

et al. 1987

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SummaryA simple method for analyzing the activation mechanism of FIX in patients with hemophilia B variants is described. The procedure consists of rapid partial purification of FIX by BaCl2 adsorption-elution from only 3 ml of plasma, incubation with FXIa/Ca2+, SDS-PAGE, western blotting and subsequent autoradiography using monoclonal anti-FIX antibody. Abnormal FIX from the plasma of 7 unrelated patients with hemophilia BR, B+ or BM was investigated. A time course study showed that FIX in the patient with hemophilia BM (Nagoya I), BM (Nagoya II) and B Kawachinagano seemed not to be cleaved by FXIa, FIX in the patient with hemophilia B Kashihara was partially cleaved, FIX in the patient with hemophilia BM (Takatsuki) showed delayed cleavage, and that FIX in the patient with hemophilia BM (Niigata) and BM (Kiryu) was cleaved completely at a rate similar to normal FIX. These findings were identical to those previously observed for the respective factors in a purified system. The procedure used here is useful for screening for a defective activation mechanism of abnormal FIX.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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A Simple Method for Analyzing Factor IX Activation in the Patients with Hemophilia B Variants

et al. 1987

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“…Another study has shown that one variant of factor IX fim acts as a competitive inhibitor of factor X when the latter is activated by the reaction product of bovine tissue factor and human factor VII (Osterud et al, 1981). A recent paper reported three variants of factor LX fim which all exhibit different rates of activation cleavage (Yoshioka et al, 1986). Thus, the B m phenotype does not appear to define a specific subgroup within the disease.…”

Section: Hemophilia B As a Heterogeneous Disordermentioning

confidence: 99%

Molecular Basis of Hemophilia B: Identification of the Defect in Factor Ix Vancouver

Geddes

Louie

Brayer

et al. 1987

XIth International Congress on Thrombosis and Haemostasis

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In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.ABSTRACT Hemophilia B., is a moderately severe hereditary disorder in which the factor r Vancouver • J LX antigen is present in relatively normal amounts but the biological activity of factor IX is markedly reduced. Previous studies have demonstrated that although the patient has 62% of the normal factor LX antigen level in his plasma, he shows only 2.6% of normal factor IX procoagulant activity. In addition, radioimmunoassays have shown that epitopes on both the heavy and light chains of activated factor LX are present.These two results were taken as an indication that the molecular defect causing the hemophilia may be a point mutation involving an amino acid change in the protein.In order to identify the mutation involved, DNA was isolated from lymphocytes in a blood sample from the patient. This DNA was used to construct a genomic library in the A. vector EMBL3. One million of the resultant clones were screened with a labeled factor IX cDNA probe to identify those clones containing portions of the factor LX gene. DNA inserts from three X clones, which together span the entire gene, were subcloned to facilitate sequence analysis of the exons and intron / exon junctions of the factor LX gene. The nucleotide sequences of the coding regions were found to match the published sequence of the normal gene, except for one nucleotide. A single mutation was found at nucleotide 31,311 of the factor LX gene (Yoshitake et al., 1985), corresponding to amino acid 397 of the mature protein. This alteration, which changes an isoleucine codon, ATA, to a threonine codon, ACA, is novel among the mutations which have been reported to cause hemophilia B. A three dimensional model of the protease domain of factor LX , which was prepared on the basis of its homology to the pancreatic serine proteases, was examined in the vicinity of residue 397. The position of threonine 397 in this model suggests that this mutation could alter the hydrogen bonding between factor IX and its substrate, factor X. Taken together, these data suggest that this mutation is the cause of the hemophilia in this patient.

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Comparison of the behavior of normal factor IX and the factor IX BM variant hilo in the prothrombin time test using tissue factors from bovine, human, and rabbit sources

et al. 1993

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A subset of hemophilia B patients have a prolonged bovine-brain prothrombin time. These CRM+ patients are classified as having hemophilia Bm. The prolongation of the prothrombin time has been reported only with bovine brain (referred to as ox brain in some literature) as the source of thromboplastin; prothrombin times determined with thromboplastin from rabbit brain or human brain are not reported to be prolonged. Factor IX from a hemophilia Bm patient (factor IX Hilo) was isolated. The activity of factor IX Hilo was compared to that of normal factor IX in prothrombin time assays when the thromboplastin source was of bovine, rabbit, or human origin. Factor IX, either normal or Hilo, prolonged a prothrombin time regardless of the tissue factor source. However, unless thromboplastin was from a bovine source, this prolongation required high concentrations of factor IX. Further, factor IX normal was as effective as factor IX Hilo in prolonging the prothrombin time when rabbit or human thromboplastin was used. With bovine thromboplastin, factor IX Hilo was significantly better than factor IX normal at prolonging the prothrombin time. The amount of prolongation was dependent on the amount of factor IX Hilo added. In addition, the prolongation was dependent on the concentration of factor X present in the sample. The prothrombin time changed as much as 20 seconds when the factor X concentration was varied from 50% to 150% to normal (fixed concentration of factor IX Hilo). These results demonstrate the difficulty of classifying the severity of a hemophilia Bm patient based on the bovine brain prothrombin time unless both the factor IX and factor X concentrations are known.

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Heterogeneity of factor IX BM difference of cleavage sites by factor XIa and Ca2+in factor IX Kashihara, Factor IX Nagoya and Factor IX Niigata

Cited by 11 publications

References 12 publications

A Simple Method for Analyzing Factor IX Activation in the Patients with Hemophilia B Variants

A Simple Method for Analyzing Factor IX Activation in the Patients with Hemophilia B Variants

Molecular Basis of Hemophilia B: Identification of the Defect in Factor Ix Vancouver

Comparison of the behavior of normal factor IX and the factor IX BM variant hilo in the prothrombin time test using tissue factors from bovine, human, and rabbit sources

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