Mutations in hemophilia Bm occur at the Arg180-Val activation site or in the catalytic domain of factor IX.

Bertina, Rogier M.; Linden, I K van der; Mannucci, P. M.; Reinalda-Poot, Hanneke H; Cupers, R; Poort, S R; Reitsma, P. H.

doi:10.1016/s0021-9258(19)38528-x

Cited by 25 publications

(9 citation statements)

References 52 publications

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“…The rate of activation of factor X by factor VIIa-TF, in the presence of plasma-purified factor IX and factor IXa39ov (180 nM), was calculated to be 64% and 67%, respectively, compared with the activation rate without factor IX (Figure 3). The reaction rate (dotted line in Figure 3) in the presence of factor IXoeventer was simulated from previous data (Bertina et al, 1990). This shows that factor IXv39o is not inhibitory in the presence of human TF.…”

Section: Resultsmentioning

confidence: 87%

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Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm

Hamaguchi¹,

Roberts²,

Stafford³

1993

Biochemistry

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Hemophilia Bm, a variant of hemophilia B, results in a marked increase in the ox brain prothrombin time. Mutations known to cause hemophilia Bm occur at residue 180, 181, or 182 near the amino terminus of the heavy chain and at residue 311, 364, 368, 390, 396, or 397 near the activation site of factor IX (Giannelli et al., 1990). In this study we replaced factor IX residues 181, 182, and 390 in separate experiments by site-directed mutgenesis. Valine 181 was replaced by isoleucine or alanine, and valine 182 was replaced by alanine or glycine. Alanine 390 was replaced by valine or aspartic acid. Recombinant factor IXs were expressed in human kidney 293 cells and purified by absorption and elution from a conformational specific monoclonal antibody column. The results show that factor IX Bm is a function not only of the position of the mutated amino acid but also of the particular amino acid substituted. For example, when valine 181 or 182 was replaced by small hydrophobic amino acids (alanine and glycine), factor IXs were found to have significantly decreased clotting activity. Unlike the naturally occurring mutations (Val181 --> Phe181 or Val182 --> Leu182), however, the small amino acid replacements did not result in prolonged ox brain prothrombin times. Surprisingly, the Ala390 --> Asp390 exchange did not affect clotting activity or binding to the macromolecular inhibitor antithrombin III. The Ala390 --> Val390 exchange resulted in loss of both clotting activity and binding to antithrombin III. These results suggest that residue 390 is not directly involved in binding to antithrombin III.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Resultsmentioning

confidence: 87%

“…Symbols: (•) without factor IX; (O) with purified plasma factor IX; (A) with factor IXA39ov. The dotted line is a simulated reaction curve in the presence of factor IXoeventer, based on previous data (Bertina et al, 1990).…”

Section: Resultsmentioning

confidence: 99%

Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm

Hamaguchi¹,

Roberts²,

Stafford³

1993

Biochemistry

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“…This mutation is known to result in the loss of >80% of total FIX protein and to increase the probability of an immune response. The p.R226W mutation affects zymogen activation processes by altering the cleavage of Factor XIa [ 20 , 21 ], which was recorded in 1 moderate and 5 severe (FIX concentration, 0.1±0.7) cases within our study group. The p.C396Y mutation was shown to disturb the environment of the active site that is involved in the conversion of the zymogen into an active enzyme, which was observed only in one severe case of HB [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis and characterisation of F9 gene in haemophilia- B population of India

Kulkarni

Hegde²,

Hegde³

et al. 2021

Blood Res

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Background: Hemophilia B (HB) is an X-linked bleeding disorder resulting from coagulation factor IX (FIX) defects. Over 3,000 pathogenic, HB-associated mutations in the F9 gene have been identified. We aimed to investigate the role of F9 variants in 150 HB patients using sequencing technology.Methods: F9 gene sequences were amplified from peripheral blood-derived DNA and sequenced on an Applied Biosystems (ABI) 3500 Sanger sequencing platform. Functional and structural predictions of mutant FIX were analyzed.Results: Among 150 HB patients, 102 (68%), 30 (20%), and 18 (12%) suffered from severe, moderate, and mild HB, respectively. Genetic analysis identified 16 mutations, including 3 novel mutations. Nine mutations (7 missense and 2 stop-gain) were found to be pathogenic. Only 3 mutations (c.127C>T, c.470G>A, and c.1070G>A) were associated with different severities. While 2 mutations were associated with mild HB cases (c.304C>T and c.580A>G), 2 (c.195G>A and c.1385A>G) and 3 mutations (c.223C>T, c.1187G>A, and c.1232G>A) resulted in moderate and severe disease, respectively.Additionally, 1 mutation each was associated with mild-moderate (c.*1110A>G) and mild-severe HB disease (c.197A>T), 4 mutations were associated with moderate-severe HB cases (c.314A>G, c.198A>T, c.676C>T, and c.1094C>A). FIX concentrations were lower in the mutated group (5.5±2.5% vs. 8.0±2.5%). Novel p.E66D and p.S365 mutations were predicted to be pathogenic based on changes in FIX structure and function. Conclusion:Novel single nucleotide polymorphisms (SNPs) largely contributed to the pathogenesis of HB. Our study strongly suggests that population-based genetic screening will be particularly helpful to identify risk prediction and carrier detection tools for Indian HB patients.

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“…Hemophilia Bm is one of the variant forms of hemophilia B and is associated with an abnormal factor IX molecule with prolongation of the prothrombin time performed with oxbrain thromboplastin. It is classified into two major groups, i.e., one with an amino acid substitution in the catalytic domain of factor IX and the other with a substitution at the second cleavage site for activation (Bertina, 1990). Our patient can be classified as hemophilia Bm, since he has an abnormal factor IX with a Val182 to Ala substitution manifesting a prolonged ox-brain prothrombin time.…”

Section: Discussionmentioning

confidence: 93%

“…0006-2960/93/0432-6146S04.00/0 prolonged plasma ox-brain prothrombin time (Hougie & Twomey, 1967) was found to possess a variety of mutations occurring either near the Arg180-Val181 activation site (Suehiro et al, 1989;Huang et al, 1989;Sakai et al, 1989;Bertina et al, 1990;Taylor et al, 1990) or in the catalytic domain (Bertina et al, 1990;Spitzer et al, 1988;Sugimoto et al, 1988).…”

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confidence: 99%

Molecular defect in factor IX Tokyo: Substitution of valine-182 by alanine at position P2' in the second cleavage site by factor XIa resulting in impaired activation

Maekawa

Sugo²,

Yamashita³

et al. 1993

Biochemistry

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Utilizing polymerase chain reaction and directly sequencing the amplified exon 6 of the factor IX gene derived from a mild hemophilia Bm patient, we have identified a T to C mutation at nucleotide 20,525. This point mutation predicted a Val182 to Ala substitution in the abnormal factor IX molecule, designated as factor IX Tokyo. The patient manifested a low factor IX activity and a moderately prolonged ox-brain prothrombin time but a normal factor IX antigen level in plasma. Immunopurified factor IX derived from the patient was found to have a normal molecular weight but a reduced specific activity (23% of normal). Limited proteolysis by activated factor XI or by a snake venom-derived factor X-activating enzyme was considerably delayed, indicating the presence of structural alteration(s) most probably at or near the second enzyme-cleavage site. Once activated, however, factor IXa Tokyo was able to activate factor X normally and was inactivated by antithrombin III also in a normal fashion. The structural model of factor IXa and a docking model of factor IX and activated factor VII (factor VIIa) suggested that the Val182 to Ala substitution would not affect the local conformation of the catalytic domain. This mutation would rather loosen the fitness of the molecule into the substrate-binding pocket of factor VIIa due to a shorter side chain of the Ala substitution at the P2' position of the second cleavage site.

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Mutations in hemophilia Bm occur at the Arg180-Val activation site or in the catalytic domain of factor IX.

Cited by 25 publications

References 52 publications

Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm

Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm

Mutation analysis and characterisation of F9 gene in haemophilia- B population of India

Molecular defect in factor IX Tokyo: Substitution of valine-182 by alanine at position P2' in the second cleavage site by factor XIa resulting in impaired activation

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