Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common restriction fragment length polymorphisms (RFLPs) associated with the FIX gene: 5' BamH I, Dde I, BamH I (2), Taq I and 3' Hha I were absent or of low incidence in Southern Chinese and are therefore not useful for linkage analysis. No deletion was detected amongst seven consecutive unrelated haemophilia B patients, but one had an insertion of a 15 kb Pvu II fragment containing exon d. Using an alternate strategy of polymerase chain reaction (PCR) amplification and direct sequencing, the molecular defect in the other six patients was defined. The four novel mutations characterized were: nucleotide (nt) 6410 G----C (Gly12----Ala); nt 31261 delta T (stop codon 31 bp downstream); nt 31260 C----G (Thr380----Ser) and nt 31122 C----A (Ala34----Asp). Two patients had the same mutation at nt 6365, G----A (Arg-4----Gln), identical to one previously described in other ethnic groups, suggesting that this is a hotspot for mutation. Each of the mutations was found to affect an enzyme recognition site and could thus be identified by direct visualization of abnormal restriction fragments in amplified genomic DNA. This allows rapid and accurate DNA diagnosis of haemophilia B in an ethnic group which otherwise shows little or no polymorphism for the common RFLP sites.
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PMID:Molecular defects in haemophilia B: detection by direct restriction enzyme analysis. 168 Mar 73

Human immunodeficiency virus (HIV) infection and hepatitis virus B or C (HBV, HCV) transmission are major risks following infusion of coagulation factor concentrates. Thus, several methods have been used to achieve viral inactivation of concentrates prepared from plasma collected from a large number of donors. In this study, 32 patients with haemophilia A or B (n = 31) or von Willebrand's disease (n = 1) were treated between 1987 and 1990 only with factor VIII or IX concentrates inactivated by the solvent-detergent procedure. During this period, none of these cases exhibited elevated liver enzymes (alanine amino transferase), and serological tests for HIV, HBV and HCV infections always remained negative. This suggests that the solvent-detergent procedure of concentrate inactivation is an efficient method to prevent not only HIV or HBV transmission but also HCV infection in haemophiliacs.
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PMID:[Efficacy in viral inactivation of the concentrates of factor VIII and IX by the solvent/detergent procedure. Evaluation in patients with hemophilia]. 183 Jun 53

Previously, from the plasma of unrelated haemophilia-B patients, we isolated two non-functional Factor IX variants, namely Los Angeles (IXLA) and Long Beach (IXLB). Both variants could be cleaved to yield Factor IXa-like molecules, but were defective in catalysing the cleavage of Factor X (macromolecular substrate) and in binding to antithrombin III (macromolecular inhibitor). In the present study we have identified the mutation of IXLA by amplifying the exons (including flanking regions) as well as the 5' end of the gene by polymerase-chain-reaction (PCR) method and sequencing the amplified DNA by the dideoxy chain-termination method. Comparison of the normal IX and IXLA sequences revealed only one base substitution (T----C) in exon VIII of IXLA, with a predicted replacement of Ile-397 to Thr in the mature protein. This mutation is the same as found recently for IXLB. The observation that IXLB and IXLA have the same mutation is an unexpected finding, since, on the basis of their ox brain prothrombin time (PT, a test that measures the ability of the variant Factor IX molecules to inhibit the activation of Factor X by Factor VIIa-tissue factor complex), these variants have been classified into two different groups and were thought to be genetically different. Our observation thus suggests that the ox brain PT does not reflect the locus of mutation in the coding region of the variant molecules. However, our analysis suggests that the ox brain PT is related to Factor IX antigen concentration in the patient's plasma. Importantly, although the mutation in IXLA or IXLB protein is in the catalytic domain, purified IXaLA and IXaLB hydrolyse L-tosylarginine methyl ester at rates very similar to that of normal IXa. These data, in conjunction with our recent data on Factor IXBm Lake Elsinore (Ala-390----Val mutant), strengthen a conclusion that the peptide region containing residues 390-397 of normal Factor IXa plays an essential role in macromolecular substrate catalysis and inhibitor binding. However, the two mutations noted thus far in this region do not distort S1 binding site in the Factor IXa enzyme.
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PMID:Replacement of isoleucine-397 by threonine in the clotting proteinase factor IXa (Los Angeles and Long Beach variants) affects macromolecular catalysis but not L-tosylarginine methyl ester hydrolysis. Lack of correlation between the ox brain prothrombin time and the mutation site in the variant proteins. 210 17

Seropositivity to HBV (HBsAg) in multi-transfused patients of haemophilia A, haemophilia B, B thalassaemia and EB thalassaemia from Eastern India, was found to be 9, 0, 22.1 and 13 per cent respectively. HIV seropositivity was detected in patients of haemophilia A (4.4%) and B thalassaemia (0.8%) who received plasma components and packed cells periodically. Seropositivity to both HBsAg and HIV was found in one patient of haemophilia A. Serum alanine amino transferase (ALT), raised in multi-transfused thalassaemics suggests concurrent hepatitis which might have enhanced the transmission of viruses due to disturbed immune status. The universal voluntary blood donation programme, screening of blood for HBV and HIV by sensitive tests, early immunisation and periodic monitoring of HBV and HIV status are prerequisites for the management of transfusion dependent thalassaemia and haemophilia.
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PMID:HBV & HIV seropositivity in multi-transfused haemophilics & thalassaemics in eastern India. 234 33

Serum creatine kinase, lactate dehydrogenase, aspartate and alanine transaminases, and aldolase were determined in 41 hospital inpatients with haemophilia or Christmas disease and no significant differences from the normal ranges were found.(3) Levels of these enzymes in a further 10 such patients who had sustained muscle haematomata were determined: in all of these there was a consistent rise in the level of creatine kinase, the peak occurring between 36 and 96 hours. In bleeding disorders a rise in serum creatine kinase levels may be useful as a diagnostic test for intramuscular haemorrhage.
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PMID:Serum enzyme changes after intramuscular bleeding in patients with haemophilia and Christmas disease. 465 56

This pilot study was designed to establish the effect of long term alpha interferon treatment in haemophilia patients with chronic hepatitis C. Overall, three of eight (37.5%) patients showed a complete response, three of eight (37.5%) a transient response, and two of eight (25.0%) no response. HCV-RNA detection by polymerase chain reaction was more sensitive in detecting relapse than alanine amino-transferase (ALT) activity measurement, suggesting that current interferon schedules based on the ALT response should be re-evaluated critically.
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PMID:Long term treatment of chronic hepatitis C with interferon alfa-2b: disappearance of HCV-RNA in a pilot study of eight haemophilia patients. 839 Sep 53

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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PMID: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. 851 23

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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PMID:Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm. 851 77

Six hundred and ninety-three European Association for the Study of the Liver (EASL) members, belonging to one of the 15 European Union (EU) member-states, were surveyed, through a standardized 45-item questionnaire, on their medical practices regarding hepatitis C virus (HCV) infection. The response rate was 45%, roughly similar in all the countries concerned. Responders were classified into three groups according to their geographical origin: North, Centre and South. A consensus existed with regard to the necessity of HCV screening in well-defined situations, such as history of blood transfusion, haemodialysis, haemophilia or intravenous drug addiction (90% of positive answers) while opinions substantially differed for vertical and nosocomial transmission of HCV. For the prevention of sexual and vertical transmission, opinions differed greatly: 22% were in favour of barrier methods for HCV-positive subjects while 34% were against; 49% allowed breast-feeding for babies born to HCV-positive mothers while 14% were against. Conversely, there was relative homogeneity in the issue of domestic prevention (70% in favour of precautions). Algorithms for prescription of virological tests were inhomogeneous (recombinant immunoblot assay was used by 60%; polymerase chain reaction was requested by 77% when alanine amino-transferase (ALT) was elevated vs 89% when normal): medical evaluation varied according to ALT values: liver biopsy and liver ultrasonography were carried out in 90 and 91% vs 40 and 70% for increased and normal ALT, respectively. Thirty per cent of respondents advised patients to stop alcohol consumption and 60% advised moderation. Two-thirds of the responders did not take into account histological severity and virological parameters before initiating antiviral therapy. Eighty per cent of the participants claimed that they administered interferon (IFN) for 12 months. For most of the items studied, there was a large variation, not only between the three groups, but also within each group. Ninety-two per cent of the responders claimed that they were well trained on HCV but they were rather critical of the quality of the information diffused (satisfaction rate: 45%). Altogether, our survey demonstrates that preventive and medical practices towards HCV are not homogeneous throughout the EU; this suggests the need for a European consensus conference in this regard.
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PMID:Medical practices regarding hepatitis C virus infection in Europe. 957 38

A novel missense mutation (codon 351, GCT (Ala) --> CCT (Pro)) of the FIX gene was characterised in a young female with mild hemophilia B. She is heterozygous for the FIX mutation inherited from her carrier mother. Analysis of the methyl-sensitive Hpa II sites at the 5' end of the hypoxanthine phosphoribosyltransferase gene showed that skewed inactivation of the X chromosome carrying her normal FIX gene accounted for the hemophilia phenotype.
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PMID:Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome. 959 Jan 53


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