Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic diseases are family diseases. Although there is considerable research on how individuals decide to have genetic testing and their individual reactions to testing, there is limited research on the familial context of genetic testing. In the present study, we focus on three aspects of the family context of genetic testing for hemophilia A carrier status among women at risk to be carriers. We look at the extent to which there was discussion of carrier testing for hemophilia before we offered DNA-based carrier testing to these at-risk women; with which family members these tested women communicated the results of their carrier testing; and concerns these women had about communicating their carrier test results with relatives, including their children. Data suggest that members of families with hemophilia discussed carrier testing prior to study participation, that the communication of testing information within families was selective, not universal, largely following gender lines for this X-linked disorder, and that there was limited concern about communicating carrier status information to children and other relatives. These data reinforce observations that families are social systems, and within these systems information is selectively communicated. A more complete understanding of how families communicate genetic test information will enable providers to develop more effective means of assisting individuals in handling the familial communication aspects of genetic testing.
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PMID:Communication about carrier testing within hemophilia A families. 1270 32

Hemophilia A is an X-linked, recessive, bleeding disorder caused by defective or deficient factor VIII (FVIII) molecules. Infusion of purified FVIII to patients with severe hemophilia A results in approximately 25% of the cases, in the emergence of anti-FVIII antibodies (inhibitors) that are known to neutralize the pro-coagulant activity of FVIII by steric hindrance. We recently reported on the proteolysis of FVIII by allo-antibodies in the plasma of high responder patients with severe hemophilia A, demonstrating a new mechanism by which FVIII inhibitors may prevent the pro-coagulant function of FVIII. Hemophilia is the first model where a direct link between the hydrolysis of the target molecule and the occurrence of the clinical manifestations may be established. It also represents the first example in humans, of the induction of catalytic antibodies following the exogenous administration of an antigen. The characterization of FVIII inhibitors as site-specific proteases may provide new approaches to the treatment of inhibitors.
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PMID:Autoantibodies to factor VIII with catalytic activity. 1284 73

Short interspersed elements, such as Alu elements, have propagated to more than one million copies in the human genome. They affect the genome in several ways, caused by retrotransposition, recombination between elements, gene conversion, and alterations in gene expression. These events, including novel insertions into active genes, have been associated with a number of human disorders. Hemophilia A is an X-linked severe bleeding disorder and is caused by mutations in the Factor VIII gene. The spectrum of mutations includes point mutations, rearrangements, insertions, and deletions. Recently, an Alu retrotransposition event in a coding exon has been reported in a family with a severe form of hemophilia A. This was the first report of an Alu insertion in the Factor VIII gene. Here, we report a second Alu insertion event that lies in an intron of the same gene that causes exon skipping and the complete disruption of gene expression.
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PMID:Exon skipping caused by an intronic insertion of a young Alu Yb9 element leads to severe hemophilia A. 1288 4

Hemophilia A is an inheritable X-linked bleeding disorder most frequently occurring as a consequence of genetic alterations within the factor VIII (FVIII) gene. In the present study, pseudotyped human immunodeficiency virus type 1 (HIV-1)-derived lentivectors expressing hFVIII were assessed for the ability to correct the hemophilia A phenotype in FVIII knockout mice. Therapeutic levels of plasma hFVIII (1-7 ng/mL) were detected in C57B1/6 mice (4-5 weeks old) after portal vein administration of hFVIII-expressing lentivectors pseudotyped with the rhabdoviral vesicular stomatitis viral G protein (VSV-G). More importantly, transduction of hemophilia A mice with FVIII expressing lentivectors resulted in transient correction of the bleeding diathesis phenotype. Moreover, the use of alternate viral pseudotypes based on the lymphocytic choriomeningitis virus (LCMV) resulted in similar circulating levels of FVIII. Interestingly, similar doses of LCMV-pseudotyped lentiviral vectors resulted in minimal systemic or hepatic injury as measured by plasma alanine transferase (ALT), aspartate transferase (AST), and tumor necrosis factor (TNF)-alpha compared to the more commonly used envelope, VSV-G. In summary, these studies demonstrated both the potential merit of lentivectors in terms of correcting monogenic inherited disorders, and also the importance of using alternate pseudotypes, such as LCMV, to safely transfer therapeutic genes in vivo without producing adverse effects.
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PMID:Correction of bleeding diathesis without liver toxicity using arenaviral-pseudotyped HIV-1-based vectors in hemophilia A mice. 1457 28

Although large deletions from the coagulation factor VIII gene, F8, are responsible for 5% of severe hemophilia A (seHA), few of them have been fully characterised. A detailed description of a large partial deletion of the F8 caused by unequal recombination between homeologous AluSx-derived sequences is presented. The proband, a case of isolated hemophilia A with a high inhibitor titre (5700 BU), showed a consistent absence of PCR-amplification of exons 4 to 10, EX4_EX10del. Two approaches were used to narrow down the deletion breakpoints: a direct physical analysis based on PCR (that additionally permits carrier detection in the family); and, under the hypothesis that the mutation resulted from homologous recombination, sequence alignments of F8 intron 3 and 10. Both approaches indicate an unequal crossing over (CO) between two Alu-related sequences. Both elements involved were derived from the AluSx-subfamily consensus and demonstrate 86% sequence identity (with only single-base mismatches), with three gaps (of 2, 3 and 14-bases) and two main tracts of perfectly homologous sequence (28 and 24-bp). The short stretch of intron 10 embedded into intron 3 sequence, linked to the CO, represents a typical hallmark of homologous recombination (double-strand break repair model). A detailed description of EX4_EX10del mutation is c.[338+3485delins1687+2223_1687+2225; 338+3551_1687+2291 del]. The common involvement of unequal homologous recombination mediated by repetitive elements allowed us to suggest that our experimental design (based on intron sequence alignments) may be successfully applied to rearrangements involved in other X-linked inherited diseases. Like other Alu-rich genes throughout the human genome, Alu-mediated homologous recombination in F8 may be an important cause of hemophilia by promoting large DNA deletions.
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PMID:Homeologous recombination between AluSx-sequences as a cause of hemophilia. 1545 70

beta-Thalassemia (thal) is an autosomal recessive disorder with a prevalence of 2-3% in Indians, while hemophilia A is X-linked with a prevalence of 1 in 5,000-10,000 male births. The chances of both these disorders being present together is extremely rare (1 in 250,000). We report an interesting consanguineous family from Western India with a combination of these two disorders, which was referred to us for prenatal diagnosis.
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PMID:Prenatal diagnosis in a family at risk for beta-thalassemia and hemophilia A: an uncommon association. 1565 91

Hemophilia A is the most frequently occurring X-linked bleeding disorder, affecting one to two out of 10,000 males worldwide. Various types of mutations in the F8 gene are causative for this condition. It is well known that the most common mutation in severely affected patients is the intron 22 inversion, which accounts for about 45% of cases with F8 residual activity of less than 1%. Therefore, the aim of the present study was to determine the spectrum and distribution of mutations in the F8 gene in a large group of patients with severe hemophilia A who previously tested negative for the common intron 22 inversion. Here we report on a mutation analysis of 86 patients collected under the above-mentioned criterion. The pathogenic molecular defect was identified in all patients, and thus our detection rate was virtually 100%. Thirty-four of the identified mutations are described for the first time. The newly detected amino acid substitutions were scored for potential gross or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling.
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PMID:Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. 1608 18

HemophiliaA is a X-linked hematologic disorder characterized by undetectable or low amounts of functional coagulation factor VIII (FVIII). Replacement therapy induces FVIII neutralizing antibody (Ab) (inhibitor) in a proportion of patients which makes further treatment of these patients ineffective and costly. To envisage mechanisms underlying inhibitor development, seven hybridoma clones specific for FVIII were generated from two hemophilia A patients with high titer of inhibitor. Specificity and isotype of the monoclonal antibodies (mAbs) were determined by ELISA. Immunoglobulin (Ig) variable region heavy (VH) chain gene family usage was identified by RT-PCR using VH1-6 specific primers. Nucleotide sequences of the VH gene of FVIII specific clones were determined and aligned to the most homologous germ line genes in the GenBank. Analysis of the expressed VH genes by RT-PCR revealed that the hybridomas utilized either the VH1 (71%) or the VH3 (29%) gene family. Three VH domains were encoded by V1-69 (DP-10),V1-2 (DP-8), and V1-8 (DP-15) genes and two by V1-18 (DP-14) gene, all from the VH1 gene family. Of theVH3-gene family expressing clones, one belonged to V3-66 (DP-86) and the other one to V3-21 (DP-77) germline genes. The CDR3 length was found to be highly different amongst these clones ranging from 11 to 22 amino acid residues. These data suggest that FVIII-specific Abs preferentially use VH gene segments derived from VH1 gene family. Diversity of the expressed VH genes and their CDR3 length implies that different epitopes are recognized by these mAbs.
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PMID:Molecular analysis of the heavy chain variable region genes of human hybridoma clones specific for coagulation factor VIII. 1641 84

Preimplantation genetic diagnosis (PGD) of hemophilia A (HA) and other X-linked diseases through sex selection implies that male embryos will be systematically discarded, even though 50% are unaffected. The objective of the present work was to develop a PGD protocol for direct mutation identification that could be applied to first polar bodies (1PBs) in several HA clinical cases. Single buccal cells from controls and patients, and 1PBs were subjected to primer extension preamplification (PEP) PCR followed by amplification of F8 gene coding and intronic flanking regions, and direct sequencing. Moreover, multiplex fluorescent amplification of four short tandem repeats was adapted to a single cell preamplification in order to rule out contamination and allele drop-out, and for confirmatory indirect diagnosis. A couple at risk of HA transmission, with a familial mutation characterized as a 41-bp duplication in exon 14 of the F8 gene, was selected for the first clinical study. After optimizing the protocol, the complete F8 gene coding sequence was obtained from single cells to demonstrate the sensitivity of our methodology although in any clinical case only the relevant region, not the whole gene, must be amplified. The woman enrolled in the first clinical case has completed the first in-vitro fertilization cycle, and seven oocytes were analyzed with concordant results by both linkage analysis and direct sequencing method. Only one oocyte, among those diagnosed as mutation free, developed to embryo at day 3. It was transferred but pregnancy was not achieved. This PGD procedure enables non-affected and noncarrier embryo selection in families with any point or small-range mutation in the F8 gene, without the need for further custom-made modifications.
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PMID:A versatile strategy for preimplantation genetic diagnosis of haemophilia A based on F8-gene sequencing. 1713 81

Hemophilia A is an X-linked bleeding disorder caused by defective coagulation Factor VIII (FVIII). Although the efficacies of existing treatment using purified or recombinant FVIII are good, there remain shortcomings in using this particular form of treatment. A few FVIII gene therapy clinical trials have been initiated with modest improvements recorded, but these are no longer being continued due to insufficient efficacy. However, with the progress in the development of gene delivery vectors and the availability of mouse and canine hemophilia A models, gene therapy of hemophilia A remains an area of hot pursuit.
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PMID:Gene therapy for hemophilia A. 1723 42


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