Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Many disease loci have been linked to the telomeric end of the long arm of the human X-chromosome, Xq28. We have isolated and sequenced cDNA sequences corresponding to two novel genes that map to Xq28. These genes, c6.1A and c6.1B, are transcribed in opposite directions from a CpG island that lies approximately 70 kilobases (kb) upstream (5') of the factor VIII locus. One of these genes, c6.1A, is highly conserved between species and expressed abundantly in many human and mouse tissues, whereas, c6.1B is moderately conserved and has a restricted tissue distribution of expression. The Xq28 gene c6.1A has an autosomal homologue that is transcriptionally inactive in B-cell lines. An open reading frame (ORF) predicting a peptide of 293 amino acids is observed for c6.1A but c6.1B does not possess a single long ORF. No striking homologies to existing genes could be found for either of the two new loci. Expressed sequences that are physically close to the factor VIII gene are candidates for disease loci that map to this region of Xq28. The relevance of these genes to disease loci was investigated using DNA and RNA from hemophilia A patients bearing deletions that extend in a 5' direction away from factor VIII. The results imply that neither of these genes are primarily responsible for the development Xq28-linked diseases. However, c6.1A and c6.1B define a region of Xq28 that is deleted in two brothers that suffer from mental handicap and dysmorphism as well as hemophilia A. Thus, this region is likely to contain loci that are important for physical and mental development.
Hum Mol Genet 1992 Jun
PMID:Isolation and sequence of two genes associated with a CpG island 5' of the factor VIII gene. 130 75

Five strains of human immunodeficiency virus type 1 (HIV-1) were isolated from five Japanese hemophilia patients. Two isolates, HIV-1[GUN-1] and HIV-1[GUN-2], were from brother patients with hemophilia B and the other three isolates, HIV-1[GUN-3], HIV-1[GUN-4], and HIV-1[GUN-5], were from hemophilia A patients. Another HIV-1 strain, HIV-1[GUN-6], was isolated from a Canadian male homosexual with AIDS. The restriction endonuclease cleavage maps of the proviral genomes of these six HIV-1 strains revealed that they were apparently different from each other. The phylogenetic trees constructed using restriction maps and nucleotide sequences were quite similar, indicating that phylogenetic analyses of Japanese HIV-1 isolates can be done using restriction maps of the proviruses. Phylogenetic analyses showed that they were more closely related to HIV-1s which had been reported to be isolated from homosexual patients in the United States than those isolated from African patients. In particular, GUN-1 and GUN-2 isolates were on the branch of a San Francisco isolate, ARV2, while GUN-5 and GUN-6 isolates were on the branch of HTLV-IIIB-related isolates.
J Mol Evol 1992 Oct
PMID:Six strains of human immunodeficiency virus type 1 isolated in Japan and their molecular phylogeny. 140 18

Progression to AIDS and death were evaluated in 112 patients, 84 with hemophilia A and 28 with hemophilia B. Seroconversion period and age at seroconversion were similar in both groups. 36/112 patients died: 21/84 with hemophilia A (25%) and 15/28 (54%) with hemophilia B. Mean survival time was 11.7 years. The 10-year cumulative survival was 75.8%. It was lower in hemophilia B (56.2%) compared to hemophilia A patients (82.4%; p = 0.002). 37 patients (33%) developed full-blown AIDS: 26 with hemophilia A (31%) and 11 with hemophilia B (39%). Mean AIDS-free survival time was 11.4 years. The 10-year cumulative AIDS-free survival was 71.2%. It was 74.8% in hemophilia A and 60.3% in hemophilia B patients. CD4 counts lower than 200/cmm occurred in 62 patients (56%): 45 with hemophilia A (54%) and 17 with hemophilia B (63%). The mean time to CD4 counts lower than 200 was 9.4 years. Mean survival time in older seroconverters (35 year old or more) was shorter than in younger (9.5 vs. 11.7 years, p < 0.05). Mean CD4 cell counts at seroconversion were similar in hemophilia A and B patients and in different age classes at seroconversion. CD4 cell counts at seroconversion affected the survival: 90% seroconverters with CD4 cell counts of 800/cmm or more were alive at 10 years vs. 60% of seroconverters with CD4 cell counts lower than 800 (p < 0.05).
Cell Mol Biol (Noisy-le-grand) 1995 May
PMID:Factors associated with progression to AIDS and mortality in a cohort of HIV-infected patients with hemophilia followed up since seroconversion. 758 Aug 30

The factor VIII gene, which is defective in hemophilia A, is located in the last megabase of the long arm of the X chromosome. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of all cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the inversion process, and that, therefore, the event originates predominantly in male germ cells. In all 20 informative cases in which the inversion originated in a maternal grandparent, DNA polymorphism analysis determined that it occurred in the male germline. In addition, all but one of 50 mothers of sporadic cases due to an inversion were carriers. Thus, these data support the hypothesis and indicate that factor VIII gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells.
Hum Mol Genet 1994 Jul
PMID:Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. 798 69

Haemophilia A is a mutationally heterogeneous disease caused by defects in the large and complex factor VIII gene. Recent studies examining the putative promoter, all exons and most intron/exon boundaries have failed to detect mutations in half the patients with severe disease leading to hypotheses such as mutations in remote controlling regions or even in genes other than factor VIII. We have amplified the factor VIII gene (putative promotor, coding region and polyadenylation/cleavage signal region) in 8 fragments from reverse transcribed mRNA and genomic DNA. Any mutation is then located by chemical mismatch detection and characterised by direct sequencing. This rapid and efficient method has been fully successful and has revealed an unusual cluster of mutations causing severe disease. Of the 28 patients we have reported, 5 had mild or moderate disease and all had a missense mutation. Twenty-three patients were severely affected and 13 of these had different detrimental mutations that were fully characterised at the genomic DNA level. The remaining 10 patients all had mRNA with exon 22 not contiguous to exon 23. Since all exons were normal and so were the splice sites of intron 22, the mutation in these patients should be in the regions of intron 22 that were not screened. These results prove that all haemophilia A cases are due to mutations of the factor VIII gene where, unexpectedly, intron 22 seems to be the target of approximately 40% of the mutations causing severe haemophilia A.
Hum Mol Genet 1993 Jan
PMID:Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. 849 Jun 18

Coagulation factor VIII is an essential cofactor required for normal hemostatic function. A deficiency in factor VIII results in the bleeding disorder hemophilia A. Despite the fact that the factor VIII gene was cloned a decade ago, the mechanisms which control its transcription remain unresolved. In our studies, we have characterized 12 protein binding sites within the factor VIII promoter by DNase I protection assays performed with rat liver nuclear extracts. Three of these elements (sites 1 to 3) are situated within the 5' untranslated region of the gene, while three other sites (sites 4 to 6) lie within the first 100 bp upstream of the transcriptional start site. We have identified an additional site (site 7) approximately 300 bp upstream from site 6, as well as a cluster of five sites in a 250-bp region which terminates approximately 1 kb from the transcriptional start site. Seven of these binding sites (sites 2, 3, 4, 6, 7, 9, and 10) bind members of the C/EBP family of transcription factors. DBP also binds to five of these sites (sites 3, 4, 6, 7, and 9). Utilizing transient transfection studies in HepG2 cells, we have shown that deletion of the factor VIII promoter sequences distal to nucleotide -44 results in a significant but small increase in promoter activity. The activity of each of the various 5' deletion constructs is significantly enhanced by cotransfection of C/EBPalpha and D-site-binding protein expression plasmids, while cotransfection of both C/EBPalpha and C/EBPbeta plasmids resulted in a further enhancement of transactivation. These studies also provide evidence of a repressor element located between nucleotides -740 and -1002. Since the minimal promoter sequence (-44 to +148) maintains the transcriptional activity of the full-length promoter sequence, we proceeded to identify additional factors binding to sites 1 to 4. Competition studies revealed that a ubiquitous transcription factor, NF-Y, binds to site 4, while the liver-enriched transcription factor hepatocyte nuclear factor I (HNF-1) binds to site 1. Mutation analysis of the minimal promoter demonstrated that HNF-1 is critical for activating transcription of the factor VIII gene in vitro. Our results also suggest that the multiple upstream elements that we have identified may act as a backup regulatory region in the event of disruption of the HNF-1 element in the 5' untranslated region.
Mol Cell Biol 1996 May
PMID:Role of the liver-enriched transcription factor hepatocyte nuclear factor 1 in transcriptional regulation of the factor V111 gene. 862 60

Hemophilia A is an X-linked bleeding disorder caused by deleterious mutations in the factor VIII gene. An inversion caused by introchromosomal homologous recombination between the A gene located in intron 22 of the factor VIII gene and one of the two telomeric A genes has been recently described as the common cause of about 50% of cases of severe hemophilia A. The rearrangement can be readily detected by a Southern blotting procedure. We report use of this procedure to detect rearrangements in 106 unrelated Chinese hemophilia A cases. In 49.3% of the patients with severe disease an inversion was found, but no inversion was detected in any of the patients with moderate or mild disease. The majority of inversions (91.4%) involved the most distal A gene; in a minority (8.6%) the more proximal A gene was involved. These results indicate that intron 22 inversion is the most important molecular defect causing Chinese hemophilia A and that analysis for intron 22 inversion may be the first-line test in the molecular diagnosis of severe hemophilia A.
Hematopathol Mol Hematol 1996
PMID:Molecular diagnosis of hemophilia A in Chinese patients by an analysis of inversions in the factor VIII gene. 879 48

Preimplantation polar body diagnosis makes it possible to detect and avoid genetic and chromosomal disorders before pregnancy. We have shown that the polar body biopsy does not affect fertilization and viability of the resulting embryos. Our present experience of polar body diagnosis includes 187 clinical cycles, performed for preimplantation diagnosis of cystic fibrosis, alpha-1-antitrypsin deficiency, Tay-Sach's disease, retinitis pigmentosa, hemophilia A, Alport and sickle cell disease, and common aneuploidy, using the FISH technique. Over three-quarters of these cycles have resulted in embryo transfer, 38 in clinical pregnancy and 12 in the birth of an unaffected child. The present review describes the results of our clinical trial on the polar body diagnosis of genetic and chromosomal disorders, demonstrating the reliability of polar body genetic analysis for preimplantation diagnosis.
Biochem Mol Med 1996 Jun
PMID:Preimplantation polar body diagnosis. 880 40

FVIII is synthesized as a single chain precursor of approximately 280 kD with the domain structure of A1-A2-B-A3-C1-C2 and it circulates as a series of metal ion-linked heterodimers that result from cleavages at B-A3 junction as well as additional cleavages within B domain. Factor VIII is converted to its active form, factor VIIIa, upon proteolytic cleavages by thrombin and is a heterotrimer composed of the A1, A2, and A3-C1-C2 subunits. A1 subunits of factor VIIIa terminates with 36 residue segment (Met337-Arg372) rich in acidic residues. This segment is removed after cleavages at Arg336 by activated protein C, which results in inactivation of the cofactor. In the present study, site-directed mutagenesis of FVIII at Arg336 to Gln336 was performed in order to produce an inactivation resistant mutant rFVIII (rFVIIIm) with an extended physiological stability. A recombinant mutant heavy chain of FVIII (rFVIII-Hm; Arg336 to Gln336) and wild-type light chain of FVIII (rFVIII-L) were expressed in Baculovirus-insect cell (Sf9) system, and a biologically active recombinant mutant FVIII (rFVIIIm) was reconstituted from rFVIII-Hm and rFVIII-L in the FVIII-depleted human plasma containing 40 mM CaCl2. The rFVIIIm exhibited cofactor activity of FVIIIa (2.85 x 10(-2) units/mg protein) that sustained the high level activity during in vitro incubation at 37 degrees C for 24 h, while the cofactor activity of normal plasma was declined steadily for the period. These results indicate that rFVIIIm (Arg336 to Gln336) expressed in Baculovirus-insect cell system is inactivation resistant in the plasma coagulation milieu and may be useful for the treatment of hemophilia A.
Exp Mol Med 1999 Jun 30
PMID:Synthesis of recombinant blood coagulation factor VIII (FVIII) heavy and light chains and reconstitution of active form of FVIII. 1041 Mar 9

Gene therapy holds great promise for the treatment of a variety of inherited diseases, including hemophilia A and mucopolysaccharidosis type VII (MPS VII). In both these disorders, subnormal levels of replacement protein have therapeutic effects. Thus we hypothesized that transduction of a small proportion of cells by feline immunodeficiency virus (FIV)-based lentiviral vectors might provide sufficient levels of transgene expression for phenotypic correction. We intravenously injected replication-deficient FIV-based vectors encoding either human factor VIII or human beta-glucuronidase into factor VIII-deficient or beta-glucuronidase-deficient mice, respectively. This route of delivery targeted multiple organs, with the liver as the primary transduction site. In the hemophilia A mice, factor VIII expression persisted for the duration of the experiments (approximately 5 months), and recipient mice survived an otherwise lethal bleeding episode (tail-clipping). In mucopolysaccharidosis type VII mice, substantial beta-glucuronidase activity was detected in several tissues and corresponded with marked reduction of lysosomal storage in liver and spleen. These findings indicate that gene transfer with FIV-based lentiviral vectors can permanently introduce transgenes into a sufficient number of hepatocytes for long-term therapeutic effect and suggest potential clinical value of FIV-based lentiviral vectors for treatment of hemophilia A and MPS VII.
Mol Ther 2001 Jun
PMID:In vivo treatment of hemophilia A and mucopolysaccharidosis type VII using nonprimate lentiviral vectors. 1140 98


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