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

Accurate first-trimester prenatal diagnosis was achieved in a Japanese haemophilia A family by the use of a restriction fragment length polymorphism (RFLP) located within the F.VIII gene. Since the pregnant woman's heterozygosity for BclI polymorphism in F.VIII/intron 18 (F8A) probe was informative, chorionic villus sampling (CVS) was performed at 9 weeks of gestation. Restriction analysis showed that the fetus was heterozygous for the BclI site and had received a normal paternal X chromosome (0.9 kb) and a normal maternal X (1.2 kb). Therefore, we concluded that the fetus was a non-carrier female. Pregnancy went to term and woman gave birth to an apparently healthy female. At one week after birth a coagulation study confirmed that the newborn infant is not a carrier. The first-trimester prenatal diagnosis of haemophilia A is possible by CVS due to a RFLP in the F.VIII gene.
 ...
PMID:First trimester prenatal diagnosis of haemophilia A using factor VIII gene probe. 257 Jan 72

Intrachromosomal rearrangements of the long arm of chromosome X, between gene A (F8A) in intron 22 of the factor VIII gene and one of its two telomeric copies, are responsible for about half of the severe cases of haemophilia A. A group of 98 unrelated patients from Northern France with moderate to severe haemophilia A was screened for this gene inversion using a non-radioactive Southern blotting method. Whereas none of the 18 moderately affected patients presented the FVIII gene rearrangement, gene inversion was found in 38 (48%) of the 80 severe haemophilia A patients. Recombinations involving the distal copy of gene A (group 1) were more frequent (79%) than those involving the proximal copy (group 2). Individual variation in the number of gene A copies on the X chromosome probably explains an alternative Southern blot profile, referred to as group 3 inversion, which was observed in one of our patients. In the severely affected patients, neither the prevalence of inhibitor development nor the frequency of sporadic cases differed significantly in the group presenting gene inversion as compared to the group without chromosomal rearrangement. Study of four families where no patient was available enabled in one case direct carrier detection and prenatal diagnosis in the absence of an affected member. The Southern blotting technique described in the present work is relevant to about 50% of cases of severe haemophilia A, can be performed without use of a radiolabelled probe and represents a major advance in the diagnosis of the disease.
 ...
PMID:Characterization of factor VIII gene inversions using a non-radioactive detection method: a survey of 102 unrelated haemophilia A families from northern France. 764 50

Factor VIII (FVIII) gene rearrangements between the intron 22 F8A sequence in the FVIII gene and either of the two homologous F8A sequences 500 kilobases telomeric to the FVIII gene have recently been found to be responsible for the severe hemophilia A phenotype. We studied 27 patients with severe hemophilia A and 19 with moderate and mild hemophilia, and found FVIII gene rearrangement in 12 patients with severe hemophilia A and none in the patients with moderate or mild disease. Nine of the rearrangements were with the distal telomeric F8A sequence, two were with the proximal sequence, and one had variant distal rearrangement with loss of the FVIII intron 22 F8A band. Two patients with FVIII gene rearrangement had high responding inhibitors, contrary to one previous study suggesting that the presence of a FVIII gene rearrangement is correlated with the absence of inhibitor development. Carrier detection was performed in 17 female relatives, at risk of being carriers, from eight kindreds; 13 were carriers, being heterozygous for the normal and rearranged alleles. The rearrangement assay is particularly useful for carrier determination in families with sporadic cases of hemophilia not helped by linkage analysis with restriction fragment-length polymorphism or intragenic dinucleotide repeat analysis. In all five families with rearrangements and sporadic hemophilia, the mothers of all index patients were found to be carriers.
 ...
PMID:Factor VIII gene rearrangement analysis and carrier determination in hemophilia A. 789 7

A total of 164 unrelated patients with severe haemophilia A were screened for partial inversions of the factor VIII (F8) gene resulting from recombination between the intronic F8A gene and one or other of two homologous upstream A gene sequences. Inversions were found in 69 (42%) patients. Most inversions (90%) involved the distal rather than the proximal A gene. This unique mutational mechanism is estimated to occur with a frequency of 7.2 x 10(-6) per gene per gamete per generation. Although two patients with an inversion possessed inhibitors (antibodies) against factor VIII, possession of inhibitors did not appear to be associated disproportionately with inversion-type mutations.
 ...
PMID:Screening for inversions in the factor VIII (F8) gene causing severe haemophilia A. 805 56

A region of intron 22 of the factor VIII gene, which contains factor VIII-associated gene A (F8A), is repeated twice more nearer the Xq telomere. It has been proposed that intrachromosomal homologous recombination occurs between the intron 22 repeat and either of the two extragenic copies, resulting in the recurrent inversions that cause almost half of all cases of severe haemophilia A. We have precisely defined the repeated region as 9.5 kb of DNA which we have termed int22h (intron 22 homologous region). The junctions of the inversions examined were shown to represent precise exchanges between the int22h repeats, thus providing conclusive evidence for homologous recombination. The three copies of int22h were compared along 8 kb of their length, using chemical mismatch analysis, and found to be 99.9% similar. The presence of such long, almost identical inverted repeats near the Xq telomere could account for the high frequency at which the inversions occur.
 ...
PMID:Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. 852 12

Hemophilia A (HemA), an X linked genetic disease, is the most common coagulation disorder with an incidence of about 1-2 in 10,000 males and is caused by mutations in the factor VIII (FVIII) coagulation gene. Firstly, some clinical aspects of the HemA are presented: the current methods to assess both the amount and activity of FVIII, the severity range observed and the presence of inhibitor antibodies against the therapeutic FVIII. Follows a discussion of the relationship of the structural domains of the FVIII protein (Figure 1), the aminoacid sequence and their functions. An activation-inactivation model of the successive peptide bonds cleavages of the FVIII is also presented (Figure 2). After the cloning of the FVIII gene in 1984, almost all types of HemA causing mutations have been characterized. However, the size and complexity of this gene prevented a screening of the full range of mutations for an accurate molecular diagnosis. Moreover, most of the patients with moderate and mild disease have missense mutations whereas approximately half of severe patients have nonsense, frameshift, and some missense mutations. There are also less frequently mutations such as deletions and insertions leading to severe phenotype and mutations affecting mRNA splicing and duplications causing both severe and mild HemA. In order to give genetic counselling in HemA families, studies at the DNA level using intragenic and/ or extragenic polymorphism analysis have been used. But this approach is not entirely satisfactory because it fails in several situations. Most of the causing mutations described above are private, and they have been found in only a few unrelated families. Recently, a common molecular inversion of the FVIII gene was identified in 50% of unrelated patients with severe HemA. The copies of a particular DNA sequence (termed F8A gene). One copy is located within intron 22 of the FVIII gene and the other two, 500 kb upstream. An homologous recombination mechanism was proposed for the inversion between an intragenic copy of the F8A gene and either the distal (80% of the inversion) or the proximal copy (20%). Both of these inversions lead to severe HemA because no intact FVIII is produced and can be easily diagnosed by Southern blot analysis. This inversion originates almost exclusively in male germ cells, because pairing Xq with its homologous in female meiosis would probably inhibit the proposed intrachromosome recombination. The molecular analysis of the inversion of intron 22 is now considered as the first line for families with severe HemA patients. In recent years the treatment of patients with hemophilia A and B has been intravenous injection of FVIII or FIX concentrates, respectively. This regimen of regular injection of plasmatic proteins bears a high risk of infection by contaminating viruses (HIV, HBV, etc). Future treatment for patients with hemophilia may include the use of either gene therapy or recombinant coagulation factors. Both strategies would completely avoid the infection risk offering a safe and effective treatment for the disease. Recombinant factors, obtained by genetic engineering methods, provide a renewable and unlimited source of FVIII or FIX. The clinical trials of recombinant factors have already started in mid-1995 giving positive results. On the other hand, gene therapy for hemophilia is now in the pre-clinical stage but offers the prospect of a cure for the disease, thus potentially freeing patients from regular injections of the lacking protein. However, experiments in animal models suggest that it may be difficult to obtain adequate therapeutic levels of factors for long periods of time. Recently, a retroviral-mediated gene delivery of human FVIII in mice has been reported using the ex vivo strategy of gene therapy. Therapeutic levels of FVIII in the circulation were obtained for > 1 week and it was also observed that the capacity of primary cells to deliver FVIII in blood was strongly dependent on
 ...
PMID:[Molecular genetics of hemophilia A]. 923 87

In the Chapel Hill colony of factor VIII-deficient dogs, abnormal sequence (ch8, for canine hemophilia 8, GenBank no. ) follows exons 1-22 in the factor VIII transcript in place of exons 23-26. The canine hemophilia 8 locus (ch8) sequence was found in a 140-kb normal dog genomic DNA bacterial artificial chromosome (BAC) clone that was completely outside the factor VIII gene, but not in BAC clones containing the factor VIII gene. The BAC clone that contained ch8 also contained a homologue of F8A (factor 8 associated) sequence, which participates in a common inversion that causes severe hemophilia A in humans. Fluorescence in situ hybridization analysis indicated that exons 1-26 normally proceed sequentially from telomere to centromere at Xq28, and ch8 is telomeric to the factor VIII gene. The appearance of an "upstream" genomic sequence element (ch8) at the end of the aberrant factor VIII transcript suggested that an inversion of genomic DNA replaced factor VIII exons 22-26 with ch8. The F8A sequence appeared also in overlapping normal BAC clones containing factor VIII sequence. We hypothesized that homologous recombination between copies of canine F8A inside and outside the factor VIII gene had occurred, as in human hemophilia A. High-resolution fluorescent in situ hybridization on hemophilia A dog DNA revealed a pattern consistent with this inversion mechanism. We also identified a HindIII restriction fragment length polymorphism of F8A fragments that distinguished hemophilia A, carrier, and normal dogs' DNA. The Chapel Hill hemophilia A dog colony therefore replicates the factor VIII gene inversion commonly seen in humans with severe hemophilia A.
 ...
PMID:The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion. 1224 34