scholarly journals Analysis of intron 22 inversions of the factor VIII gene in severe hemophilia A: implications for genetic counseling

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2197-2201
Author(s):  
PV Jenkins ◽  
PW Collins ◽  
E Goldman ◽  
A McCraw ◽  
A Riddell ◽  
...  
Keyword(s):  
Factor Viii ◽  
Genetic Counselling ◽  
Hemophilia A ◽  
Family Members ◽  
Rflp Analysis ◽  
Homologous Region ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Intron 22 Inversion ◽  
Blotting Technique

Intrachromosomal recombinations involving F8A, in intron 22 of the factor VIII gene, and one of two homologous regions 500 kb 5′ of the factor VIII gene result in large inversions of DNA at the tip of the X chromosome. The gene is disrupted, causing severe hemophilia A. Two inversions are possible, distal and proximal, depending on which homologous region is involved in the recombination event. A simple Southern blotting technique was used to identify patients and carriers of these inversions. In a group of 85 severe hemophilia A patients, 47% had an inversion, of which 80% were of the distal type. There was no association with restriction fragment length polymorphism (RFLP) haplotypes. The technique has identified a definitive genetic marker in families previously uninformative on RFLP analysis and provided valuable information for genetic counselling information may now be provided for carriers without the need to study intervening family members and the diagnosis of severe hemophilia A made in families with only a nonspecific history of bleeding. Analysis of intron 22 inversion should now be the first-line test for carrier diagnosis and genetic counselling for severe hemophilia A and may be particularly useful when there is no affected male family member or when intervening family members are unavailable for testing.

scholarly journals Analysis of intron 22 inversions of the factor VIII gene in severe hemophilia A: implications for genetic counseling

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2197-2201 ◽  
Author(s):  
PV Jenkins ◽  
PW Collins ◽  
E Goldman ◽  
A McCraw ◽  
A Riddell ◽  
...  
Keyword(s):  
Factor Viii ◽  
Genetic Counselling ◽  
Hemophilia A ◽  
Family Members ◽  
Rflp Analysis ◽  
Homologous Region ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Intron 22 Inversion ◽  
Blotting Technique

Abstract Intrachromosomal recombinations involving F8A, in intron 22 of the factor VIII gene, and one of two homologous regions 500 kb 5′ of the factor VIII gene result in large inversions of DNA at the tip of the X chromosome. The gene is disrupted, causing severe hemophilia A. Two inversions are possible, distal and proximal, depending on which homologous region is involved in the recombination event. A simple Southern blotting technique was used to identify patients and carriers of these inversions. In a group of 85 severe hemophilia A patients, 47% had an inversion, of which 80% were of the distal type. There was no association with restriction fragment length polymorphism (RFLP) haplotypes. The technique has identified a definitive genetic marker in families previously uninformative on RFLP analysis and provided valuable information for genetic counselling information may now be provided for carriers without the need to study intervening family members and the diagnosis of severe hemophilia A made in families with only a nonspecific history of bleeding. Analysis of intron 22 inversion should now be the first-line test for carrier diagnosis and genetic counselling for severe hemophilia A and may be particularly useful when there is no affected male family member or when intervening family members are unavailable for testing.

Factor VIII gene mutations and RFLP analysis in hemophilia A

Stem Cells ◽  
1993 ◽  
Vol 11 (S1) ◽  
pp. 72-76 ◽  
Author(s):  
A. Křepelová ◽  
R. Brdicka ◽  
Z. Vorlová
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Gene Mutations ◽  
Rflp Analysis ◽  
Factor Viii Gene

Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

1999 ◽  
Vol 82 (08) ◽  
pp. 555-561 ◽  
Author(s):  
Douglas Jolly ◽  
Judith Greengard
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Hemophilia A ◽  
Joint Damage ◽  
Coagulation Factor ◽  
The United States ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Bleeding Episodes

IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.

scholarly journals Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells

1994 ◽  
Vol 3 (7) ◽  
pp. 1035-1039 ◽  
Author(s):  
Judith Pratt Rosslter ◽  
Michele Young ◽  
Michelle L. Kimberland ◽  
Pierre Hutter ◽  
Rhett P. Ketterling ◽  
...  
Keyword(s):  
Factor Viii ◽  
Germ Cells ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Male Germ Cells

Genetic Counseling by Analysis of Intron 22 Inversions of the Factor VIII Gene

1998 ◽  
Vol 4 (2) ◽  
pp. 111-113
Author(s):  
Etsuko Yamazaki ◽  
Hiroshi Mohri ◽  
Hiroshi Harano ◽  
Heiwa Kanamori ◽  
Hiroshi Inaba ◽  
...  
Keyword(s):  
At Risk ◽  
Genetic Counseling ◽  
Factor Viii ◽  
Key Words ◽  
Gene Rearrangement ◽  
Hemophilia A ◽  
Carrier Detection ◽  
Severe Hemophilia ◽  
Normal Allele ◽  
Factor Viii Gene

Ten patients with severe hemophilia A and 10 with moderate and mild hemophilia A were studied. Five of 10 unrelated patients with severe hemophilia A had the distal telo meric int22h sequence, none had the proximal sequence, and one had a unique variant factor VIII gene rearrangement. Car rier detection was done in these six families. All mothers and two daughters of the patients were to be carriers. Six of the 15 at-risk female relatives were heterozygous for the rearranged and normal allele and were carriers. These results indicate that the rearrangement assay is very useful for carrier detection in families with severe hemophilia A. Key Words: Hemophilia A—Factor VIII gene rearrangement—Genetic counseling.

French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

1998 ◽  
Vol 80 (11) ◽  
pp. 779-783 ◽  
Author(s):  
Y. Laurian ◽  
E. P. Satre ◽  
A. Borel Derlon ◽  
H. Chambost ◽  
P. Moreau ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Intron 22 Inversion ◽  
Median Period

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

scholarly journals Detection of Intron22 Mutations in Iraqi Female Carriers in Wasit City with Hemophilia A

2017 ◽  
pp. 13-24
Author(s):  
Maysoon Mohammed Hassan
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Gene Identification ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Intron 1 ◽  
Detection Mechanisms ◽  
Female Carriers ◽  
Chromosomal Recombination

The background:One of the prevalent main concerns in the medical world is the identification of Intron22 mutations in the Factor VIII gene carried by Iraqi patient in Wasit town, in Iraq suffering Hemophilia A (classical hemophilia) which is related to a X-chromosome recessive haemorrhage afflictions as the result of a flaw in the coagulation factor VIII (FVIII). It is essentially related with F8 mutations of Intron22 in version which forms the most typical kind of mutations of blood afflictions worldwide involving half the patients suffering from severe Hemophilia A that possesses mutations, in addition to Intron 1 inversion suffered by 5% of severe Hemophilia A patients.All of the inversion mutations are suffered mainly by males,and uncommonly by females due to the intra chromosomal recombination among the homologous areas, in inversion 1 or 22, with extragenic copy posited the telomeric to the Factor VIII gene. Unfortunately, there is an absence in Iraq on researches pertaining blood affliction gene identification in persons who carries the Intron22 mutations exception in the current research.Aims of study:The objectives of the research is to to analyze through the detection mechanisms, the existence of Intron 22 mutations in the Factor VIII gene of 10 Hemophilia A Iraqi carriers cohort families. The hypothesis and anticipated result is that there will be a minimal margin of hazardous possibility for the recurrence. The hereditary F8 mutation is unknown to be present on the maternal side of the patient sufferer due to the possibilty of germline mosaics that exists within the community.

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