Identification of intron 1 and 22 inversion mutations in the factor VIII gene of 124 Iranian families with severe haemophilia A

Lari, Ghasem Rastegar; Enayat, M. S.; Arjang, Z.; Lavergne, J. M.; Ala, F.

doi:10.1111/j.1365-2516.2004.00920.x

Cited by 16 publications

(8 citation statements)

References 9 publications

(13 reference statements)

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“…We detected 25 different mutations as causative for sHA, with the F8 intron 22 inversion as the most common mutation (41%), which is consistent with other reports that show that this inversion affects approximately 40–50% of the cases [7,12,21–25]. The intron 1 inversion frequency varies between populations, ranging from 0% to 5% in patients with sHA [5,12,22,23,25–27]. In our study, we did not detect this mutation, which is in agreement with some of the above studies [23,26,27].…”

Section: Discussionsupporting

confidence: 92%

“…The incidence of inhibitor development among our patients with intron 22 inversions was 36%. The prevalence of inhibitors among patients from several populations with this inversion varies widely (5-51%) [12,21,[23][24][25][32][33][34] and these differences could be explained by the presence of other risk factors [7,[35][36][37]. As expected [31], 22% of our patients who had stop codon mutations and 100% of sHA patients with gross deletions developed inhibitors against exogenous FVIII.…”

Section: Discussionmentioning

confidence: 64%

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Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

et al. 2011

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Haemophilia A is caused by mutations in the gene encoding coagulation factor VIII (FVIII). In severe Haemophilia A (sHA), two inversions are responsible for approximately 50% of the genetic alterations (intron 22 and intron 1 inversions). The other mutations are extremely diverse and each affected family generally has its own mutation. Our aim was to detect the genetic alterations present in the FVIII gene (F8) in 54 unrelated male patients with sHA in Venezuela. We initially detected the presence of the intron 22 inversion by performing inverse PCR, and the negative patients for this inversion were analysed for the intron 1 inversion by PCR. Patients negative for both inversions were analysed using Conformation Sensitive Gel Electrophoresis for mutations in all exons, promoter region and 3¢-UTR. sHA causative mutations were identified in 49 patients. Intron-22 and -1 inversions were detected in 41% and 0% of patients respectively. Besides these two mutations, 25 different mutations were identified, including nine nonsense, four small deletions, two small insertions, four missense, three splicing mutations and three large deletions. Seven novel mutations were identified, including two nonsense mutations, two small deletions, one small insertion, one missense mutation and one splicing mutation. Thirty one percent of the patients with identified mutations developed inhibitors against exogenous FVIII. This is the first report of F8 mutations in patients with sHA in Venezuela; the data from this study suggests that the spectrum of gene defects found in these patients is as heterogeneous as reported previously for other populations.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 64%

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

et al. 2011

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“…As a consequence of technological progress made in this field in Iran, especially during the last 3 years [49], the early detection of an affected fetus through diagnosis of families with a diseased child to reduce incidence with a chance to terminate pregnancy is a young programme in the country. There are two main limitations in this issue.…”

Section: Treatment and Diagnostic Facilitiesmentioning

confidence: 99%

Haemophilia in the developing countries: the Iranian experience

Eshghi¹,

Mahdavi‐Mazdeh²,

Karimi³

et al. 2010

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IntroductionManagement of haemophilia and inherited bleeding disorders is a major challenge especially in developing countries, because of a shortage or absence of products, the cost and the infrastructural health problems. Development of local expertise which results in an improved outlook and reduction in mortality and morbidity in these countries can be helpful for advocators in other developing countries. However, very little information on demography and organizational models for haemophilia care in developing countries are available in the literature. Our aim is a comprehensive report of haemophilia status and its management in Iran.Material and methodsThe Management Center of Transplantation and Special Diseases (MCTSD) of the Ministry of Health of Iran decided to carry out a complete review and compilation of all of the published or available data about patients with haemophilia (PWH) in Iran: their health status, their management planning, organizations, treatment products, facilities and care problems during 2007.Results6496 patients with congenital bleeding disorders were registered. Most of them had haemophilia A and B and von Willebrand disease (vWD). However, rare bleeding disorders are seen more than expected. Inhibitor development is 14–28%. There are different data about virological status of PWH. Factor products and facilities are fairly available with more than 1.5 units per capita of inhabitant factor consumption.ConclusionsA national formulary based on facilities of the country should be considered and followed by collaboration among the Ministry Of Health, universities and non-governmental organizations.

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“…In Iran, HA carrier detection has been carried out by others for over 15 years, through tracking the defective gene by polymorphic DNA markers, but the efficacy of this method is limited due to the homozygosity of these polymorphic markers, the absence of the index patients, or the unavailability of all key family members [5]. However, the direct identification of mutations among HA patients, followed by carrier detection, has been carried out in our laboratory for the past decade, resulting in the identification of a diverse group of mutations [6]. Part of the data represented in this study have been presented before in an abstract [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of 123 previously unreported mutations in the F8 gene of Iranian patients with Haemophilia A

et al. 2011

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In Haemophilia A (HA), the deficiency in coagulation factor VIII is caused by mutations in the F8 gene. In the past, HA carrier detection in Iran used to be carried out by tracking polymorphic DNA markers - a technical strategy with poor efficacy and accuracy. For some 10 years, however, mutations have been identified by direct DNA sequencing at the Iranian Comprehensive Haemophilia Care Centre (ICHCC), resulting in the detection of 580 different mutations and accurate carrier detection. The aim of this study was to characterize and report the unreported mutations not recorded in the F8 HAMSTeRS database and HGMD, which we have detected amongst all the mutations hitherto identified. After excluding introns 1 and 22 inversions, direct DNA sequencing was used to detect mutations among our patients. These were then confirmed in another affected relative or obligate carrier. Severe cases of HA, where no mutation could be identified, were further investigated by the MLPA method. The new, unreported mutations identified include: 51 missense, 15 nonsense, 45 frame-shifts, 11 splice-site, 1 duplications. We report a large spectrum of mutations identified in the course of the past 10 years at the ICHCC, which offers this service to all patients from regions throughout Iran. Aside from the common introns 1 and 22 inversions, this work demonstrates a high degree of heterogeneity in F8 mutations. The establishment of a comprehensive Iranian HA database will improve the care and genetic counselling of Iranian HA families.

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Identification of intron 1 and 22 inversion mutations in the factor VIII gene of 124 Iranian families with severe haemophilia A

Cited by 16 publications

References 9 publications

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

Haemophilia in the developing countries: the Iranian experience

Identification of 123 previously unreported mutations in the F8 gene of Iranian patients with Haemophilia A

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