Sequencing of the <i>factor 8(F8)</i> coding regions in 10 Turkish hemophilia A patients reveals three novel pathological mutations, and one rediagnosis of von Willebrand's disease type 2N

Berber, Ergül; Fidancı, İnanç Değer; Ün, Cemal; El‐Maarri, Osman; Aktuğlu, Gülten; Gürgey, Aytemiz; Çelkan, Tiraje; Meral, Adalet; Oldenburg, Johannes; Graw, Jochen; Akar, Nejat; Çağlayan, Hande

doi:10.1111/j.1365-2516.2006.01302.x

Cited by 10 publications

(6 citation statements)

References 9 publications

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“…Thus, the sensitivity of DHPLC was around 90% (20/23 identified changes), similar to that already reported [4]. Furthermore, it suggests that the rate of misdiagnosis should be low, although sporadic cases of misdiagnosis with type 2N VWD are still reported [15].…”

Section: Discussionsupporting

confidence: 85%

Spectrum of mutations in Albanian patients with haemophilia A: identification of ten novel mutations in the factor VIII gene

et al. 2007

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Genetic analysis was carried out in 37 Albanian patients with haemophilia A. The factor VIII intron 22 inversion was detected only in 2/19 (10.5%) apparently unrelated patients with severe haemophilia A, while the intron 1 inversion was absent. A total of 19 different gene mutations were identified. Ten mutations were novel: four null mutations in severe haemophilia A patients (Gln1090X, Cys1832X, 2374delT, 5676insT) and six missense mutations (five in severe haemophilia A) (Ile76Thr, Leu299Pro, Asp525Glu, Cys692Tyr, His1755Leu and Trp1835Cys). None of these novel mutations occurred at CpG hotspots. These results further emphasize the extreme heterogeneity of the molecular basis of haemophilia A. The low prevalence of intron 22 inversion in Albanian patients with severe haemophilia A should be addressed by further studies.

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Section: Discussionsupporting

confidence: 85%

Spectrum of mutations in Albanian patients with haemophilia A: identification of ten novel mutations in the factor VIII gene

et al. 2007

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“…We failed to identify any mutation in two male patients (6.5% of examined patients) even after a complete sequencing of the coding regions and splice junctions of the F8 gene (Table 1). This phenomenon seems not uncommon as it was also observed in many other studies [25–27]. In these studies, it was reported that the proportion of patients with undetected F8 mutations varies between 1.5 and 15%.…”

Section: Resultssupporting

confidence: 66%

The spectrum of the factor 8 (F8) defects in Taiwanese patients with haemophilia A

Chang

Chen

et al. 2008

Haemophilia

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Summary. Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by various types of pathological defects in the factor VIII gene (F8), which encodes coagulation factor VIII (FVIII). To date, several studies on the spectra of F8 defects have been performed in Western populations, but similar studies in Asian races are scarce. Here, we report the distribution of the mutations within the F8 gene in 31 Taiwanese unrelated HA patients (19 severe and 10 moderate/mild males and two severe females). Of these, 12 (38.7%) and one (3.2%) severe males were genotyped with the recurrent IVS22 and IVS1 inversion, respectively, similar to that in general populations (IVS22: 40-50%; IVS1: 2-5%). The F8 defects in the remaining 18 inversion-negative patients cover a wide spectrum, in which 17 different mutations were identified (10 missense and three nonsense mutations, and two small and two large deletions).Eleven of these mutations are novel: seven caused missense substitutions and four resulted in truncated proteins. To assess the putative pathogenetic impacts of the newly amino acid substitutions, computer analyses were performed based on molecular 3D modelling. The degree of conservation in crossspecies FVIIIs and the position in known functional FVIII regions were studied. The novel missense mutations found in our series all occurred at evolutionary conserved residues that may carry a functional importance in our analyses. The results of this study add the short list of Taiwanese/Chinese F8 mutations, and will enhance our understanding of the molecular basis of FVIII function and the mechanism underlying HA.

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“…Inhibitor information was available for one high-responder patient with a large deletion and two low-responder patients with a missense mutation and a small deletion [15,21]. With these additional three patients who had severe phenotype and very low levels of FVIII : C, the total number of the high-responder and lowresponder patients were 30 and six, respectively ( Table 4).…”

Section: Identification Of Mutations In Severe Hemophilia a Patients mentioning

confidence: 99%

Factor 8 (F8) gene mutation profile of Turkish hemophilia A patients with inhibitors

Kavaklı²,

Uçar³

et al. 2008

Blood Coagulation &Amp; Fibrinolysis

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Factor VIII (FVIII) replacement therapy is ineffective in hemophilia A patients who develop alloantibodies (inhibitors) against FVIII. The type of factor 8 (F8) gene mutation, genes in the major histocompatibility complex loci, and also polymorphisms in IL-10 and tumor necrosis factor-alpha are the major predisposing factors for inhibitor formation. The present study was initiated to reveal the F8 gene mutation profile of 30 severely affected high-responder patients with inhibitor levels of more than 5 Bethesda U (BU)/ml and four low-responder patients with inhibitors less than 5 BU/ml. Southern blot and PCR analysis were performed to detect intron 22 and intron 1 inversions, respectively. Point mutations were screened by DNA sequence analysis of all coding regions, intron/exon boundaries, promoter and 3' UTR regions of the F8 gene. The prevalent mutation was the intron 22 inversion among the high-responder patients followed by large deletions, small deletions, and nonsense mutations. Only one missense and one splicing error mutation was seen. Among the low-responder patients, three single nucleotide deletions and one intron 22 inversion were found. All mutation types detected were in agreement with the severe hemophilia A phenotype, most likely leading to a deficiency of and predisposition to the development of alloantibodies against FVIII. It is seen that Turkish hemophilia A patients with major molecular defects have a higher possibility of developing inhibitors.

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Sequencing of the factor 8(F8) coding regions in 10 Turkish hemophilia A patients reveals three novel pathological mutations, and one rediagnosis of von Willebrand's disease type 2N

Cited by 10 publications

References 9 publications

Spectrum of mutations in Albanian patients with haemophilia A: identification of ten novel mutations in the factor VIII gene

Spectrum of mutations in Albanian patients with haemophilia A: identification of ten novel mutations in the factor VIII gene

The spectrum of the factor 8 (F8) defects in Taiwanese patients with haemophilia A

Factor 8 (F8) gene mutation profile of Turkish hemophilia A patients with inhibitors

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