Identification of seven novel mutations of F8C by DHPLC

Frusconi, Sabrina; Passerini, Ilaria; Girolami, Francesca; Masieri, Maddalena; Linari, Silvia; Longo, Giovanni; Morfini, Massimo; Torricelli, Francesca

doi:10.1002/humu.9052

Cited by 12 publications

(6 citation statements)

References 28 publications

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“…This phenomenon was also observed by others [7,8]. The observed frequency of S1269S polymorphism in the Turkish population was higher than previously reported frequency in Europe (6%) and China (18%) [9]. In addition, the observed 38% heterozygosity of the S1269S polymorphism, qualified it as an informative intragenic marker for F8 linkage analysis in the population.…”

Section: Introductionsupporting

confidence: 83%

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

Berber¹,

Fidancı²,

Ün³

et al. 2006

Haemophilia

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The most common cause for severe cases of hemophilia A is the homologous recombination involving intron 22 and related sequences outside the F8 gene. F8 coding regions of the gene including the exon/intron junctions were sequenced in 10 Turkish hemophilia A patients all of whom have been typed negative for intron 22 inversion and who did not have a detectable change by DGGE analysis. Pathological changes including two novel deletions (c. 205del CT and c. 3699del ACAT), one novel missense mutation (9546A) and two recurrent missense mutations were observed in five patients. The c. 2110C > T is another novel pathological change affecting exonic splicing enhancer site in two patients. One of the remaining three patients had a recurrent vWD type 2N mutation in the F8 binding site of the vWF (C788R). The S1269S polymorphism (c. 3864A > C) detected phenotype. Conclusively, sequencing of the promoter and the coding regions of 10 hemophilia A patients contributes four novel pathological mutations to the F8 mutations list and reveals a rediagnosis of hemophilia A but is still not sufficient to confirm hemophilia A phenotype in two patients.

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Section: Introductionsupporting

confidence: 83%

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

Berber¹,

Fidancı²,

Ün³

et al. 2006

Haemophilia

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“…Interestingly, polyA tract insertions do not always cause severe HA. Indeed the c.3864_3870insA mutation identified here has been reported twice before and in one case causes only a mild phenotype [17,18]. It has been proposed that the reason some individuals with polyA tract insertions escape severe HA is that just as polyA stretches are regions of frequent errors in DNA replication they are also likely sites for errors in transcription, which may restore the reading frame and allow traces of a functional protein to be produced [19,20], as was observed in this case.…”

Section: Discussionsupporting

confidence: 58%

The molecular aetiology of haemophilia A in a New Zealand patient group

Laurie¹,

Sheen²,

Hanrahan

et al. 2007

Haemophilia

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The genetic basis of haemophilia A (HA) is well-established, and many haematology services are supported by molecular biology laboratories that offer factor VIII genetic testing for HA patients. This report describes the results from factor VIII gene (F8) analysis of a New Zealand cohort of 45 proband HA patients. We screened all proband HA patients attending local clinics to determine the molecular basis of disease in each case. We also aimed to evaluate the significance of founder effect in this population and to explain an unusual case of HA in a female patient. HA patients were screened for the common F8 gene inversion mutations using previously described PCR-based techniques, and for single base substitution mutations using denaturing high performance liquid chromatography and DNA sequencing. Analysis of microsatellite markers located within or near F8 was used to determine identity by descent and trace inheritance patterns of disease alleles. X-chromosome inactivation (XCI) patterns were detected using methylation specific PCR. Pathogenic F8 gene mutations were detected in all 45 HA patients in this cohort and non-random XCI was confirmed in a female haemophiliac. We report nine novel F8 mutations, including two splicing mutations, a five nucleotide deletion and a large deletion at the 5' end of the gene. The molecular aetiology of HA was similar to that described in other studies but the distribution of mutations was unusual due to founder effects, with almost a quarter of all probands being descended from just three individuals.

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“…Forthis reason, we have decided to directlysequence factor VIII and factor IX genes,although DGGE waspreviously used in the laboratory (16). DHPLC technology could represent an intermediate choice, as recentlys hown by different groups (17)(18)(19),with lowrunning costs and excellent sensitivity compared with direct sequencing. In this study,9 6d ifferent mutations were identified.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France

Vinciguerra¹,

Zawadzki²,

Dargaud³

et al. 2006

Thromb Haemost

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Direct sequencing of the coding region of factor VIII (F8) gene was used to determine the mutations responsible for severe haemophilia A (FVIII<1%) in 128 unrelated haemophiliacs A, negative for intron 22 and intron 1 inversions. A mutation was found in 122/128 patients (95%). Ninety-six distinct mutations were identified in this cohort, 62 of these are novel. They consisted of deletions (7 large and 24 small deletions), insertions (n = 9), associations of insertion/deletion (n = 2), association of deletion/substitution (n = 1), and single nucleotide substitutions (53 point mutations consisting of 31 missense, 20 nonsense, and 2 splicing mutations). Twenty-two patients had developed inhibitors, and among this subgroup 3 large deletions, 6 frameshift, 9 nonsense and 4 missense mutations were detected. For 6 patients, among which one developed an anti-FVIII inhibitor, no mutations were detected in the coding and splicing regions of factor VIII gene. Different approaches of molecular modelling were performed in addition to familial linkage analysis to determine the pathophysiological responsibility of these novel missense mutations.

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Identification of seven novel mutations of F8C by DHPLC

Cited by 12 publications

References 28 publications

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

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

The molecular aetiology of haemophilia A in a New Zealand patient group

Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France

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