Factor VIII gene explains all cases of haemophilia A

Naylor, J.A.; Green, P.M.; Giannelli, F.; Rizza, C. R.

doi:10.1016/0140-6736(92)93080-7

Cited by 81 publications

(52 citation statements)

References 6 publications

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“…1). Some findings support this hypothesis, thus, the F8 mRNA of a patient with an inversion involving int22h-2 indicated that transcription of the inverted part of the F8 gene had extended from exon 22 into cryptic exons in the distal arm of the palindrome and to an exon external and telomeric to this arm [4,5]. Furthermore, long PCR in one of our inversion patients has indicated that the centromeric portion of int22h-1 is joined to an int22h copy flanked by sequences that are at the centromeric end of the loop of the palindrome described by the new sequence data [2].…”

supporting

confidence: 50%

Polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture

Bagnall

Giannelli

Green

2005

Journal of Thrombosis and Haemostasis

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supporting

confidence: 50%

Polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture

Bagnall

Giannelli

Green

2005

Journal of Thrombosis and Haemostasis

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“…12 Therefore, this absence of detectable expression in this patient could be because the studied mRNA are isolated from total blood that expresses only low levels of F8. Two reasons argue against this: (1) in humans an ectopic expression of F8 in total blood can be detected, and this is widely used to screen for mutations or rearrangements in the F8 cDNA [13][14][15] ; (2) the results obtained in control subjects and the reproducibility and consistency of the experiments in the patient, his mother, and his sister should exclude any bias being specific for ectopic lymphocyte RT-PCR. BLOOD, 1 APRIL 2006 ⅐ VOLUME 107, NUMBER 7 For personal use only.…”

Section: Discussionmentioning

confidence: 99%

Lack of F8 mRNA: a novel mechanism leading to hemophilia A

El‐Maarri

Singer

Klein

et al. 2006

Blood

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Hemophilia A (HA) is caused by partial or total deficiency of F8 protein activity. In a small group, about 1.8% of patients with HA, no mutation is found in the F8 gene. Among this group, we report here on one patient with severe HA in whom no mRNA of the F8 gene was detected. Using 2 common polymorphisms in F8 exon 14, we were able to show that the same allele shared by the patient, his mother, and his sister was not detected by reverse transcription-polymerase chain reaction (RT-PCR) from total blood mRNA. Skewed X-chromosome inactivation in both the mother and the sister was excluded by studying the methylation profile of the androgen receptor gene (HUMARA locus). These findings strongly suggest that the cause of HA in this patient is either absence or rapid degradation of the F8 mRNA, which points to a novel mechanism leading to HA. (Blood. 2006; 107:2759-2765)

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“…Traces of factor VIII messenger RNA (mRNA) from peripheral lymphocytes soon revealed that this high failure rate was largely due to mutations affecting internal regions of intron 22 of the F8 gene. 3 These mutations were later shown to be inversions resulting from homologous intrachromatid or intrachromosome (ie, intranemic) recombination between a 9503-base pair (bp) sequence (int22h-1) in intron 22 of the F8 gene and one or other of 2 inverted copies of this sequence (int22h-2, int22h-3) located, respectively, 500 and 600 kb more telomeric. [4][5][6] The int22h-related inversions appeared to be sufficiently frequent to account for the shortfall in mutation detection experienced using methods based on the screening of all exons of the F8 gene.…”

Section: Introductionmentioning

confidence: 99%

Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A

Bagnall

Waseem

Green

et al. 2002

Blood

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The messenger RNA (mRNA) from 5 of 69 patients with severe hemophilia A did not support amplification of complementary DNA containing the first few exons of the factor VIII (F8) gene but supported amplification of mRNA containing exon 1 of F8 plus exons of the VBP1 gene. This chimeric mRNA signals an inversion breaking intron 1 of the F8 gene. Using an inversion patient, one deleted for F8 exons 1 to 6, and cosmids mapped 70 to 100 kb telomeric of the F8 gene, this study shows that this break strictly affects a sequence (int1h-1) repeated (int1h-2) about 140 kb more telomerically, between the C6.1A and VBP1 genes. The 1041-base pair repeats differ at a single nucleotide (although int1h-2 also showed one polymorphism) and are in opposite orientation. The results demonstrate that they cause inversions by intrachromosome or intrachromatid homologous recombination. The genomic structure of the inversion region shows that transcription traverses intergenic spaces to produce the 2 chimeric mRNAs containing the F8 sequences and characteristic of the inversion. This observation prompts the suggestion that nature may use such extended transcription to test whether the addition of novel domains from neighboring genes creates desirable new genes. A rapid polymerase chain reaction test was developed for the inversion in both patients and carriers. This has identified 10 inversions, affecting F8 genes with 5 different haplotypes for the BclI, IntroductionHiguchi et al 1,2 observed that thorough screening of all the exons of the factor VIII (F8) gene was efficient in detecting the mutations of patients with mild and moderate hemophilia A and yet failed in 50% of patients with severe disease. Traces of factor VIII messenger RNA (mRNA) from peripheral lymphocytes soon revealed that this high failure rate was largely due to mutations affecting internal regions of intron 22 of the F8 gene. 3 These mutations were later shown to be inversions resulting from homologous intrachromatid or intrachromosome (ie, intranemic) recombination between a 9503-base pair (bp) sequence (int22h-1) in intron 22 of the F8 gene and one or other of 2 inverted copies of this sequence (int22h-2, int22h-3) located, respectively, 500 and 600 kb more telomeric. [4][5][6] The int22h-related inversions appeared to be sufficiently frequent to account for the shortfall in mutation detection experienced using methods based on the screening of all exons of the F8 gene. However, analysis of factor VIII mRNA continued to detect further mutations that escape detection by this approach. Base substitutions deep inside introns were found that generate novel exons disrupting the factor VIII coding sequence 7 (R. D. Bagnall, unpublished observations, January 2001). Moreover, an inversion was identified that broke the F8 gene at intron 1 and resulted in the production of 2 chimeric mRNAs. 8 One of these mRNAs, presumably under the control of the factor VIII promoter, contains the first exon of the F8 gene followed by facultative exons and then exons 2 to 6 of a gene (VBP...

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Factor VIII gene explains all cases of haemophilia A

Cited by 81 publications

References 6 publications

Polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture

Polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture

Lack of F8 mRNA: a novel mechanism leading to hemophilia A

Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A

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