Start of UK Confidential Haemophilia A Database: Analysis of 142 Patients by Solid Phase Fluorescent Chemical Cleavage of Mismatch

Waseem, Naushin; Bagnall, Richard D.; Green, Peter M.; Giannelli, F.

doi:10.1055/s-0037-1614595

Cited by 48 publications

(49 citation statements)

References 32 publications

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“…Initially, polymorphisms contained within the FVIII gene, or closely linked to it, made it possible to carry out linkage studies in haemophilia families (reviewed in Peake et al, 1993); however, more recently, technical advances have permitted the characterization of causative mutations (Waseem et al, 1999) and direct mutation detection is the preferred route for family studies.…”

Section: Discussionmentioning

confidence: 99%

“…Inclusion of loci with the highest frequency of heterozygosity and lowest degree of linkage disequilibrium maximizes the probability of an informative result. Such loci include two (CA)n microsatellites in intron 13 (Lalloz et al, 1991) and intron 22 (Lalloz et al, 1992) of the FVIII gene, a BclI restriction fragment length polymorphism (RFLP) in intron 18 (Gitschier et al, 1985) and an XbaI RFLP in intron 22 (Wion et al, 1986). The last is contained within a 9´5-kb stretch of sequence (int22h-1), which is repeated extragenically at Xq28 (int22h-2 and int22h-3) (Naylor et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

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A new polymorphism in the human factor VIII gene: implications for linkage analysis in haemophilia A and for the evolution of int22h sequences

et al. 2000

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Summary.A new polymorphism in the human factor VIII gene has been localized and characterized. It is a biallelic, single nucleotide polymorphism located in intron 22 of the gene, within the 9´5 kb int22h-1 segment. The allelic forms are G (frequency 0´65) and A (frequency 0´35), giving a predicted rate of heterozygosity of 0´46. The polymorphism occurs within a CG dinucleotide and affects an MspI site (CCGG). Int22h-1 is duplicated twice extragenically at Xq28; both extragenic copies (int22h-2 and -3) are also polymorphic with respect to MspI. Investigation of 156 MspI [±] alleles, comprising 30 intragenic and 126 extragenic sites, indicated that all were due to A alleles and none had arisen by C to T transition within the CG dinucleotide. The intragenic MspI site (designated MspI A) is located 737 bases downstream of a previously described XbaI restriction fragment length polymorphism. Despite their close proximity, the polymorphisms are not in complete linkage disequilibrium; haplotype analysis in 85 factor VIII genes from a Caucasian population predicts an informativity of approximately 60% in linkage studies using both, compared with an informativity of approximately 47% in studies using either on its own.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A new polymorphism in the human factor VIII gene: implications for linkage analysis in haemophilia A and for the evolution of int22h sequences

et al. 2000

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“…12 From the Division of Medical and Molecular Genetics, Guy's, King's, and St Thomas' School of Medicine, London, United Kingdom. …”

Section: Blood Samplesmentioning

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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“…Common missense mutations in the A domain include Glu321Lys, Tyr346Cys, Val357Gly, Val376Gly, Thr770Ser, Thr751Ser Glu720Lys; all of the residues that are affected by these mutations lie either adjacent to or within the a1 or a2 acidic region (Stoilova-Mcphie et al, 2002;Goodeve et al, 2001;Mumfordet al, 2002). Other mutations that have contributed to understanding the structure-function relationship of F8 occur at the thrombin cleavage sites at Arg372 (Arg372Cys) (Pattinson et al, 1990;Vidal et al, 2002) and Arg372His (Jayandharan et al, 2005) and Arg1689 (Arg1689Cys) Cutler et al, 2002;Arai et al, 1990;Waseem et al, 1990;Hill Deam et al, 2005). Several mutations affect residues that are located at the interface of the A domains (Arg 282Ser, Ala284Glu and Arg531His at the A1-A2 interface, Ser289Leu at the A1-A3 interface, Asn694Ile, Arg698Trp and Arg698Leu at the A2-A3 interface).…”

Section: Mutations That Affect the A Domainsmentioning

confidence: 99%

Factor VIII genetic mutations and protein alterations in hemophilia A: A review

Faridi¹,

Kumar²,

Husain³

et al. 2014

Clin. Rev. Opinions

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Start of UK Confidential Haemophilia A Database: Analysis of 142 Patients by Solid Phase Fluorescent Chemical Cleavage of Mismatch

Cited by 48 publications

References 32 publications

A new polymorphism in the human factor VIII gene: implications for linkage analysis in haemophilia A and for the evolution of int22h sequences

A new polymorphism in the human factor VIII gene: implications for linkage analysis in haemophilia A and for the evolution of int22h sequences

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

Factor VIII genetic mutations and protein alterations in hemophilia A: A review

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