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Blood, 1 January 2002, Vol. 99, No. 1, pp. 168-174
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Recurrent inversion breaking intron 1 of the factor
VIII gene is a frequent cause of severe hemophilia
A
Richard D. Bagnall,
Naushin Waseem,
Peter M. Green, and
Francesco Giannelli
From the Division of Medical and Molecular Genetics,
Guy's, King's, and St Thomas' School of Medicine, London, United
Kingdom.
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, introns
13 and 22 VNTR polymorphism, among 209 unrelated families with severe
hemophilia A. This indicates a prevalence of 4.8% and frequent
recurrence of the inversion. This should result in absence of
F8, and one inversion patient is known to have inhibitors.
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