Hemophilia A and the F8 Gene at Xq28

Hemophilia A (HEMA, MIM 306700) is a common X-liked coagulation disorder affecting 1 in 5000 males (28). It is caused by defects in the factor VIII (F8) gene, located approx 1 Mb from the Xq telomere. The F8 gene consists of 26 exons and spans more than 141 kb (29). Within its intron 22 reside two genes, factor Vlll-associated gene A (F8A) and factor VIII-associated gene B (F8B), that are transcribed in the opposite and the same direction, respectively, as F8. F8A is a small 1.8-kb intronless gene that is ubiquitously expressed. There are two additional copies of F8A situated approx 300 and 400 kb, respectively, 5' and telomeric to F8 (Fig. 2B). These genes are transcribed in the same direction as F8. The homology between F8 intron 22 (int22h-1) and the 5' regions (int22h-2 and int22h-3) extends beyond the F8A genes, and the inverted repeats share 9.5 kb of 99.9% sequence similarity (30). About 45% of severe hemophilia A cases (25% of all cases of hemophilia A) have an inversion of the F8 gene caused by NAHR between int22h-1 and int22h-2 or int22h-3 (31). The inversions are detected by Southern blotting that gives different fragments for inversions involving int22h-2 or int22h-3. No DNA is lost or gained during the inversion process. Interestingly, inversions involving the more distal int22h-3 are four times more common than those involving the more

Fig. 2. Nonallelic homologous recombination (NAHR) between inverted low-copy repeats. (A) A model of NAHR. Recombination between inverted repeats on the same chromatid results in the inversion of the intervening sequence. When one or both repeats are within a gene (the open arrow), the inversion disrupts the gene structure and may produce a phenotype. When both repeats are outside a gene (the solid arrow) the inversion creates a polymorphism without disrupting the gene. (B) The F8 gene and its flanking repeats. The open arrow depicts the F8 gene with the included gray arrow depicting the F8B gene. The gray arrowheads represent the int22h repeats, and the F8A genes inside the repeats. The truncated int22h (tint22h) that has been identified in a single family is bracketed. Recombination occurs mainly between int22h1 and int22h3, and its product is depicted. (C) The IDS gene and its pseudogene IDSy. IDSy contains sequences homologous to exon2-intron3 (black arrowhead) and intron7 (gray arrowhead) of IDS. All IDS inversions characterized so far result from recombination between the intron7 homologous sequences. (D) The EMD/FLN1 region and its flanking repeats. Recombination between the repeats generates an inversion polymorphism of the region.

Fig. 2. Nonallelic homologous recombination (NAHR) between inverted low-copy repeats. (A) A model of NAHR. Recombination between inverted repeats on the same chromatid results in the inversion of the intervening sequence. When one or both repeats are within a gene (the open arrow), the inversion disrupts the gene structure and may produce a phenotype. When both repeats are outside a gene (the solid arrow) the inversion creates a polymorphism without disrupting the gene. (B) The F8 gene and its flanking repeats. The open arrow depicts the F8 gene with the included gray arrow depicting the F8B gene. The gray arrowheads represent the int22h repeats, and the F8A genes inside the repeats. The truncated int22h (tint22h) that has been identified in a single family is bracketed. Recombination occurs mainly between int22h1 and int22h3, and its product is depicted. (C) The IDS gene and its pseudogene IDSy. IDSy contains sequences homologous to exon2-intron3 (black arrowhead) and intron7 (gray arrowhead) of IDS. All IDS inversions characterized so far result from recombination between the intron7 homologous sequences. (D) The EMD/FLN1 region and its flanking repeats. Recombination between the repeats generates an inversion polymorphism of the region.

proximal int22h-2. It is possible that the longer distance between int22h-1 and int22h-3 favors the looping of the DNA strand that brings the LCRs together. In addition to inversions involving int22h-2 and int22h-3, a hemophilia A patient was found to have a third kind of inversion disrupting F8 (32). This inversion involves an extra-truncated copy of int22h (tint22h) located between int22h-2 and F8 (Fig. 2B). The tint22h repeat contains only 1.9 kb of the 9.5 kb int22h sequence. It is detected only in the patient's family and does not appear to be a common polymorphism in the UK population studied.

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