Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A by Richard D. Bagnall, Naushin Waseem, Peter M.

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Presentation transcript:

Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A by Richard D. Bagnall, Naushin Waseem, Peter M. Green, and Francesco Giannelli Blood Volume 99(1):168-174 January 1, 2002 ©2002 by American Society of Hematology

RT-PCR amplification products from factor VIII-VBP1 chimeric mRNA transcripts in 5 severe hemophilia A patients.Nested primers in factor VIII exon 1 combined with primers in VBP1 exon 2 produced a 500-bp band. RT-PCR amplification products from factor VIII-VBP1 chimeric mRNA transcripts in 5 severe hemophilia A patients.Nested primers in factor VIII exon 1 combined with primers in VBP1 exon 2 produced a 500-bp band. The control lane RT-PCR contained normal lymphocyte RNA. Sequence analysis (not shown) revealed factor VIII exon 1 and 2 facultative exons followed by VBP1 exon 2. Richard D. Bagnall et al. Blood 2002;99:168-174 ©2002 by American Society of Hematology

PCR amplification of factor VIII intron 1 in control and intron 1 inversion patient (UKA 29).(A) Amplification strategy. PCR amplification of factor VIII intron 1 in control and intron 1 inversion patient (UKA 29).(A) Amplification strategy. Lines with numbers show position and length of each segment amplified. Segment 9 has been expanded to show 4 adjacent reactions, 9a to 9d. (B). PCR products from control (left) and UKA29 (right) genomic DNA. Segment 9 consistently failed to amplify in UKA29 (arrow). (C) PCR amplification of sections of segment 9 in control (left) and UKA29 DNA (right). The 1.5 kb comprising sections a to c (9ac, arrow) could not be amplified from the DNA of UKA29. However, the 1-kb overlapping segments comprising sections a + b and b + c (9ab and 9bc) were amplified as readily as the individual sections 9a to 9d. Richard D. Bagnall et al. Blood 2002;99:168-174 ©2002 by American Society of Hematology

Diagram of factor VIII intron 1 and proposed model for inversion Diagram of factor VIII intron 1 and proposed model for inversion.(A) Bar shows factor VIII intron 1, flanked by exons (drawn to indicate the direction of transcription), and containing a repeated sequence 9b (shaded) flanked by unique sequences 9a and 9c. Diagram of factor VIII intron 1 and proposed model for inversion.(A) Bar shows factor VIII intron 1, flanked by exons (drawn to indicate the direction of transcription), and containing a repeated sequence 9b (shaded) flanked by unique sequences 9a and 9c. The line shows DNA outside the F8 gene with the repeated sequence as a shaded box. Arrowheads indicate orientation of repeated sequences. The large curved arrow indicates the folding required for homologous recombination. (B,C) Homologous recombination between the two 9b repeats proposed to explain origin of inversion. (D) Inversion resulting from recombination. This shows why in the DNA of UKA29 PCR amplification succeeds for fragments 9ab and 9bc but not for 9ac. CEN indicates centromeric; TEL, telomeric. Richard D. Bagnall et al. Blood 2002;99:168-174 ©2002 by American Society of Hematology

Nucleotide sequence alignment of int1h-1 and int1h-2 and flanking sequences. Nucleotide sequence alignment of int1h-1 and int1h-2 and flanking sequences. Bold letters show the 1041-bp repeats. Nucleotide numbers are specific to intron 1 of the F8 gene where nt 1 is the G residue at the start of the intron. Primer binding sites are underlined with arrows to indicate orientation of primers. Polymorphic site in int1h-2 is indicated by alternative nucleotides in box. Difference between int1h-1 and int1h-2 is shown boxed. Richard D. Bagnall et al. Blood 2002;99:168-174 ©2002 by American Society of Hematology

Genomic map of the region surrounding the int1h repeats in Xq28. Genomic map of the region surrounding the int1h repeats in Xq28. Int1h repeats are shown as black boxes. Only the first 6 exons of factor VIII and first 3 exons of VBP1 are shown, with arrows indicating direction of transcription. Hatched boxes indicate facultative exons spliced into chimeric mRNAs of patients with int1h-related inversions. Exons A, B, 1, 2, 3, and 4 represent seq 29A, seq 29B, 45 bp, 30 bp, 100 bp, and 142 bp exons, respectively.8 28 Size bars indicate the location and extent of DNA sequence contigs constructed from entries in GenBank human DNA sequence database. Richard D. Bagnall et al. Blood 2002;99:168-174 ©2002 by American Society of Hematology

PCR test for the FVIII int1h-related inversion. PCR test for the FVIII int1h-related inversion. (A) Diagram of normal (top) and inversion (bottom) DNA showing the location and orientation of relevant sequences as well as PCR primers and reactions (thin bars). (B) Amplification of int1h-1 using 9cR, 9F, andint1h-2F primers (lanes 1, 2, and 3) and int1h-2using int1h-2F, int1h-2R, and 9F primers (lanes 4, 5, and 6). Control and inversion are males; carrier is female. Richard D. Bagnall et al. Blood 2002;99:168-174 ©2002 by American Society of Hematology