Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A
Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A
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DOI：
10.1182/blood.v99.1.168
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发表时间：
2002-01-01
期刊：
影响因子：
20.3
通讯作者：
Giannelli, F
中科院分区：
文献类型：
--
作者：
Bagnall, RD;Waseem, N;Giannelli, F
69例重度血友病A患者中有5例的信使RNA（mRNA）不支持含有因子VIII（F8）基因前几个外显子的互补DNA扩增，但支持含有F8外显子1加VBP 1基因外显子的mRNA扩增。该嵌合mRNA信号传导F8基因的倒位破坏内含子1。使用倒位患者，一个删除的F8外显子1至6，和cosmetry映射70至100 kb端粒的F8基因，这项研究表明，这种中断严格影响的序列（int 1h-1）重复（int 1h-2）约140 kb端粒之间的C6.1A和VBP 1基因。1041个碱基对的重复序列在一个核苷酸上不同（尽管int 1h-2也显示出一种多态性），并且方向相反。结果表明，它们通过染色体内或染色体内同源重组引起倒位。倒位区的基因组结构显示转录穿过基因间空间以产生含有F8序列和倒位特征的2种嵌合mRNA。这一观察提示了这样一种建议，即自然界可能使用这种延伸的转录来测试是否从相邻基因中添加新的结构域来创建所需的新基因。一种快速的聚合酶链反应试验，在病人和携带者的倒位。在209个无血缘关系的重度血友病A家族中，发现了10个倒位，影响F8基因的BcII、内含子13和22 VNTR多态性的5种不同单倍型。这表明4.8%的患病率和频繁复发的倒位。这应该导致F8的缺失，并且已知一个倒位患者具有抑制剂。
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 BcII, 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.