Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis
Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis
复制标题
早期胚胎发生过程中由 int22h 拷贝介导的 F8 缺失和 TMLHE 重复的复杂重组
DOI：
10.1160/th17-01-0046
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发表时间：
2017-08-01
影响因子：
6.7
通讯作者：
Ding, Qiulan
中科院分区：
文献类型：
--
作者：
Chen, Changming;Xie, Xiaoling;Ding, Qiulan
甲型血友病（HA）是一种常见的X连锁隐性出血性疾病，近一半的重型HA患者是由F8基因内含子22倒位（Inv22）所致。Inv22被认为几乎完全源于精子发生过程中生殖细胞的减数分裂，截至目前，仅报道过1例胚胎有丝分裂过程中可能发生该突变的嵌合型Inv22女性携带者。此前，我们在一个散发的重型HA家系中鉴定出一种由int22h拷贝介导的新型复杂重组，在此，我们利用基因组步移技术、AccuCopy技术、基因芯片和实时荧光定量PCR对断点区域两侧的序列进行了定位。致病的遗传变异表现为18.1 kb的缺失，缺失区域包括int22h - 1的部分序列至F8基因内含子23，以及113.3 kb的重复，重复区域为int22h - 2的部分序列至TMLHE基因内含子1，并插入到F8基因重新连接的区域。两种内在关联的依赖重组的DNA复制机制：微同源介导的断裂诱导复制（MMBIR），随后发生断裂诱导复制（BIR），可能是先证者母亲早期胚胎发生过程中出现该复杂重组事件的原因。
Summary Haemophilia A (HA) is a common X-linked recessive bleeding disorder and almost one half of patients with severe HA are caused by intron 22 inversion (Inv22) in the F8. Inv22 is considered to be almost exclusively of meiotic origin in germ cells during spermatogenesis and only one mosaic Inv22 female carrier with the mutation possibly occurring during mitosis of the embryo has been reported so far. Previously we have identified a novel complex recombination mediated by int22h copies in a sporadic severe HA pedigree and herein we have localised the sequences flanking the breakpoint region using genome walking technique, AccuCopy technique, gene chip and real-time PCR. The disease causing genetic variant registered an 18.1 kb deletion including part of int22h-1 through the intron 23 of F8 and a 113.3 kb duplication of part of int22h-2 through the intron 1 of TMLHE inserted in the religated region of the F8. Two intrinsically linked mechanisms of recombination-dependent DNA replication: microhomology-mediated break-induced replication (MMBIR) followed by break-induced replication (BIR) might be responsible for the incident of the complex recombination during early embryogenesis of the proband’s mother. Supplementary Material to this article is available online at www.thrombosis-online.com.