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首页> 外文期刊>Clinical and applied thrombosis/hemostasis : >Spectrum of Molecular Defects in 216 Chinese Families With Hemophilia A: Identification of Noninversion Mutation Hot Spots and 42 Novel Mutations
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Spectrum of Molecular Defects in 216 Chinese Families With Hemophilia A: Identification of Noninversion Mutation Hot Spots and 42 Novel Mutations

机译：216例中国血友病家庭的分子缺陷谱：同相突变热点和42个新型突变的鉴定

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Hemophilia A (HA) is an X-linked bleeding disorder caused by heterogeneous mutations in the factor VIII gene (F8). Our aim is to identify the causative mutations in a large HA cohort from China. We studied 216 unrelated HA families. Molecular analyses of F8 were performed using a combination of molecular techniques, including polymerase chain reaction, direct sequencing, and multiplex ligation-dependent probe amplification. The deleterious consequences of the unreported missense mutations were evaluated using various bioinformatics approaches. Causative mutations in F8 were identified in 209 families, intron 22 inversion (Inv22) was identified in 89 severe families, and intron 1 inversion (Inv1) was positive in 5 severe families; 95 mutations were detected among 115 noninversion families, of which 42 were novel, including 29 null variations and 13 missense mutations for which causality was demonstrated via bioinformatics. Among the 53 previously reported mutations, more nonsense (5 of 9) and missense (10 of 26) mutation sites were found to occur at Arginine (Arg) sites and multiple small deletions/insertions (5 of 10) located within the poly-A runs of the B domain. The majority of these sequence variants frequently recurred in the database. The odds ratios for the likelihood of developing inhibitors significantly increased in the presence of nonsense mutation. Our F8 defect spectrum was heterogeneous. Small deletions/insertions in the poly-A runs of the B domain and nonsense and missense mutations at Arg sites were identified as mutation hot spots. Nonsense mutation increased the risk of developing inhibitors.
机译：A型血友病（HA）是由VIII因子基因（F8）的异源突变引起的X连锁出血性疾病。我们的目的是鉴定来自中国的大型HA队列中的致病突变。我们研究了216个不相关的HA家庭。 F8的分子分析是使用分子技术的组合进行的，包括聚合酶链反应，直接测序和多重连接依赖性探针扩增。使用各种生物信息学方法评估了未报告的错义突变的有害后果。在209个家庭中鉴定出F8的致病性突变，在89个严重家庭中鉴定出内含子22倒位（Inv22），在5个严重家庭中鉴定出内含子1倒置（Inv1）。在115个非反向家族中检测到95个突变，其中42个是新颖的，包括29个无效变异和13个错义突变，这些突变通过生物信息学证实了因果关系。在先前报道的53个突变中，发现更多的无义（9个中的5个）和错义（26个中的10个）突变位点发生在精氨酸（Arg）位点，并且在poly-A内有多个小缺失/插入（10个中的5个） B域的运行。这些序列变体中的大多数经常在数据库中重复出现。在无义突变的存在下，发展抑制剂的可能性的比值比显着增加。我们的F8缺陷谱是异质的。 B结构域的poly-A序列中的小缺失/插入以及Arg位点的无义和错义突变被鉴定为突变热点。无意义的突变增加了产生抑制剂的风险。

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