Hemophilia A (HA) is an X-linked hereditary bleeding disorder defined by a qualitative and/or quantitative factor VIII (FVIII) deficiency. The molecular diagnosis of HA is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. The putative role of the novel mutations, especially missense mutations, may be difficult to interpret as causing HA. We identified 95 novel mutations out of 180 different mutations responsible for HA in 515 patients from 406 unrelated families followed up at a single hemophilia treatment center of the Bicêtre university hospital (Assistance Publique-Hôpitaux de Paris [AP-HP], Le Kremlin-Bicêtre). These 95 novel mutations comprised 55 missense mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small insertions/deletions. We therefore developed a mutation analysis based on a body of proof that combines the familial segregation of the mutation, the resulting biological and clinical HA phenotype, and the molecular consequences of the amino acid (AA) substitution. For the latter, we studied the putative biochemical modifications: its conservation status with cross-species FVIII and homologous proteins, its putative location in known FVIII functional regions, and its spatial position in the available FVIII 3D structures. The usefulness of such a strategy in interpreting the causality of novel F8 mutations is emphasized.

译文

:A血友病(HA)是X连锁遗传性出血性疾病,由定性和/或定量因子VIII(FVIII)缺乏症定义。 HA的分子诊断具有挑战性,因为分布在整个F8大基因中的大量不同的致病突变。新突变(尤其是错义突变)的推定作用可能难以解释为引起HA。我们在比塞特尔大学医院的一个血友病治疗中心(巴黎援助医院-巴黎大学[AP-HP],勒·克里姆林宫-比塞特尔医院)的一个血友病治疗中心对406个无关家庭的515名患者中的负责HA的180种不同突变中鉴定出95种新突变。 )。这95个新突变包括55个错义突变,12个无意义突变,11个剪接位点突变和17个小插入/缺失。因此,我们基于证据集开发了一种突变分析方法,该方法结合了突变的家族分离,产生的生物学和临床HA表型以及氨基酸(AA)取代的分子后果。对于后者,我们研究了假定的生化修饰:其在跨物种FVIII和同源蛋白中的保存状态,在已知FVIII功能区中的假定位置以及在可用FVIII 3D结构中的空间位置。强调了这种策略在解释新型F8突变的因果关系方面的有用性。

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