Print Emily H T, Simmons Anna M, Spencer Holly J, Efthymiou Christos, Harris Victoria A, Perkins Stephen J
Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.
Blood Vessel Thromb Hemost. 2025 Jan 21;2(3):100053. doi: 10.1016/j.bvth.2025.100053. eCollection 2025 Aug.
Hemophilia A is a rare genetic disease that occurs with mild, moderate, or severe phenotypes and involves dysfunctional or reduced amounts of plasma factor VIII (FVIII). Identifying causal genetic variants in the gene is vital for patient care. Our original interactive MySQL database for FVIII in 2013 presented clinical data on 2014 unique FVIII variants in 5072 patients. Here, we expand our database almost threefold with a new total of 6211 unique FVIII variants in 10 064 patients, spanning 1529 of the 2351 FVIII residues (65%). We have also developed a new full-length FVIII structural model that incorporates both its crystal structure and its disordered B domain, which is not visible in available experimental structures. This enabled the assessment of these variants on FVIII. Of the 6211 unique variants identified, 730 (12%) were associated with mild phenotypes, 526 (8%) with moderate phenotypes, 2509 (39%) with severe phenotypes, 53 (1%) with multiple severities, and 2393 (40%) with unreported phenotypes. Most variants occurred in the disordered B domain (1281 variants), followed by the A1, A2, and A3 domains (1130, 1071, and 923 variants, respectively) and the C1 and C2 domains (442 and 439 variants, respectively). Inhibitors were associated with 451 variants (7%). Our new structural analyses often revealed changes to the residue solvent surface accessibilities caused by many FVIII variants. The FVIII variant analyses are supported by similar observations in the structurally related FV protein. Our web-accessible FVIII database will enable easier and improved clinical analyses of FVIII genetic variants.
甲型血友病是一种罕见的遗传疾病，具有轻度、中度或重度表型，涉及血浆凝血因子VIII（FVIII）功能异常或数量减少。确定该基因中的致病遗传变异对患者护理至关重要。我们2013年最初的FVIII交互式MySQL数据库展示了5072例患者中2014种独特FVIII变异的临床数据。在此，我们将数据库扩充了近三倍，新增了10064例患者中的6211种独特FVIII变异，涵盖了2351个FVIII残基中的1529个（65%）。我们还开发了一种新的全长FVIII结构模型，该模型结合了其晶体结构和无序的B结构域，而在现有的实验结构中看不到B结构域。这使得能够评估这些变异对FVIII的影响。在鉴定出的6211种独特变异中，730种（12%）与轻度表型相关，526种（8%）与中度表型相关，2509种（39%）与重度表型相关，53种（1%）与多种重度表型相关，2393种（40%）与未报告的表型相关。大多数变异发生在无序的B结构域（1281种变异），其次是A1、A2和A3结构域（分别为1130、1071和923种变异）以及C1和C2结构域（分别为442和439种变异）。抑制剂与451种变异（7%）相关。我们新的结构分析常常揭示出许多FVIII变异导致的残基溶剂表面可及性变化。FVIII变异分析得到了结构相关的FV蛋白中类似观察结果的支持。我们的可通过网络访问的FVIII数据库将使FVIII遗传变异的临床分析更加容易和完善。
