Henan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang 471023, China.
School of Basic Medical Science, Henan University of Science and Technology, Luoyang 471023, China.
Int J Mol Sci. 2022 Mar 2;23(5):2762. doi: 10.3390/ijms23052762.
Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX's translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment.
凝血因子 IX（FIX）是一种维生素 K 依赖性蛋白，其缺乏会导致乙型血友病，这是一种 X 连锁隐性出血性疾病。在乙型血友病患者中，已经发现了超过 1000 种基因中的突变。在这里，我们系统地总结了 FIX 的结构和功能特征以及迄今为止已确定的突变的致病机制。这些突变导致 FIX 缺乏的机制多种多样。缺失、插入、重复和插入缺失通常导致严重的乙型血友病。那些在外显子区域产生移码或框内突变，而那些在内含子中通常导致异常剪接。至于点突变，乙型血友病患者的出血表型从严重到轻度不等。一般来说，启动子区域的点突变导致乙型血友病 Leyden，而内含子中的点突变导致异常剪接。编码序列中的点突变可以是错义、无义或沉默突变。无义突变产生的截断 FIX 通常失去功能，导致严重的乙型血友病。沉默突变可能导致异常剪接或影响 FIX 翻译。然而，错义突变的机制尚未完全阐明。它们导致 FIX 缺乏，通常通过影响 FIX 的翻译、蛋白质折叠、蛋白质稳定性、翻译后修饰、FIXa 的激活或形成功能性 Xase 复合物的能力。了解 FIX 缺乏的分子机制将为患者的诊断和治疗提供重要的见解。
