Department of Hematology, The Second Hospital of Shanxi Medical University, No. 382 Wuyi Road, Taiyuan, 030001, Shanxi, People's Republic of China.
Int J Hematol. 2020 Jul;112(1):8-16. doi: 10.1007/s12185-020-02877-y. Epub 2020 Apr 13.
Factor X (FX) deficiency is an inherited autosomal recessive bleeding disorder. Here, we analyzed a proband with FX deficiency in a Chinese family. Genetic analysis revealed that the proband and his affected sister was homozygous for c.1085G>A mutation, corresponding to a Ser362Asn substitution. In vitro expression experiments showed that the FX Ser362Asn mutation led to a significant reduction in activity levels in the culture medium. This Ser to Asn substitution may change the shape of the active site. Moreover, simulations of molecular dynamics indicated that the binding energy of the FX Ser362Asn to the substrate is higher than that of wild type and the side-chain conformation of the catalytic residue His276 (His42) is changed. This impairs the conformational switch of the protein from zymogen to proteinase, thus causing the functional defect of FX protein. Our findings suggest that the Ser362Asn substitution is a pathogenic mutation that causes inherited FX deficiency.
因子 X (FX) 缺乏症是一种遗传性常染色体隐性出血性疾病。在这里，我们分析了一个中国家庭中 FX 缺乏症的先证者。基因分析显示，先证者及其患病的姐姐均为 c.1085G>A 突变的纯合子，对应丝氨酸 362 突变为天冬酰胺。体外表达实验表明，FX Ser362Asn 突变导致培养基中活性水平显著降低。这种丝氨酸到天冬酰胺的取代可能会改变活性位点的形状。此外，分子动力学模拟表明，FX Ser362Asn 与底物的结合能高于野生型，且催化残基 His276（His42）的侧链构象发生改变。这会损害蛋白质从酶原到蛋白酶的构象转换，从而导致 FX 蛋白的功能缺陷。我们的研究结果表明，Ser362Asn 取代是导致遗传性 FX 缺乏症的致病性突变。
