Gitschier J, Drayna D, Tuddenham E G, White R L, Lawn R M
Nature. 1985;314(6013):738-40. doi: 10.1038/314738a0.
Haemophilia A is the most common inherited bleeding disorder in man, affecting approximately 1 male in 10,000. The disease is caused by a deficiency in the gene for factor VIII, a component of the intrinsic coagulation pathway. Due to the broad range of clotting activity in normal and heterozygous females, it is often difficult to confirm the status of women at risk for carrying the disease. A genetic marker in the form of a restriction fragment length polymorphism (RFLP) within or tightly linked to the factor VIII gene would serve as a tag for the haemophilia gene, thus allowing both accurate carrier detection and improved, earlier prenatal diagnosis by chorionic villi sampling. The recent isolation of the factor VIII gene has allowed a search for RFLPs within the gene, and we report here the identification of a common polymorphism within the factor VIII gene, revealed by the restriction enzyme BclI, which can be used diagnostically in about 42% of all families. Although the disease haemophilia A has been mapped to the distal portion of Xq, the BclI RFLP makes possible higher-resolution genetic linkage mapping with respect to other polymorphic markers on this portion of the X chromosome. We have established close linkage of the factor VIII gene to several useful RFLP markers, including the highly informative marker St14. These markers should also be useful for prenatal diagnosis of haemophilia A and for detection of its carriers.
甲型血友病是人类最常见的遗传性出血性疾病，每10000名男性中约有1人患病。该疾病是由内源性凝血途径的一个组成部分——凝血因子VIII基因缺陷引起的。由于正常女性和杂合子女性的凝血活性范围较广，通常很难确定有患病风险的女性的状况。凝血因子VIII基因内或与之紧密连锁的限制性片段长度多态性（RFLP）形式的遗传标记，可作为血友病基因的标签，从而实现准确的携带者检测，并通过绒毛取样改善和提前进行产前诊断。最近凝血因子VIII基因的分离使得在该基因内寻找RFLP成为可能，我们在此报告在凝血因子VIII基因内鉴定出一种常见的多态性，该多态性可由限制性内切酶BclI揭示，约42%的家庭可用于诊断。尽管甲型血友病已被定位到Xq的远端部分，但BclI RFLP使得在X染色体这一部分相对于其他多态性标记进行更高分辨率的遗传连锁图谱绘制成为可能。我们已确定凝血因子VIII基因与几个有用的RFLP标记紧密连锁，包括信息丰富的标记St14。这些标记对于甲型血友病的产前诊断及其携带者的检测也应是有用的。
