Genetic mapping and diagnosis of haemophilia A achieved through a BclI polymorphism in the factor VIII gene
Genetic mapping and diagnosis of haemophilia A achieved through a BclI polymorphism in the factor VIII gene
复制标题
通过因子 VIII 基因中的 BclI 多态性实现 A 型血友病的遗传图谱和诊断
作者：
J. Gitschier;D. Drayna;E. Tuddenham;Raymond White;R. Lawn
A型血友病是男性中最常见的遗传性出血性疾病，大约每10000名男性中就有1名患有此病（参考文献1）。这种疾病是由因子VIII基因缺乏引起的，因子VIII是内在凝血途径的一个组成部分。由于正常和杂合子女性的凝血活性范围很广，因此通常难以确定携带该疾病的女性的状况2。在因子VIII基因内或与因子VIII基因紧密相连的限制性片段长度多态性（RFLP）形式的遗传标记将作为血友病基因的标记，从而允许准确的携带者检测和通过绒毛膜绒毛取样改进的早期产前诊断3,4。最近分离的因子VIII基因5,6允许在基因内搜索RFLPs，我们在这里报告了因子VIII基因内常见多态性的鉴定，该多态性由限制性内切酶BclI揭示，可用于约42%的所有家庭的诊断。虽然血友病A已经被定位到Xq的远端部分（参考文献7），但BclI RFLP使得相对于X染色体这部分的其他多态性标记的更高分辨率的遗传连锁定位成为可能。我们已经建立了因子VIII基因与几个有用的RFLP标记的密切联系，包括高信息量的标记St14（参考文献8）。这些标记也可用于血友病A的产前诊断和检测其携带者。
Haemophilia A is the most common inherited bleeding disorder in man, affecting approximately 1 male in 10,000 (ref. 1). 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 disease2. 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 sampling3,4. The recent isolation of the factor VIII gene5,6 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 (ref. 7), 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 (ref. 8). These markers should also be useful for prenatal diagnosis of haemophilia A and for detection of its carriers.