Larner A J
Oxford University Medical School, John Radcliffe Hospital, Headington.
Q J Med. 1987 Jun;63(242):473-91.
The great success of recombinant DNA technology in unravelling the pathology of the thalassaemias at a molecular level has encouraged the application of these methods to other single gene disorders of man in the hope of gaining a deeper insight into the biochemical defects underlying them. An example of this approach is provided by the sex-linked recessive disorders of blood clotting: haemophilia and Christmas disease. These clinically indistinguishable, life-long disorders result from the deficiency or abnormality of the clotting proteins factor VIII and factor IX, respectively, which both participate in the activation of factor X in the intrinsic pathway of blood coagulation. This paper looks at the information concerning the molecular biology and pathology of the haemophilias which has recently been forthcoming. The genes for factor VIII and factor IX have both been successfully cloned within the past five years, with that of factor VIII, achieved in 1984, being a particular tour de force. It encompasses 0.1 per cent of the human X chromosome and is the largest gene yet characterised. Gene cloning is the starting point from which gene probes can be designed to elucidate the molecular pathology of the haemophilias. The implications of these discoveries for the practice of clinical medicine are reviewed, with special emphasis on prenatal diagnosis and carrier detection by means of restriction fragment length polymorphisms, and replacement therapy with recombinant factor VIII.
重组DNA技术在分子水平上揭示地中海贫血病理方面取得的巨大成功，促使人们将这些方法应用于人类的其他单基因疾病，以期更深入地了解其潜在的生化缺陷。凝血的X连锁隐性疾病——血友病和克里斯马斯病就是这种方法的一个例子。这些临床上难以区分的终身疾病，分别是由于凝血蛋白因子VIII和因子IX的缺乏或异常所致，它们都参与内源性凝血途径中因子X的激活。本文探讨了最近获得的有关血友病分子生物学和病理学的信息。因子VIII和因子IX的基因在过去五年内均已成功克隆，其中1984年完成的因子VIII基因克隆堪称一大壮举。它占据人类X染色体的0.1%，是迄今已鉴定的最大基因。基因克隆是设计基因探针以阐明血友病分子病理学的起点。本文回顾了这些发现对临床医学实践的影响，特别强调了利用限制性片段长度多态性进行产前诊断和携带者检测，以及用重组因子VIII进行替代疗法。
