Poon M C, Low S, Sinclair G D
Department of Medicine, University of Calgary, Alberta, Canada.
J Lab Clin Med. 1995 Mar;125(3):402-6.
Factor VIII (FVIII) gene rearrangements between the intron 22 F8A sequence in the FVIII gene and either of the two homologous F8A sequences 500 kilobases telomeric to the FVIII gene have recently been found to be responsible for the severe hemophilia A phenotype. We studied 27 patients with severe hemophilia A and 19 with moderate and mild hemophilia, and found FVIII gene rearrangement in 12 patients with severe hemophilia A and none in the patients with moderate or mild disease. Nine of the rearrangements were with the distal telomeric F8A sequence, two were with the proximal sequence, and one had variant distal rearrangement with loss of the FVIII intron 22 F8A band. Two patients with FVIII gene rearrangement had high responding inhibitors, contrary to one previous study suggesting that the presence of a FVIII gene rearrangement is correlated with the absence of inhibitor development. Carrier detection was performed in 17 female relatives, at risk of being carriers, from eight kindreds; 13 were carriers, being heterozygous for the normal and rearranged alleles. The rearrangement assay is particularly useful for carrier determination in families with sporadic cases of hemophilia not helped by linkage analysis with restriction fragment-length polymorphism or intragenic dinucleotide repeat analysis. In all five families with rearrangements and sporadic hemophilia, the mothers of all index patients were found to be carriers.
最近发现，凝血因子VIII（FVIII）基因内含子22中的F8A序列与FVIII基因端粒方向500千碱基处的两个同源F8A序列之一之间发生基因重排，是导致严重A型血友病表型的原因。我们研究了27例严重A型血友病患者和19例中度及轻度血友病患者，发现12例严重A型血友病患者存在FVIII基因重排，而中度或轻度血友病患者中未发现。其中9例重排发生在远端端粒F8A序列，2例发生在近端序列，1例发生变异的远端重排，FVIII内含子22 F8A条带缺失。2例FVIII基因重排患者有高反应性抑制剂，这与之前一项研究结果相反，该研究表明FVIII基因重排的存在与抑制剂的产生无关。对来自8个家族的17名有携带者风险的女性亲属进行了携带者检测；其中13人为携带者，是正常等位基因和重排等位基因的杂合子。对于散发性血友病家族，若通过限制性片段长度多态性连锁分析或基因内二核苷酸重复分析无法确定携带者，重排检测对于携带者的判定特别有用。在所有5个存在重排且为散发性血友病的家族中，所有先证者的母亲均被发现为携带者。
