Youssoufian H, Antonarakis S E, Aronis S, Tsiftis G, Phillips D G, Kazazian H H
Proc Natl Acad Sci U S A. 1987 Jun;84(11):3772-6. doi: 10.1073/pnas.84.11.3772.
Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, we have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes.
甲型血友病是一种由凝血因子 VIII 缺乏引起的 X 连锁凝血障碍疾病。通过使用克隆的 DNA 探针，我们对来自 83 名甲型血友病患者的一组样本中凝血因子 VIII 基因的以下五种不同的部分缺失进行了特征分析：（i）一个 7 千碱基（kb）的缺失，它消除了外显子 6；（ii）一个 2.5 kb 的缺失，它消除了外显子 14 的 5' 序列；（iii）一个至少 7 kb 的缺失，它消除了外显子 24 和 25；（iv）一个至少 16 kb 的缺失，它消除了外显子 23 - 25；以及（v）一个 5.5 kb 的缺失，它消除了外显子 22。前四种缺失与严重甲型血友病相关。相比之下，最后一种缺失与中度疾病相关，这可能是由于相邻外显子的框内剪接导致中度疾病。那些基因部分缺失的患者均未出现针对凝血因子 VIII 的循环抑制物。一种缺失在外祖母的生殖细胞中新生出现，而另一种缺失在外祖父的生殖细胞中出现。这些观察结果表明，X 连锁基因的新生缺失可发生在雄性或雌性配子中。
