Woods-Samuels P, Kazazian H H, Antonarakis S E
Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205.
Genomics. 1991 May;10(1):94-101. doi: 10.1016/0888-7543(91)90489-2.
Four deletions in the human factor VIII gene have been characterized at the sequence level in patients with hemophilia A. Deletion JH 1 extends 57 kb from IVS 10 to IVS 18. Intron 13 and exon 14 are partially deleted in patients JH 7 and JH 37, with a loss of 3.2 and 2.4 kb of DNA, respectively. The 3' deletion breakpoint of the JH 21 event resides in intron 3 and extends 5' into intron 1, resulting in the loss of exons 2 and 3. Seven of the eight breakpoints sequenced (5' and 3' for each of the four deletions) occur in nonrepetitive sequence, while the 3' breakpoint of the JH 1 resides in an Alu repetitive element. All of the deletions are the result of nonhomologous recombination. The 5' and 3' breakpoints of JH 1, JH 7, and JH 37 share 2- to 3-bp homologies at the deletion junctions. In contrast, two nucleotides have been inserted at the JH 21 deletion junction. Short sequence homologies may facilitate end-joining reactions in nonhomologous recombination events.
在甲型血友病患者中，已在序列水平上对人凝血因子VIII基因的四处缺失进行了表征。缺失JH 1从内含子10延伸至内含子18，长度达57 kb。在患者JH 7和JH 37中，内含子13和外显子14部分缺失，分别缺失了3.2 kb和2.4 kb的DNA。JH 21事件的3'缺失断点位于内含子3中，并向5'端延伸至内含子1，导致外显子2和3缺失。在测序的八个断点中（四个缺失的5'和3'断点），有七个位于非重复序列中，而JH 1的3'断点位于一个Alu重复元件中。所有缺失均为非同源重组的结果。JH 1、JH 7和JH 37的5'和3'断点在缺失连接处具有2至3个碱基对的同源性。相比之下，在JH 21缺失连接处插入了两个核苷酸。短序列同源性可能有助于非同源重组事件中的末端连接反应。
