HEMOPHILIA-A RESULTING FROM DENOVO INSERTION OF L1 SEQUENCES REPRESENTS A NOVEL MECHANISM FOR MUTATION IN MAN
HEMOPHILIA-A RESULTING FROM DENOVO INSERTION OF L1 SEQUENCES REPRESENTS A NOVEL MECHANISM FOR MUTATION IN MAN
复制标题
DOI：
10.1038/332164a0
复制
发表时间：
1988-03-10
期刊：
影响因子：
64.8
通讯作者：
ANTONARAKIS, SE
中科院分区：
文献类型：
--
作者：
KAZAZIAN, HH;WONG, C;ANTONARAKIS, SE
L1 序列是人类特有的长、散布、重复元件家族，以约 105 个副本的形式分布在整个基因组中1。全长 L1 序列为 6.1 KB，但大多数 L1 元素在 5' 端被截短，导致 3' 序列的拷贝数增加了五倍。 L1 元件的核苷酸序列包括富含 A 的 3' 末端和两个长开放阅读框 (orf-1 andorf-2)，其中第二个编码与逆转录酶 1-4 具有序列同源性的潜在多肽。该结构表明 L1 元件代表一类非病毒逆转录转座子 1,2。许多 L1 互补 DNA，包括几乎全长的元件，已从未分化的畸胎癌细胞系中分离出来。现在，我们报告了 240 名无关的 A 型血友病患者中的两名将 L1 元件插入到因子 VIII 基因的外显子 14 中。这两个插入（分别为 3.8 和 2.3 KB）均包含 L1 序列的 3' 部分，包括聚 (A) 束，并产生因子 VIII 基因的至少 12 和 13 个核苷酸的靶位点重复。此外，它们在orf-2之后的3'拖尾序列与L1cDNA的共有序列几乎相同（参考文献6）。这些结果表明，人体中的某些 L1 序列可能是通过 RNA 中间体而分散的，并通过插入突变引起疾病。
L1sequences are a human-specific family of long, interspersed, repetitive elements, present as ∼105copies dispersed throughout the genome1. The full-length L1sequence is 6.1 kilobases, but the majority of L1elements are truncated at the 5' end, resulting in a fivefold higher copy number of 3' sequences1. The nucleotide sequence of L1elements includes an A-rich 3' end and two long open reading frames (orf-1 andorf-2), the second of which encodes a potential polypeptide having sequence homology with the reverse transcriptases1–4. This structure suggests that L1elements represent a class of non-viral retrotransposons1,2. A number of L1complementary DNAs, including a nearly full-length element, have been isolated from an undifferentiated teratocarcinoma cell line5. We now report insertions of L1elements into exon 14 of the factor VIII gene in two of 240 unrelated patients with haemophilia A. Both of these insertions (3.8 and 2.3 kilobases respectively) contain 3' portions of the L1sequence, including the poly (A) tract, and create target site duplications of at least 12 and 13 nucleotides of the factor VIII gene. In addition, their 3'-trailer sequences followingorf-2 are nearly identical to the consensus sequence of L1cDNAs (ref. 6). These results indicate that certain L1sequences in man can be dispersed, presumably by an RNA intermediate, and cause disease by insertional mutation.