Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man (original) (raw)

Nature volume 332, pages 164–166 (1988)Cite this article

Abstract

L_1_ sequences are a human-specific family of long, interspersed, repetitive elements, present as ∼105 copies dispersed throughout the genome1. The full-length L_1_ sequence is 6.1 kilobases, but the majority of L_1_ elements are truncated at the 5' end, resulting in a fivefold higher copy number of 3' sequences1. The nucleotide sequence of L_1_ elements includes an A-rich 3' end and two long open reading frames (orf_-1 and orf_-2), the second of which encodes a potential polypeptide having sequence homology with the reverse transcriptases1–4. This structure suggests that L_1 elements represent a class of non-viral retrotransposons1,2. A number of L_1 complementary DNAs, including a nearly full-length element, have been isolated from an undifferentiated teratocarcinoma cell line5. We now report insertions of L_1_ elements 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 L_1_ sequence, 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 following orf_-2 are nearly identical to the consensus sequence of L_1 cDNAs (ref. 6). These results indicate that certain L_1_ sequences in man can be dispersed, presumably by an RNA intermediate, and cause disease by insertional mutation.

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Author notes

  1. Hagop Youssoufian
    Present address: Hematology-Oncology Unit, Cox 6, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114, USA
  2. Alan F. Scott: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Authors and Affiliations

  1. Genetics Unit, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
    Haig H. Kazazian Jr, Corinne Wong, Hagop Youssoufian, Alan F. Scott, Deborah G. Phillips & Stylianos E. Antonarakis

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  1. Haig H. Kazazian Jr
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  2. Corinne Wong
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  3. Hagop Youssoufian
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  4. Alan F. Scott
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  5. Deborah G. Phillips
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  6. Stylianos E. Antonarakis
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Kazazian, H., Wong, C., Youssoufian, H. et al. Haemophilia A resulting from de novo insertion of L_1_ sequences represents a novel mechanism for mutation in man.Nature 332, 164–166 (1988). https://doi.org/10.1038/332164a0

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