TY - JOUR
T1 - Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man
AU - Kazazian, Haig H.
AU - Wong, Corinne
AU - Youssoufian, Hagop
AU - Scott, Alan F.
AU - Phillips, Deborah G.
AU - Antonarakis, Stylianos E.
PY - 1988/1/1
Y1 - 1988/1/1
N2 - L1 sequences are a human-specific family of long, interspersed, repetitive elements, present as ∼105 copies dispersed throughout the genome1. The full-length L1 sequence is 6.1 kilobases, but the majority of L1 elements are truncated at the 5' end, resulting in a fivefold higher copy number of 3' sequences1. The nucleotide sequence of L1 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 L1 elements represent a class of non-viral retrotransposons1,2. A number of L1 complementary DNAs, including a nearly full-length element, have been isolated from an undifferentiated teratocarcinoma cell line5. We now report insertions of L1 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 L1 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 L1 cDNAs (ref. 6). These results indicate that certain L1 sequences in man can be dispersed, presumably by an RNA intermediate, and cause disease by insertional mutation.
AB - L1 sequences are a human-specific family of long, interspersed, repetitive elements, present as ∼105 copies dispersed throughout the genome1. The full-length L1 sequence is 6.1 kilobases, but the majority of L1 elements are truncated at the 5' end, resulting in a fivefold higher copy number of 3' sequences1. The nucleotide sequence of L1 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 L1 elements represent a class of non-viral retrotransposons1,2. A number of L1 complementary DNAs, including a nearly full-length element, have been isolated from an undifferentiated teratocarcinoma cell line5. We now report insertions of L1 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 L1 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 L1 cDNAs (ref. 6). These results indicate that certain L1 sequences in man can be dispersed, presumably by an RNA intermediate, and cause disease by insertional mutation.
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U2 - 10.1038/332164a0
DO - 10.1038/332164a0
M3 - Article
C2 - 2831458
AN - SCOPUS:0023867459
SN - 0028-0836
VL - 332
SP - 164
EP - 166
JO - Nature
JF - Nature
IS - 6160
ER -