Human Molecular Genetics, Vol 5, 1945-1951, Copyright © 1996 by Oxford University Press
A Brinke, L Tagliavacca, J Naylor, P Green, P Giangrande and F Giannelli
Analysis of mRNA in two haemophilic monozygotic twins offers novel
information on the organisation of expressed sequences distal to the
coagulation factor VIII gene. These patients show an inversion that, in
contrast to the common inversions responsible for 1/5 of all haemophilia A,
affects the first rather than intron 22 of the gene. This displaces the
most telomeric of the factor VIII exons (exon 1) by approximately 100 kb
towards the telomere, and close to the region of the C6.1A gene. This novel
inversion creates two hybrid transcription units: one formed by the
promoter and first exon of the factor VIII gene followed by a widely
expressed sequence; the other by the promoter and coding region of the
C6.1A gene plus most of the factor VIII gene (part of intron 1 and exons
2-26). Investigation of this transcription unit reveals that the C6.1A gene
has an unsuspected intron in the region coding for the previously described
3'-untranslated tail of the message. Furthermore, exons located beyond the
known C6.1A sequence and present in normal transcripts precede exons 2-26
of the factor VIII gene in the hybrid mRNA of the haemophilic twins. The
factor VIII sequences in this hybrid mRNA are not expected to be expressed
because they lack the first exon, encoding the prepeptide, and follow a
translation stop in the C6.1A gene. Leukaemia-related translocations in the
C6.1A region suggest that this region may be somewhat unstable.
ARTICLES
Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia
Division of Medical and Molecular Genetics, UMDS, Guy's Hospital, London, UK.
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