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© 1993 Oxford University Press

OTHER

A G -> A substitution in an HNF I binding site in the human {alpha}-fetoprotein gene is associated with hereditary persistence of {alpha}-fetoprotein (HPAFP)

John H. McVey*, Katerina Michaelides, Linda P. Hansen1, Malcolm Ferguson-Smith2, Shirley Tilghman3, Robb Krumlauf4 and Edward G.D. Tuddenham

Haemostasis Research Group, Clinical Research Centre Watford Road, Harrow HA1 3UJ, UK 1Howard Hughes Medical Institute, Unit in Molecular and Genetic Medicine, Beckman Center, Stanford University School of Medicine Stanford, CA 94305-5425, USA 2Department of Pathology, University of Cambridge Tennis Court Road, Cambridge CB2 1QP, UK 3Howard Hughes Medical Institute and the Department of Molecular Biology, Princeton University Princeton, NJ 08544, USA 4National Institute for Medical Research Mill Hi l, London NW7 1AA, UK

* To whom correspondence should be addressed

Received December 18, 1992; Revised January 22, 1993; Accepted January 22, 1993

A family displaying hereditary persistence of {alpha}-fetoprotein (HPAFP) in adult life was detected in an antenatal screening programme for spina bifida. RFLP linkage analysis shows that the trait is linked with the albumin-AFP locus. The molecular mechanism responsible for the post-natal repression of the AFP gene is unknown. We wished to determine the molecular mechanism underlying HPAFP in this family. Sequence analysis of the 5'-flanking sequences of their gene revealed a GA substitution at position — 119 associated with the trait. This substitution occurs in a potential HNF I binding site, and increases the similarity of the sequence to a consensus HNF I recognition site. In a competitive gel retardation assay the mutant sequence binds HNF I{alpha} more tightly than the wild type sequence. Furthermore, 5'-flanking sequences of the human AFP gene containing the G -> A susbtitution direct a higher level of CAT expression in transfected human hepatoma cells than the wild type sequences. We conclude that the G -> A substitution at position — 119 of the AFP gene is the mutation causing HPAFP in this family. These results highlight the importance of this HNF I binding site in the developmental regulation of the AFP gene.


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