A g → a substitution in an HNF I binding site in the human α-fetoprotein gene is associated with hereditary persistence of α-fetoprotein (HPAFP)

John H. Mcvey, Katerina Michaelides, Linda P. Hansen, Malcolm Ferguson-smith, Shirley Tilghman, Robb Krumlauf, Edward G.D. Tuddenham

Research output: Contribution to journalArticle

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Abstract

A family displaying hereditary persistence of α-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 Iα 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.

Original languageEnglish (US)
Pages (from-to)379-384
Number of pages6
JournalHuman molecular genetics
Volume2
Issue number4
DOIs
StatePublished - Apr 1 1993

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Mcvey, J. H., Michaelides, K., Hansen, L. P., Ferguson-smith, M., Tilghman, S., Krumlauf, R., & Tuddenham, E. G. D. (1993). A g → a substitution in an HNF I binding site in the human α-fetoprotein gene is associated with hereditary persistence of α-fetoprotein (HPAFP). Human molecular genetics, 2(4), 379-384. https://doi.org/10.1093/hmg/2.4.379