title: Hereditary persistence of alpha-fetoprotein is due to both proximal and distal hepatocyte nuclear factor-1 site mutations.
abstract: OBJECTIVE
  The molecular mechanism of hereditary persistence of alpha-fetoprotein (HPAFP) has been previously described in a large Scottish family, consisting of a -119G>A substitution in the distal hepatocyte nuclear factor 1 (HNF-1) binding site of the alpha-fetoprotein (AFP) gene promoter. We report here the molecular mechanisms of HPAFP in 2 new unrelated families.
  
  
  METHODS
  Family 1 was of Bengali origin, and family 2 was Italian. Four of 5 subjects (family 1) and 3 of 9 (family 2) showed HPAFP. The AFP gene promoter was studied in all available family members.
  
  
  RESULTS
  All subjects with high AFP levels had mutated promoter sequences. Family 1 showed the reported -119G>A substitution. Family 2 showed -55C>A and -65C>T substitutions in the proximal putative HNF-1 binding region of the promoter. The -55C>A mutation increased the similarity of the proximal HNF-1 binding region to a consensus binding region. Gel shift assays confirmed its increased affinity toward HNF-1, and transfection experiments revealed an increased level of gene transcription. The -65C>T substitution theoretically created a CCAAT box. However, gel shift and transfection experiments failed to show any biological effect of this substitution that is associated with the -55C>A mutation.
  
  
  CONCLUSIONS
  Two different mutations localized in either HNF-1 binding sites of the AFP gene promoter may result in HPAFP. This highlights the importance of HNF-1 in AFP gene expression. Unexplained persistent AFP should lead to family study and/or AFP gene promoter sequencing to avoid inappropriate explorations and treatment decisions.
authors.affiliation: INSERM U135 Hormones, Hôpital Bicêtre, Cedex, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Alj
authors.forename: Maria
authors.initials: M
authors.lastname: Georgiakaki
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Savouret
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mal
authors.forename: Pierre
authors.initials: P
authors.lastname: Attali
authors.forename: Gilles
authors.initials: G
authors.lastname: Pelletier
authors.forename: Catherine
authors.initials: C
authors.lastname: Fourré
authors.forename: Edwin
authors.initials: E
authors.lastname: Milgrom
authors.forename: Catherine
authors.initials: C
authors.lastname: Buffet
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Gabriel
authors.initials: G
authors.lastname: Perlemuter
mesh_terms: D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D009687:Nuclear Proteins; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D000509:alpha-Fetoproteins; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta