Hereditary persistence of -fetoprotein is due to both proximal and distal hepatocyte nuclear factor-1 site mutations1

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GASTROENTEROLOGY

January 2004 . Volume 126 . Number 1

Case report

Hereditary persistence of -fetoprotein is due to both proximal and distal

hepatocyte nuclear factor-1 site mutations1

Youssef Al j* , Georgiakaki* ,Jean-François Savouret* [FrÉdÉric Mal?

,Pierre Attali§ ,Gilles Pelletier§

Fourré|| ,Edwin Milgrom* , Buffet§ ,

Anne Guiochon-Mantel* * Perlemuter¶

Abstract

Background & Aims: The molecular mechanism of hereditary persistence

of -fetoprotein (HPAFP) has been previously described in a large ish

family, consisting of a -119G>A substitution in the distal hepatocyte

nuclear factor 1 (HNF-1) binding site of the -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.

Publishing and Reprint Information

*INSERM U135 Hormones, Gènes et Reproduction, and Laboratoire d'Hormonologie

et Biologie Moléculaire, Hôpital Bicêtre, Cedex, France

?Département Médico-Chirurgical de Pathologie Digestive, Institut Mutualiste

Montsouris-Porte de Choisy, Paris, France

§Service des maladies du foie et de l'appareil digestif, Hôpital Bicêtre, Le

Kremlin-Bicêtre, France

||Service de Médecine Nucléaire, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre,

France

¶Service d'hépato-gastro-entérologie, Hôpital Antoine Béclère, Clamart,

France

Supported by Institut National de la Santé et de la Recherche Médicale,

Assistance Publique des Hôpitaux de Paris, Faculté de Médecine Paris-Sud,

Association pour la Recherche sur le Cancer, Fondation pour la Recherche

Médicale.

1The authors thank Dr. A. Chauchereau for the gift of A9TKCAT vector, Dr. O.

Lahuna for helpful discussion, C. Aumas for excellent technical assistance,

and S. Wenk for careful English proofreading of the text. We are grateful

for the cooperation of the patients and their families.

*Address requests for reprints to: Anne Guiochon-Mantel, INSERM U135,

Laboratoire d'Hormonologie et Biologie Moléculaire, Secteur Broca,

niveau 3, Hòpital Bicêtre, 78, rue du Général Leclerc, 94275-Le

Kremlin-Bicêtre, Cedex, France; fax: (33) 1-45-21-27-51; Email:

anne.mantel@...

Submitted February 5, 2003.

Accepted on October 2, 2003.

Copyright © 2004 by American Gastroenterological Association

doi:10.1053/j.gastro.2003.10.073