Hereditary persistence of alpha-fetoprotein is due to both proximal and distal hepatocyte nuclear factor-1 site mutations.
Hereditary persistence of alpha-fetoprotein is due to both proximal and distal hepatocyte nuclear factor-1 site mutations.
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发表时间：
2004
期刊：
影响因子：
29.4
通讯作者：
Y. Alj;M. Georgiakaki;J. Savouret;F. Mal;P. Attali;G. Pelletier;C. Fourré;E. Milgrom;C. Buffet;A. Guiochon‐Mantel;G. Perlemuter
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作者：
Y. Alj;M. Georgiakaki;J. Savouret;F. Mal;P. Attali;G. Pelletier;C. Fourré;E. Milgrom;C. Buffet;A. Guiochon‐Mantel;G. Perlemuter
背景和目的甲胎蛋白（HPAFP）遗传性持续存在的分子机制先前已在一个大的苏格兰家族中描述，包括甲胎蛋白（AFP）基因启动子的远端肝细胞核因子1（HNF-1）结合位点的-119G>A置换。我们在这里报告的分子机制HPAFP在2个新的无关家庭。方法家系1为孟加拉人，家系2为意大利人。5例受试者中的4例（家族1）和9例受试者中的3例（家族2）显示HPAFP。在所有可用的家族成员中研究AFP基因启动子。结果所有AFP水平高的受试者都有突变的启动子序列。家族1显示报道的-119G>A置换。家族2在启动子的近端推定HNF-1结合区显示-55C>A和-65C>T取代。-55 C>A突变增加了近端HNF-1结合区与共有结合区的相似性。凝胶迁移实验证实其对HNF-1的亲和力增加，转染实验显示基因转录水平增加。理论上，-65 C>T取代产生了CCAAT盒。然而，凝胶移位和转染实验未能显示与-55C>A突变相关的这种取代的任何生物学效应。结论AFP基因启动子HNF-1结合位点的两个不同突变可能导致HPAFP。这突出了HNF-1在AFP基因表达中的重要性。不明原因的持续性AFP应进行家系研究和/或AFP基因启动子测序，以避免不适当的探索和治疗决定。
BACKGROUND AND AIMS 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.