Katsube T, Fucharoen S, Tojo H, Fukumaki Y
Institute of Genetic Information, Kyushu University, Fukuoka, Japan.
Southeast Asian J Trop Med Public Health. 1995;26 Suppl 1:212-20.
Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by continued expression of the gamma-globin gene in adult life. Analysis of a Japanese HPFH family had revealed that the C-T transition at position -114 within the distal CCAAT box of the gamma-globin gene associated with the HPFH allele. In the vicinity of the distal CCAAT box, other two mutations (-117 C-T, 13 bp del) had been identified in individuals with a HPFH phenotype. Functional analysis of these mutant promoters in erythroid cell lines suggested that the distal CCAAT box works positively in the fetus but negatively in the adult on the expression of the gamma-globin gene. Further study on transgenic mice showed that the -114 mutation was responsible for the elevated expression of the gamma-globin gene in the adult. To elucidate the molecular mechanism underlying the persistent expression of the gamma-globin genes associated with the HPFH mutations, interaction of the mutant promoters with nuclear factors was analyzed. Relevance of the nuclear factor, NFE3, to the gamma-globin regulation was suggested by the affected binding of NFE3 to the altered distal CCAAT boxes with HPFH mutations (-117, -114, 13 bp del).
遗传性胎儿血红蛋白持续存在（HPFH）是一种以成人期γ珠蛋白基因持续表达为特征的病症。对一个日本HPFH家族的分析显示，γ珠蛋白基因远端CCAAT盒内-114位的C-T转换与HPFH等位基因相关。在远端CCAAT盒附近，在具有HPFH表型的个体中还鉴定出另外两个突变（-117 C-T，13 bp缺失）。对这些突变启动子在红系细胞系中的功能分析表明，远端CCAAT盒在胎儿期对γ珠蛋白基因的表达起正向作用，而在成人期起负向作用。对转基因小鼠的进一步研究表明，-114突变是导致成人期γ珠蛋白基因表达升高的原因。为了阐明与HPFH突变相关的γ珠蛋白基因持续表达的分子机制，分析了突变启动子与核因子的相互作用。NFE3核因子与γ珠蛋白调控的相关性是通过NFE3与具有HPFH突变（-117、-114、13 bp缺失）的改变的远端CCAAT盒的结合受影响而提出的。
