A SINGLE POINT MUTATION IS THE CAUSE OF THE GREEK FORM OF HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
A SINGLE POINT MUTATION IS THE CAUSE OF THE GREEK FORM OF HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN
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DOI：
10.1038/358499a0
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发表时间：
1992-08-06
期刊：
影响因子：
64.8
通讯作者：
DILLON, N
中科院分区：
文献类型：
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作者：
BERRY, M;GROSVELD, F;DILLON, N
在正常人中，胎儿期特异性γ-珠蛋白基因在出生后沉默，并且在成人中不表达。胎儿血红蛋白遗传性持续存在（HPFH）。这些在临床上是重要的，因为γ-珠蛋白水平的升高可以减轻β-地中海贫血和镰状细胞贫血。一类突变与γ-珠蛋白基因启动子中的点突变（非缺失HPFH）相关，而其他突变似乎是由γ-珠蛋白基因3'端的大缺失引起的1。为了测试在希腊非缺失型HPFH 2，3中发现的点突变（核苷酸位置-117处的鸟嘌呤变为腺嘌呤）是否是成人阶段γ-珠蛋白水平升高的原因，而不仅仅是连锁多态性，我们将该突变工程化到γ-珠蛋白基因中。当将该基因引入小鼠时，-117突变的存在导致胎儿和成年小鼠中γ-珠蛋白表达持续高水平，并伴随β-珠蛋白表达的降低。我们发现，这些变化与转录因子GATA 1的结合γ-珠蛋白启动子的损失，这表明它可能作为一个负调节器的γ-珠蛋白基因在成人。
IN normal humans the fetal stage-specific gamma-globin genes are silenced after birth and not expressed in the adult. Exceptions are seen in cases of hereditary persistence of fetal haemoglobin (HPFH). These are clinically important because the elevated levels of gamma-globin can alleviate beta-thalassaemia and sickle cell anaemia. One class of mutations is associated with point mutations in the promoter of the gamma-globin genes (non-deletion HPFH), whereas others seem to be caused by large deletions 3' to the gamma-globin genes1. To test whether the point mutation found in the Greek non-deletion HPFH2,3 (guanine to adenine at nucleotide position -117) is the cause of the raised gamma-globin levels in the adult stage and is not just a linked polymorphism, we engineered this mutation into a gamma-globin gene. When this gene was introduced into mice, the presence of the -117 mutation results in persistence of gamma-globin expression at a high level and a concomitant decrease in beta-globin expression in fetal and adult mice. We show that these changes correlate with the loss of binding of the transcription factor GATA1 to the gamma-globin promoter, suggesting that it may act as a negative regulator of the gamma-globin gene in adults.