Elion J, Berg P E, Lapouméroulie C, Trabuchet G, Mittelman M, Krishnamoorthy R, Schechter A N, Labie D
INSERM Unité 120, Hôpital Robert Debré, Paris, France.
Blood. 1992 Feb 1;79(3):787-92.
The clinical diversity of sickle cell anemia is strongly related to the degree of intracellular hemoglobin S (Hb S) polymerization, which in turn is dependent on the intracellular concentration of Hb S. We have recently defined a region of DNA approximately 500 bp 5' to the human beta-globin gene that acts as a silencer for the transcription of this gene and have shown that a polymorphism in this sequence is associated with a thalassemic phenotype of the beta-globin gene. In this work we have examined the correlation of DNA sequence polymorphisms in this silencer with binding of a previously identified putative repressor protein, BP1, and with the expression of Hb S in individuals heterozygous for the beta s allele. It was found that specific configurations of the motif, (AT)x(T)y, are homogeneous for the major haplotypes of the beta-globin gene cluster described on beta s chromosomes. Binding of BP1 was measured to DNA of three haplotypes: Indian, Benin, and Bantu. BP1 binds most tightly to DNA of the Indian haplotype, and these patients produce less beta s protein than Benin patients, whose DNA exhibits weaker affinity for BP1. Binding of BP1 is the weakest to DNA of the Bantu haplotype, which is associated with clinically more severe sickle cell symptoms. These data are consistent with the hypothesis that these polymorphisms may not be neutral and that the DNA sequence at this site may affect the expression of the beta s gene. Such an effect may be synergistic with other genetic variables, such as fetal hemoglobin levels, F-cell numbers, and the number of alpha-globin genes, in determining intracellular polymerization and, thus, the severity of the sickle cell syndromes.
镰状细胞贫血的临床多样性与细胞内血红蛋白S（Hb S）聚合程度密切相关，而这又取决于Hb S的细胞内浓度。我们最近确定了人类β-珠蛋白基因5'端约500 bp的一个DNA区域，该区域可作为该基因转录的沉默子，并表明该序列中的多态性与β-珠蛋白基因的地中海贫血表型相关。在这项研究中，我们检测了该沉默子中DNA序列多态性与先前鉴定的假定阻遏蛋白BP1的结合以及βs等位基因杂合个体中Hb S表达之间的相关性。结果发现，对于βs染色体上描述的β-珠蛋白基因簇的主要单倍型，基序(AT)x(T)y的特定构型是一致的。测量了BP1与三种单倍型DNA的结合：印度型、贝宁型和班图型。BP1与印度单倍型的DNA结合最紧密，这些患者产生的βs蛋白比贝宁患者少，贝宁患者的DNA对BP1的亲和力较弱。BP1与班图单倍型的DNA结合最弱，该单倍型与临床上更严重的镰状细胞症状相关。这些数据与以下假设一致，即这些多态性可能不是中性的，并且该位点的DNA序列可能影响βs基因的表达。在确定细胞内聚合以及镰状细胞综合征的严重程度方面，这种效应可能与其他遗传变量协同作用，如胎儿血红蛋白水平、F细胞数量和α-珠蛋白基因数量。
