Ragusa A, Lombardo M, Beldjord C, Ruberto C, Lombardo T, Elion J, Nagel R L, Krishnamoorthy R
I.R.C.C.S., OASI, Troina, Italy.
Am J Hematol. 1992 Jul;40(3):199-206. doi: 10.1002/ajh.2830400308.
The present epidemiological study of the molecular characteristics of beta-thalassemia in Sicily was prompted by the disparate phenotypic expression (in clinical status and absolute HbF level) observed in two beta-thalassemic homozygotes who were also homozygous for the beta-like globin gene cluster haplotype III. We suspected that polymorphisms within haplotype III could be the cause for the discrepancy. Based on the association of particular conformations of the (AT)xT(y) motif (-540 5' to the beta gene) with milder forms of thalassemia and sickle cell anemia, 38 homozygous beta-thalassemia patients were studied to define their haplotypes, the -158 site 5' to the G gamma gene (linked to haplotype III) and the structure of the (AT)xT(y) motif. We found that the patient who was phenotypically mild and homozygous for beta-thalassemia, haplotype III, and the -158 C----T mutation was homozygous for the rare (AT)9T5 motif. In contrast, the patient homozygous for beta-thalassemia, haplotype III, and the -158 mutation, but exhibiting a severe clinical course, was homozygous for the (AT)7T7 configuration. Others have suggested that (AT)9T5 is a negative regulatory protein binding sequence, and it is a silent carrier state for beta-thalassemia. The usual configuration (AT)7T7, has considerably less affinity for regulatory protein binding, and it is the most common configuration in Sicilian beta-thalassemics (67 of the 78 chromosomes studied). Within the 38 patients studied, seven were informative because they had various combinations of the (AT)9T5 and (AT)7T7 motif, and the -158 C----T mutation. The results in these patients suggest that only the co-presence of the (AT)9T5 configuration and a C----T change at -158 5' to the G gamma gene is associated with high HbF expression and a mild clinical phenotype. We postulate that these two regions of the beta-like globin gene cluster interact, when endowed with the proper sequences, to enhance the expression of HbF secondary to anemia.
西西里岛β地中海贫血分子特征的当前流行病学研究，是由两名β地中海贫血纯合子（他们也是β样珠蛋白基因簇单倍型III的纯合子）中观察到的不同表型表达（临床状态和绝对HbF水平）所推动的。我们怀疑单倍型III内的多态性可能是导致差异的原因。基于（AT）xT（y）基序（β基因5'端-540处）的特定构象与较轻形式的地中海贫血和镰状细胞贫血的关联，对38名纯合β地中海贫血患者进行了研究，以确定他们的单倍型、Gγ基因5'端-158位点（与单倍型III连锁）以及（AT）xT（y）基序的结构。我们发现，表型轻度且为β地中海贫血、单倍型III和-158 C→T突变纯合子的患者，其罕见的（AT）9T5基序为纯合子。相比之下，β地中海贫血、单倍型III和-158突变纯合子但临床病程严重的患者，其（AT）7T7构象为纯合子。其他人曾提出（AT）9T5是一种负调控蛋白结合序列，并且它是β地中海贫血的沉默携带状态。通常的构象（AT）7T7对调控蛋白结合的亲和力要低得多，并且它是西西里岛β地中海贫血患者中最常见的构象（在所研究的78条染色体中有67条）。在研究的38名患者中，有7名提供了信息，因为他们具有（AT）9T5和（AT）7T7基序以及-158 C→T突变的各种组合。这些患者的结果表明，只有（AT）9T5构象和Gγ基因5'端-158处的C→T变化同时存在，才与高HbF表达和轻度临床表型相关。我们推测，当β样珠蛋白基因簇的这两个区域具有适当序列时，它们会相互作用，以增强贫血继发的HbF表达。
