Cao A, Rosatelli C, Pirastu M, Galanello R
Istituto di Clinica e Biologia dell'eta Evolutiva, Università Studi Cagliari, Sardinia, Italy.
Am J Pediatr Hematol Oncol. 1991 Summer;13(2):179-88.
This article reviews the molecular bases of alpha- and beta-thalassemias in Sardinia. In addition, it describes the characteristics and the effects of a genetic program designed to prevent homozygous beta-thalassemia. In the large majority of the cases (95.7%), beta-thalassemia is caused by the nonsense mutation at codon 39, followed by frameshifts at codon 6 (2.1%). Homozygous beta-thalassemia most commonly results in thalassemia major, but in a small proportion this genotype produces milder forms referred to as thalassemia intermedia. The reasons for the attenuated forms were determined only in a small proportion of the cases. The reduced clinical severity was due to either of two factors: (a) There could be the presence of cytosine-thymidine (C----T) substitution of position - 158 G gamma, which is able to increase the G gamma chain output (as in homozygotes for frameshift at codon 6 or compound heterozygote for frameshift at codon 6 and codon 39 nonsense mutation). (b) Reduced clinical severity could be the result of co-inheritance of alpha-thalassemia in the form of two alpha-globin gene deletions of functional loss of the alpha 2-globin gene (homozygote for codon 39 nonsense mutation). The most prominent clinical form of alpha-thalassemia is hemoglobin H disease, which may result from the compound heterozygous state for deletion alpha 0- and alpha(+)-thalassemia (in 83.1% of cases) or deletion and nondeletion alpha-thalassemia (in 16.9%). Deletion Hb disease shows a milder clinical picture as compared to the nondeletion form. The most common nondeletion alpha-thalassemia is the ATG----ACG substitution at the initiation codon of the alpha 2 gene. Double heterozygotes of alpha (-alpha/-alpha) and beta-thalassemia or delta- and beta-thalassemia are relatively common and may cause confusion in carrier identification. The preventive program aimed to control beta-thalassemia is based on voluntary carrier screening., counselling, and prenatal diagnosis. Prenatal diagnosis is carried out by dot blot analysis with allelic specific oligonucleotides on amplified trophoblast DNA. This procedure gave very reliable results; in fact, no misdiagnosis has occurred so far. The preventive program was highly effective, resulting in a decline of the incidence of thalassemia major from 1:250 to 1:1,000 live births.
本文综述了撒丁岛α和β地中海贫血的分子基础。此外，还描述了一项旨在预防纯合子β地中海贫血的遗传计划的特点和效果。在大多数病例（95.7%）中，β地中海贫血由第39密码子的无义突变引起，其次是第6密码子的移码突变（2.1%）。纯合子β地中海贫血最常导致重型地中海贫血，但在一小部分病例中，这种基因型会产生较轻的形式，称为中间型地中海贫血。只有一小部分病例确定了症状减轻的原因。临床严重程度降低是由于以下两个因素之一：（a）可能存在-158 Gγ位置的胞嘧啶-胸腺嘧啶（C→T）替换，这能够增加Gγ链的产量（如第6密码子移码突变的纯合子或第6密码子移码突变与第39密码子无义突变的复合杂合子）。（b）临床严重程度降低可能是由于α地中海贫血以两个α珠蛋白基因缺失或α2珠蛋白基因功能丧失的形式共同遗传（第39密码子无义突变的纯合子）。α地中海贫血最突出的临床形式是血红蛋白H病，它可能由α0-和α（+）-地中海贫血缺失的复合杂合状态引起（83.1%的病例）或缺失型和非缺失型α地中海贫血引起（16.9%）。与非缺失型相比，缺失型血红蛋白H病的临床表现较轻。最常见的非缺失型α地中海贫血是α2基因起始密码子处的ATG→ACG替换。α（-α/-α）与β地中海贫血或δ与β地中海贫血的双重杂合子相对常见，可能会在携带者鉴定中造成混淆。旨在控制β地中海贫血的预防计划基于自愿携带者筛查、咨询和产前诊断。产前诊断通过对等位基因特异性寡核苷酸进行斑点印迹分析，对扩增的滋养层DNA进行检测。该程序给出了非常可靠的结果；事实上，到目前为止尚未发生误诊。该预防计划非常有效，导致重型地中海贫血的发病率从每250例活产1例下降到每1000例活产1例。
