Fortina P, Parrella T, Sartore M, Gottardi E, Gabutti V, Delgrosso K, Mansfield E, Rappaport E, Schwartz E, Camaschella C
Molecular Biology Diagnostic Unit, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104.
Blood. 1994 Jun 1;83(11):3356-62.
The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of alpha thalassemia caused by coinheritance of a rare alpha-globin gene deletion and a nondeletional defect in a southern Italian family. The proband, a 7-year-old girl, exhibited an abnormal hemoglobin electrophoresis pattern with hemoglobin H and hemoglobin Barts, indicating inheritance of H and hemoglobin Barts, indicating inheritance of a severe form of alpha thalassemia. Southern blot analysis of DNA showed normal as well as aberrant alpha-globin gene fragments indicating heterozygosity for a deletional form of alpha thalassemia in the proband and her mother. The coinheritance of a nondeletional form of alpha thalassemia (alpha alpha T) was suspected because of the severity of the proband's phenotype and the presence of normal alpha-globin gene fragments in the father. Selective polymerase chain reaction of the paternal alpha 1- and alpha 2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the alpha 2-globin gene. Genomic DNA mapping and sequence analysis of a unique polymerase chain reaction product generated across the deletion breakpoint of the maternal allele showed a 5,201-bp deletion extending from 870 nucleotides 5' of the alpha 2-globin gene to nucleotide +519 in the alpha 1-globin gene. This deletion is similar to that previously suggested by blotting studies in a Greek family (Pressley et al, Nucleic Acids Res 8:4889, 1980) and removes the entire alpha 2-globin gene and a portion of the 5' end of the alpha 1-globin gene. Sequence characterization of the resultant aberrant truncated alpha 1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3' end of the alpha-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event.
地中海贫血的临床多样性取决于多种基因缺陷的相互作用。我们在一个意大利南部家庭中发现了一种严重的α地中海贫血，其由一个罕见的α珠蛋白基因缺失和一个非缺失性缺陷共同遗传所致。先证者是一名7岁女孩，其血红蛋白电泳图谱异常，出现了血红蛋白H和血红蛋白Barts，这表明她遗传了严重形式的α地中海贫血。DNA的Southern印迹分析显示，既有正常的α珠蛋白基因片段，也有异常的α珠蛋白基因片段，这表明先证者及其母亲为缺失型α地中海贫血杂合子。由于先证者表型严重且父亲存在正常的α珠蛋白基因片段，因此怀疑存在非缺失型α地中海贫血（ααT）的共同遗传。对先证者父亲的α1和α2珠蛋白基因进行选择性聚合酶链反应，随后进行DNA序列分析，结果显示α2珠蛋白基因的多聚腺苷酸化信号序列中存在AATAAA到AATGAA的突变。对跨越母亲等位基因缺失断点产生的独特聚合酶链反应产物进行基因组DNA定位和序列分析，结果显示有一个5201bp的缺失，该缺失从α2珠蛋白基因5'端的870个核苷酸延伸至α1珠蛋白基因中的核苷酸+519。这种缺失与先前希腊一个家庭通过印迹研究推测的缺失相似（Pressley等人，《核酸研究》8:4889，1980），它去除了整个α2珠蛋白基因以及α1珠蛋白基因5'端的一部分。对先证者产生的异常截短α1珠蛋白基因进行序列分析，结果显示有一个27个核苷酸的重复，对应于α珠蛋白基因IVS-2区域的3'端，中间插入了一个四核苷酸（GGTT），这表明该缺失是由非法重组事件引起的。
