Tse W T, Gallagher P G, Jenkins P B, Wang Y, Benoit L, Speicher D, Winkelmann J C, Agre P, Forget B G, Marchesi S L
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520-8021, USA.
Am J Hematol. 1997 Mar;54(3):233-41. doi: 10.1002/(sici)1096-8652(199703)54:3<233::aid-ajh10>3.0.co;2-e.
Nondominant hereditary spherocytosis (ndHS) is a disorder characterized in some patients by severe hemolytic anemia and marked deficiency of erythrocyte spectrin. This report describes the identification of a variant spectrin chain, alpha-spectrin Bughill or alpha(BH), that is associated with this disorder in a number of patients. Tryptic maps of spectrin from affected individuals revealed an acidic shift in isoelectric point of the alphaII domain peptides at 46 kD and 35 kD. A point mutation at codon 970 of the alpha-spectrin gene (GCT-->GAT), that changes the encoded amino acid from an alanine to an aspartic acid, was identified in genomic DNA of affected patients. The alpha(BH) variant was present in 8 patients with ndHS from five different kindreds but was absent in 4 patients from two other kindreds. The 8 ndHS patients with the alpha(BH) variant appeared to be homozygous for the alpha(BH) variant by analysis of peptide maps of limited tryptic digests of erythrocyte spectrin. However, following genomic DNA analysis, only 2 of these patients were true homozygotes, whereas 6 were found to be doubly heterozygous for the alpha(BH) allele and a second, presumably abnormal, alpha-spectrin gene. These results suggest that, in these 6 patients, the second alpha-spectrin allele is in fact associated with one or more genetic defect(s), causing decreased accumulation of alpha-spectrin. The pattern of transmission of the alpha(BH) allele in certain families suggests that the alpha(BH) amino-acid substitution is not itself responsible for ndHS but is more likely a polymorphic variant that, in some but not all cases, is in linkage disequilibrium with another uncharacterized alpha-spectrin gene defect that itself is a cause of ndHS.
非显性遗传性球形红细胞增多症（ndHS）是一种疾病，部分患者的特征为严重溶血性贫血和红细胞血影蛋白明显缺乏。本报告描述了一种变异血影蛋白链α-血影蛋白布吉尔（alpha-spectrin Bughill）或α（BH）的鉴定，该蛋白链与许多患者的这种疾病有关。来自受影响个体的血影蛋白胰蛋白酶图谱显示，46 kD和35 kD处αII结构域肽的等电点发生酸性偏移。在受影响患者的基因组DNA中鉴定出α-血影蛋白基因第970位密码子的点突变（GCT→GAT），该突变将编码的氨基酸从丙氨酸变为天冬氨酸。α（BH）变异体存在于来自五个不同家族的8例ndHS患者中，但在来自其他两个家族的4例患者中不存在。通过对红细胞血影蛋白有限胰蛋白酶消化产物的肽图谱分析，8例携带α（BH）变异体的ndHS患者似乎对α（BH）变异体呈纯合状态。然而，经过基因组DNA分析，这些患者中只有2例是真正的纯合子，而6例被发现对α（BH）等位基因和另一个可能异常的α-血影蛋白基因呈双重杂合状态。这些结果表明，在这6例患者中，第二个α-血影蛋白等位基因实际上与一个或多个遗传缺陷相关，导致α-血影蛋白积累减少。α（BH）等位基因在某些家族中的传递模式表明，α（BH）氨基酸取代本身并非ndHS的病因，而更可能是一种多态性变异体，在某些但并非所有情况下，与另一个未表征的α-血影蛋白基因缺陷处于连锁不平衡状态，该缺陷本身是ndHS的病因。
