Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia and a homozygous 40glutamic acid-->lysine substitution in the cytoplasmic domain of band 3 (band 3Montefiore).
Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia and a homozygous 40glutamic acid-->lysine substitution in the cytoplasmic domain of band 3 (band 3Montefiore).
复制标题
DOI：
10.1182/blood.v81.8.2155.bloodjournal8182155
复制
发表时间：
1993-04
期刊：
影响因子：
20.3
通讯作者：
A. Rybicki;JJ Qiu;S. Musto;NL Rosen;RL Nagel;RS Schwartz
中科院分区：
文献类型：
--
作者：
A. Rybicki;JJ Qiu;S. Musto;NL Rosen;RL Nagel;RS Schwartz
红细胞（RBC）蛋白4.2缺乏通常与中度非免疫性溶血性贫血、脾肿大和红细胞脆性相关，类似但不等同于遗传性球形红细胞增多症（HS）。在日本型蛋白4.2缺乏症（蛋白4.2 Nippon）中，贫血与蛋白4.2 cDNA中的点突变有关。在这份报告中，我们描述了一个病人中度和明显的间歇性非免疫性溶血性贫血与脾肿大，球形红细胞增多症，红细胞脆性，减少全细胞变形性，和异常致密的细胞。先证者红细胞膜蛋白的十二烷基硫酸钠-聚丙烯酰胺凝胶电泳分析显示蛋白4.2缺乏88%，甘油醛-3-磷酸脱氢酶（条带6）缺乏30%。先证者蛋白4.2的结构和分子分析正常。相反，先证者条带3的有限胰蛋白酶消化显示胞质结构域中的纯合异常。对该家系的分析显示，6名成员为带3结构异常的杂合子，1名成员为正常纯合子。对异常条带3胰蛋白酶肽的直接序列分析表明，结构异常位于残基40处或附近。先证者带3cDNA的序列分析显示232 G → A突变导致40位谷氨酸→赖氨酸取代（带3 Montefiore）。用等位基因特异性寡核苷酸杂交方法检测该家系的突变，结果显示先证者为纯合子，而家系中带3结构异常的杂合子成员也为带3 Montefiore突变的杂合子。带3 Montefiore突变是不存在的26条染色体，从种族匹配的控制和一个家系成员谁不表达带3结构异常。在脾切除术的同时，先证者的贫血得到了很大程度的纠正，沿着，大部分球形红细胞消失，红细胞渗透脆性、全细胞变形性和细胞密度得到了相当大的改善。我们的结论是，这种遗传性溶血性贫血与带3 Montefiore（40谷氨酸->赖氨酸）的纯合状态和红细胞膜蛋白4.2含量降低有关。我们推测，带3结构异常可能导致与蛋白4.2和带6的相互作用缺陷，特别是，带3中含有40谷氨酸的区域直接或间接地参与与这些蛋白的相互作用。
Red blood cell (RBC) protein 4.2 deficiency is often associated with a moderate nonimmune hemolytic anemia, splenomegaly, and osmotically fragile RBCs resembling, but not identical to, hereditary spherocytosis (HS). In the Japanese type of protein 4.2 deficiency (protein 4.2Nippon), the anemia is associated with a point mutation in the protein 4.2 cDNA. In this report, we describe a patient with moderate and apparently episodic nonimmune hemolytic anemia with splenomegaly, spherocytosis, osmotically fragile RBCs, reduced whole cell deformability, and abnormally dense cells. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the proposita's RBC membrane proteins showed an 88% deficiency of protein 4.2 and a 30% deficiency of glyceraldehyde-3-phosphate dehydrogenase (band 6). Structural and molecular analyses of the proposita's protein 4.2 were normal. In contrast, limited tryptic digestion of the proposita's band 3 showed a homozygous abnormality in the cytoplasmic domain. Analysis of the pedigree disclosed six members who were heterozygotes for the band 3 structural abnormality and one member who was a normal homozygote. Direct sequence analysis of the abnormal band 3 tryptic peptide suggested that the structural abnormality resided at or near residue 40. Sequence analysis of the proposita's band 3 cDNA showed a 232G-->A mutation resulting in a 40glutamic acid-->lysine substitution (band 3Montefiore). Allele-specific oligonucleotide hybridization was used to probe for the mutation in the pedigree, showing that the proposita was homozygous, and the pedigree members who were heterozygous for the band 3 structural abnormality were also heterozygous for the band 3Montefiore mutation. The band 3Montefiore mutation was absent in 26 chromosomes from race-matched controls and in one pedigree member who did not express the band 3 structural abnormality. In coincidence with splenectomy, the proposita's anemia was largely corrected along with the disappearance of most spherocytes and considerable improvements of RBC osmotic fragility, whole cell deformability, and cell density. We conclude that this hereditary hemolytic anemia is associated with the homozygous state for band 3Montefiore (40glutamic acid-->lysine) and a decreased RBC membrane content of protein 4.2. We speculate that band 3 structural abnormalities can result in defective interactions with protein 4.2 and band 6, and in particular, that the region of band 3 containing 40glutamic acid is involved directly or indirectly in interactions with these proteins.