Miwa S, Kanno H, Hirono A, Fujii H
Okinaka Memorial Institute for Medical Research, Tokyo Women's Medical College, Japan.
Southeast Asian J Trop Med Public Health. 1995;26 Suppl 1:112-9.
The molecular abnormalities of erythroenzymopathies associated with hereditary hemolytic anemia have been determined using molecular techniques. Pyruvate kinase (PK) deficiency is the most common and well-characterized enzyme deficiency involving the glycolytic pathway and causing hereditary hemolytic anemia. We have identified six distinct missense mutations and a form of splicing mutation in 11 unrelated families with homozygous PK deficiency. Mutations located near the substrate binding site may change the conformation of the active site, resulting in a drastic loss of activity and severe clinical symptoms. Up to now, including these genetic defects, 21 missense, 1 nonsense and 2 splicing mutations, 2 insertions, and 3 deletions have been determined. G6PD deficiency is the most common metabolic disorder, and is associated with chronic and drug- or infection-induced hemolytic anemia. To date, sixty different mutations have now been identified. Except for three kinds of variants with small gene deletions or three nucleotide substitutions, all of those were found to be produced by one or two nucleotide substitutions. Molecular studies disclosed that all the class 1 variants associated with chronic hemolysis have the mutations surrounding either the substrate or the NADP binding site. Among rare enzymopathies, missense mutations have been determined in glucosephosphate isomerase deficiency, aldolase deficiency, triosephosphate isomerase (TPI) deficiency, phosphoglycerate kinase deficiency, and adenylate kinase deficiency. Compound heterozygous cases with missense mutation/nonsense mutation and missense mutation/decreased mRNA have been reported in TPI deficiency and diphosphoglyceromutase deficiency, respectively. In phosphofructokinase (PFK) deficiency, three kinds of 5'-splice junction mutations resulting in abnormally spliced PFK-M mRNA were identified. An exception is a hemolytic anemia due to increased adenosine deaminase activity. The basic abnormality appears to result from overproduction of structurally normal enzyme.
运用分子技术已确定了与遗传性溶血性贫血相关的红细胞酶病的分子异常情况。丙酮酸激酶（PK）缺乏症是涉及糖酵解途径且导致遗传性溶血性贫血的最常见且特征明确的酶缺乏症。我们在11个患有纯合PK缺乏症的无关家族中鉴定出6种不同的错义突变和1种剪接突变形式。位于底物结合位点附近的突变可能会改变活性位点的构象，导致活性急剧丧失和严重的临床症状。截至目前，包括这些基因缺陷在内，已确定了21种错义突变、1种无义突变、2种剪接突变、2种插入突变和3种缺失突变。葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症是最常见的代谢紊乱疾病，与慢性以及药物或感染诱发的溶血性贫血相关。迄今为止，现已鉴定出60种不同的突变。除了3种具有小基因缺失或三个核苷酸替换的变体之外，所有这些突变均被发现是由一两个核苷酸替换产生的。分子研究表明，所有与慢性溶血相关的1类变体在底物或NADP结合位点周围均存在突变。在罕见的酶病中，已在磷酸葡萄糖异构酶缺乏症、醛缩酶缺乏症、磷酸丙糖异构酶（TPI）缺乏症、磷酸甘油酸激酶缺乏症和腺苷酸激酶缺乏症中确定了错义突变。分别在TPI缺乏症和二磷酸甘油酸变位酶缺乏症中报道了错义突变/无义突变和错义突变/ mRNA减少的复合杂合病例。在磷酸果糖激酶（PFK）缺乏症中，鉴定出三种导致PFK-M mRNA异常剪接的5'-剪接连接突变。一个例外是由于腺苷脱氨酶活性增加导致的溶血性贫血。基本异常似乎是由结构正常的酶过度产生所致。
