Vulliamy T J, D'Urso M, Battistuzzi G, Estrada M, Foulkes N S, Martini G, Calabro V, Poggi V, Giordano R, Town M
Department of Haematology, Royal Postgraduate Medical School, London, Great Britain.
Proc Natl Acad Sci U S A. 1988 Jul;85(14):5171-5. doi: 10.1073/pnas.85.14.5171.
Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) deficiency is a common genetic abnormality affecting an estimated 400 million people worldwide. Clinical and biochemical analyses have identified many variants exhibiting a range of phenotypes, which have been well characterized from the hematological point of view. However, until now, their precise molecular basis has remained unknown. We have cloned and sequenced seven mutant G6PD alleles. In the nondeficient polymorphic African variant G6PD A we have found a single point mutation. The other six mutants investigated were all associated with enzyme deficiency. In one of the commonest, G6PD Mediterranean, which is associated with favism among other clinical manifestations, a single amino acid replacement was found (serine----phenylalanine): it must be responsible for the decreased stability and the reduced catalytic efficiency of this enzyme. Single point mutations were also found in G6PD Metaponto (Southern Italy) and in G6PD Ilesha (Nigeria), which are asymptomatic, and in G6PD Chatham, which was observed in an Indian boy with neonatal jaundice. In G6PD "Matera," which is now known to be the same as G6PD A-, two separate point mutations were found, one of which is the same as in G6PD A. In G6PD Santiago, a de novo mutation (glycine----arginine) is associated with severe chronic hemolytic anemia. The mutations observed show a striking predominance of C----T transitions, with CG doublets involved in four of seven cases. Thus, diverse point mutations may account largely for the phenotypic heterogeneity of G6PD deficiency.
葡萄糖-6-磷酸脱氢酶（G6PD；EC 1.1.1.49）缺乏症是一种常见的遗传异常，全球约有4亿人受其影响。临床和生化分析已鉴定出许多表现出一系列表型的变体，从血液学角度对其进行了充分表征。然而，迄今为止，它们确切的分子基础仍不清楚。我们克隆并测序了七个突变的G6PD等位基因。在非缺陷型多态性非洲变体G6PD A中，我们发现了一个单点突变。所研究的其他六个突变体均与酶缺乏有关。在最常见的变体之一G6PD地中海型中，它与蚕豆病及其他临床表现相关，发现了一个氨基酸替换（丝氨酸→苯丙氨酸）：这必定是该酶稳定性降低和催化效率下降的原因。在无症状的G6PD梅塔蓬托（意大利南部）和G6PD伊莱沙（尼日利亚）变体中，以及在一名患有新生儿黄疸的印度男孩中观察到的G6PD查塔姆变体中，也发现了单点突变。在现在已知与G6PD A-相同的G6PD“马泰拉”变体中，发现了两个独立的点突变，其中一个与G6PD A中的相同。在G6PD圣地亚哥变体中，一个新生突变（甘氨酸→精氨酸）与严重的慢性溶血性贫血相关。观察到的突变显示出C→T转换明显占优势，七个案例中有四个涉及CG双联体。因此，多种点突变可能在很大程度上解释了G6PD缺乏症的表型异质性。
