Ho L, Wexler I D, Kerr D S, Patel M S
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
Ann N Y Acad Sci. 1989;573:347-59. doi: 10.1111/j.1749-6632.1989.tb15010.x.
The nature of PDC deficiency has been characterized at the levels of total and component catalytic activities as well as at the levels of component proteins and specific mRNAs. Defects in 14 cases were shown to involve the E1 component, and there was one case each of an apparent E2 and E3 deficiency. Defects involving the E1 component exhibit heterogeneous expression of E1 proteins and mRNAs, indicating that different types of mutations cause E1 deficiency. E1 deficiencies can occur either in the presence or absence of E1 proteins, representing catalytic mutations or mutations affecting the expression of E1 proteins, respectively. In every case where the content of E1 proteins is reduced, both the E1 alpha and the E1 beta peptides are simultaneously affected. This is likely to be due to rapid degradation of any E1 peptide that is not complexed into the alpha 2 beta 2 conformation. Among subjects with reduced levels of both E1 peptides, some had normal amounts of specific E1 alpha and E1 beta mRNAs. In these subjects, the primary mutations affect either translational or post-translational processes leading to the formation of mature E1 proteins in the mitochondria. In contrast, two cases of simultaneous reduction of both E1 alpha and E1 beta proteins had decreases in the amounts of E1 alpha mRNA only. Mutations in these cases may impair the transcription, nuclear processing, or stability of E1 alpha mRNA. E1 deficiency may manifest in a variable manner. Further characterization of this phenomenon might provide insight into the discrepancy between the clinical severity of the defect and the residual level of PDC catalytic activity. Available information indicates that the E1 alpha gene is located on the X chromosome, but sex distribution of E1 alpha defects suggests that the mode of inheritance may not follow a simple X-linked pattern. The availability of specific PDC antibodies and cDNA clones, as well as the application of molecular biological techniques, should facilitate the characterization of the molecular basis of various PDC deficiencies. This information should provide better understanding of the function of PDC, pathophysiology of PDC deficiency, and mechanisms of inheritance and expression of these genes.
丙酮酸脱氢酶复合体（PDC）缺乏症的本质已在总催化活性和各组分催化活性水平以及各组分蛋白质和特定信使核糖核酸（mRNA）水平上得到了表征。14例患者的缺陷被证明涉及E1组分，另有1例分别表现为明显的E2和E3缺乏。涉及E1组分的缺陷表现出E1蛋白质和mRNA的异质性表达，这表明不同类型的突变会导致E1缺乏。E1缺乏症可在有或没有E1蛋白质的情况下发生，分别代表催化性突变或影响E1蛋白质表达的突变。在每一个E1蛋白质含量降低的病例中，E1α和E1β肽都会同时受到影响。这很可能是由于任何未复合成α2β2构象的E1肽都会迅速降解。在E1肽水平均降低的受试者中，一些人的特定E1α和E1βmRNA含量正常。在这些受试者中，原发性突变影响翻译或翻译后过程，导致线粒体中成熟E1蛋白质的形成。相比之下，2例E1α和E1β蛋白质同时减少的病例仅E1αmRNA含量降低。这些病例中的突变可能会损害E1αmRNA的转录、核加工或稳定性。E1缺乏症可能以多种方式表现出来。对这一现象的进一步表征可能有助于深入了解缺陷的临床严重程度与PDC催化活性残余水平之间的差异。现有信息表明，E1α基因位于X染色体上，但E1α缺陷的性别分布表明，其遗传模式可能不遵循简单的X连锁模式。特异性PDC抗体和cDNA克隆的可用性，以及分子生物学技术的应用，应有助于表征各种PDC缺乏症的分子基础。这些信息应能更好地理解PDC的功能、PDC缺乏症的病理生理学以及这些基因的遗传和表达机制。
