Gregersen N, Andresen B S, Corydon M J, Corydon T J, Olsen R K, Bolund L, Bross P
Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Aarhus, Denmark.
Hum Mutat. 2001 Sep;18(3):169-89. doi: 10.1002/humu.1174.
Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype-phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype-phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders.
与传统酶学检测相比，对脂肪酸氧化缺陷等代谢紊乱进行突变分析，为特异性诊断提供了一种额外且通常更具优势的工具。随着人类基因组计划结构部分的推进以及突变数据库的建立，正在开发便捷可靠的基因分析程序。突变分析最直接的应用是对疑似患者进行特异性诊断，特别是在家族研究以及产前/植入前分析的背景下。此外，从这些实际应用中产生了研究基因型 - 表型关系以及研究特定突变或突变组导致的分子发病机制的可能性。在本综述中，我们总结了关于线粒体脂肪酸氧化的三种疾病中基因型 - 表型关系的现有知识：极长链酰基辅酶A脱氢酶（VLCAD，也称为ACADVL）、中链酰基辅酶A脱氢酶（MCAD，也称为ACADM）和短链酰基辅酶A脱氢酶（SCAD，也称为ACADS）缺乏症。基于这些知识，我们讨论了目前对突变类型的结构影响的理解，以及由分子伴侣和细胞内蛋白酶组成的线粒体蛋白质质量控制系统的调节作用。我们提出，揭示蛋白质质量控制系统调节作用的遗传和细胞决定因素可能有助于评估给定突变临床表达中遗传和环境因素之间的平衡。认识到单基因的作用，如VLCAD、MCAD和SCAD基因中的致病突变，可能会因其他基因的变异而改变，这预示着需要对其他遗传变异进行谱分析。突变检测系统，如芯片技术的快速发展，使得这种谱分析成为可能。然而，突变分析在脂肪酸氧化缺陷和其他代谢紊乱诊断中的应用程度还有待观察。
