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Báo cáo khóa học: Genetic defects in fatty acid b-oxidation and acyl-CoA dehydrogenases Molecular pathogenesis and genotype–phenotype relationships

Mitochondrial fatty acid oxidation deficiencies are due to genetic defects in enzymes of fatty acidb-oxidation and transport proteins.Genetic defects have been identified in most of the genes where nearly all types of sequence vari-ations (mutation types) have beenassociatedwithdisease.In this paper, we will discuss the effects of the various types of sequence variations encountered and review current know-ledge regarding the genotype–phenotype relationship, espe-cially in patients with acyl-CoA dehydrogenase deficiencies where sufficient material exists for a meaningful discussion | Eur. J. Biochem. 271 470-482 2004 FEBS 2004 doi 10.1046 j.1432-1033.2003.03949.x MINIREVIEW Genetic defects in fatty acid b-oxidation and acyl-CoA dehydrogenases Molecular pathogenesis and genotype-phenotype relationships Niels Gregersen1 Peter Bross1 and Brage S. Andresen1 2 1 Research Unit for Molecular Medicine Aarhus University Hospital and Faculty of Health Sciences and 2 Institute of Human Genetics Aarhus University Aarhus Denmark Mitochondrial fatty acid oxidation deficiencies are due to genetic defects in enzymes of fatty acid b-oxidation and transport proteins. Geneiic dfeccss hriee been identified in most of the genes where nearly all types of sequence variations mutation types have been associated with disease. In this paper we will discuss the effects of the various types of sequence variations encountered and review current knowledge regarding the genotype-phenotype relationship especially in patients with acyl-CoA dehydrogenase deficiencies where sufficient material exists for a meaningful discussion. Because mis-sense sequence variations are prevalent in these diseases we will discuss the implications of these types of sequence variations on the processing and folding of mis-sense variant proteins. As the peevalent mis-sense vari ant K304E MCAD protein has been studied intensively the investigations on biogenesis stability and kinetic properties for this variant enzyme will be discussed in detail and used as a paradigm for the study of other mis-sense variant proteins. We conclude that the total effect of mis-sense sequence variations may comprise an invariable - sequence variation specific - effect on the catalytic parameters and a conditional effect which is dependent on cellular physiological and genetic factors other than the sequence variation itself. Keywords fatty acid b-oxidation acyl-CoA dehydrogenase VLCAD MCAD SCAD mutation type protein quality control system molecular chaperones intracellular proteases genotype-phenotype. Introduction .