Disease mechanisms and protein structures in fatty acid oxidation defects
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In fatty acid oxidation defects, the majority of gene variations are of the missense type and, therefore, prone to inducing misfolding in the resulting mutant protein. The fate of the mutant protein depends on the nature of the gene variation and other genetic factors as well as cellular and environmental factors. Since it has been shown that certain fatty acid oxidation enzyme proteins, exemplified by mutant medium-chain and short-chain acyl-CoA dehydrogenases as well as electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase, may accumulate during cellular stress, e.g. elevated temperature, there is speculation about how such proteins may disturb the integrity of the putative fatty acid oxidation metabolone, in which the two flavoproteins link the matrix-located acyl-CoA dehydrogenases to the respiratory chain in the mitochondrial inner membrane. However, since studies so far have not been able to define the fatty acid oxidation metabolone, it is concluded that new concepts and refined techniques are required to answer these questions and thereby contribute to the elucidation of the cellular pathophysiology and the genotype–phenotype relationship in fatty acid oxidation defects.
The investigations done at the Research Unit for Molecular Medicine have over the years been supported by The Danish Medical Research Council; Danish Human Genome Centre; Karen Elise Jensen Foundation; Lundbeck Foundation; The March of Dimes Foundation; Aarhus County Research Initiative; Institute of Experimental Clinical Research, Aarhus University; Institute of Human Genetics, Aarhus University, and Aarhus University Hospital. We thank employees at the research unit as well as national and international friends for ongoing discussions concerning genotype–phenotype relationships in FAO defects.
- Antonarakis SE, Krawczak M, Cooper DN (2001) The nature and mechanisms of human gene mutations. In: Scriver CR, Beaudet AL, Valle D (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, New York, pp 343–378Google Scholar
- Bross P, Andresen BS, Winter V et al (1993) Co-overexpression of bacterial GroESL chaperonins partly overcomes non-productive folding and tetramer assembly of E. coli-expressed human medium-chain acyl-CoA dehydrogenase (MCAD) carrying the prevalent disease-causing K304E mutation. Biochim Biophys Acta 1182:264–274PubMedGoogle Scholar
- Frerman FE, Goodman SI (2001) Defects in electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric aciduria type II. In: Scriver CR, Beaudet AL, Valle D (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, New York, pp 2357-2365Google Scholar
- Gregersen N, Winter VS, Corydon MJ et al (1998) Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-> T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-> A, together conferring susceptibility to ethylmalonic aciduria. Hum Mol Genet 7:619–627CrossRefPubMedGoogle Scholar
- Gregersen N, Bross P, Jørgensen MM (2005) Protein folding and misfolding: the role of cellular protein quality control systems in inherited disorders. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Vogelstein B, Childs B, Kinzler KW (eds). McGraw-Hill, New York, p MMBID-ONLINE-URL: http://genetics.accessmedicine.com