title: Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.
abstract: Mitochondrial trifunctional protein (MTP) is a recently identified enzyme involved in mitochondrial beta-oxidation, harboring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain 3-ketothiolase activity. A deficiency of this protein is associated with impaired oxidation of long-chain fatty acids which can lead to sudden infant death. Furthermore, it is clear that this inborn error of fatty acid oxidation is very frequent, second to medium chain acyl-CoA dehydrogenase deficiency. In most patients only the LCHAD activity of MTP is deficient with near normal activity of the two other enzyme activities of the complex. We recently described the occurrence of a frequent G1528C mutation in the cDNA coding for the a subunit of MTP. Using S. cerevisiae for expression of wild type and mutant protein we show that the G1528C mutation is directly responsible for the loss of LCHAD activity. Furthermore, we describe a newly developed method allowing identification of the G1528C mutation in genomic DNA. The finding of an 87% allele frequency of the G1528C mutation in 34 LCHAD deficient patients makes this a valuable test for prenatal diagnosis. Finally, we show that the gene encoding the alpha subunit of MTP is located on chromosome 2p24.1-23.3.
authors.affiliation: Department of Pediatrics, Institute of Human Genetics, University Hospital Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: IJlst
authors.forename: J P
authors.initials: JP
authors.lastname: Ruiter
authors.forename: J M
authors.initials: JM
authors.lastname: Hoovers
authors.forename: M E
authors.initials: ME
authors.lastname: Jakobs
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics*; D001483:Base Sequence; D002889:Chromosomes, Human, Pair 2; D017931:DNA Primers / Q000737:chemistry; D005796:Genes; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics; D063991:Mitochondrial Trifunctional Protein; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics*; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D011994:Recombinant Proteins; D012441:Saccharomyces cerevisiae
chemical_list: D017931:DNA Primers; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063991:Mitochondrial Trifunctional Protein