Glutaric acidemia type II. Heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha subunit of electron transfer flavoprotein in eight patients.
Open Access
- 1 November 1992
- journal article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 90 (5) , 1679-1686
- https://doi.org/10.1172/jci116040
Abstract
We studied metabolic, polypeptide and genetic variation in eight glutaric acidemia type II (GA II) patients with electron transfer flavoprotein (ETF) deficiency. As measured by 3H-fatty acid oxidations in fibroblasts, beta-oxidation pathway flux correlated well with clinical phenotypes. In six patients with severe neonatal onset GA II, oxidation of [9,10(n)-3H]-palmitate ranged from 2% to 22% of control and of [9,10(n)-3H]myristate, from 2% to 26% of control. Of two patients with late onset GA II, one had intermediate residual activities with these substrates and the other normal activities. Radiolabeling and immunoprecipitation studies revealed that three of the six neonatal onset GA II patients had greatly diminished or absent alpha- and beta-ETF subunits, consistent with a failure to assemble a stable heterodimer. Another neonatal onset patient showed normal synthesis of beta-ETF but decreased synthesis of alpha-ETF. Two neonatal onset and two late onset GA II patients showed normal synthesis of both subunits. Analysis of the pre-alpha-ETF coding sequence revealed seven different mutations in the six patients with neonatal onset GA II. The most common mutation was a methionine for threonine substitution at codon 266 found in four unrelated patients, while all the other mutations were seen in single patients. No mutations were detected in the two patients with late onset GA II.Keywords
This publication has 22 references indexed in Scilit:
- Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable mature protein in a patient.1991
- Newly Identified Forms of Electron Transfer Flavoprotein Deficiency in Two Patients with Glutaric Aciduria Type IIPediatric Research, 1991
- Biosynthesis, molecular cloning and sequencing of electron transfer flavoprotein.1990
- Attachment of a 40-base-pair G + C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes.Proceedings of the National Academy of Sciences, 1989
- Molecular cloning and nucleotide sequence of cDNAs encoding the alpha-subunit of human electron transfer flavoprotein.Journal of Biological Chemistry, 1988
- Clinical and Biochemical Variation and Family Studies in the Multiple Acyl-CoA Dehydrogenation DisordersPediatric Research, 1987
- Biosynthesis of electron transfer flavoprotein in a cell-free system and in cultured human fibroblasts. Defect in the alpha subunit synthesis is a primary lesion in glutaric aciduria type II.Journal of Clinical Investigation, 1986
- Molecular heterogeneity of variant isovaleryl-CoA dehydrogenase from cultured isovaleric acidemia fibroblasts.Proceedings of the National Academy of Sciences, 1985
- Nearly all single base substitutions in DNA fragments joined to a GC-clamp can be detected by denaturing gradient gel electrophoresisNucleic Acids Research, 1985
- DNA sequencing with chain-terminating inhibitorsProceedings of the National Academy of Sciences, 1977