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

Eric Freneaux; Val C Sheffield; Lisa Molin; Ann Shires; William J Rhead

doi:10.1172/JCI116040

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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

Journal article

Open access

Peer reviewed

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

Eric Freneaux, Val C Sheffield, Lisa Molin, Ann Shires and William J Rhead

The Journal of clinical investigation, Vol.90(5), pp.1679-1686

11/1992

DOI: 10.1172/JCI116040

PMCID: PMC443224

PMID: 1430199

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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.

Mutation

Polymerase Chain Reaction

Lipid Metabolism, Inborn Errors - genetics

Lipid Metabolism, Inborn Errors - metabolism

Oxidation-Reduction

Flavoproteins - genetics

Humans

Cells, Cultured

Electron-Transferring Flavoproteins

Molecular Sequence Data

Glutarates - blood

DNA - genetics

Amino Acid Metabolism, Inborn Errors - metabolism

Peptide Biosynthesis

Amino Acid Metabolism, Inborn Errors - genetics

Base Sequence

Fatty Acids - metabolism

Details

Title: Subtitle: 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
Creators: Eric Freneaux - Department of Pediatrics, University of Iowa, Iowa City 52242
Val C Sheffield
Lisa Molin
Ann Shires
William J Rhead
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.90(5), pp.1679-1686
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI116040
PMID: 1430199
PMCID: PMC443224
ISSN: 0021-9738
eISSN: 1558-8238
Grant note: HG00457 / NHGRI NIH HHS\nP30HD27748 / NICHD NIH HHS\nDK-33289 / NIDDK NIH HHS
Language: English
Date published: 11/1992
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9984065485502771

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