HGNC Approved Gene Symbol: ETFA
Cytogenetic location: 15q24.2-q24.3 Genomic coordinates (GRCh38) : 15:76,215,353-76,311,469 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.2-q24.3 | Glutaric acidemia IIA | 231680 | Autosomal recessive | 3 |
Electron transfer flavoprotein (ETF) exists in the mitochondrial matrix as a heterodimer of 30-kD alpha subunits (ETFA) and 28-kD beta subunits (ETFB; 130410) and contains 1 flavin adenine dinucleotide (FAD) and 1 adenosine 5-prime monophosphate (AMP) per heterodimer. ETFDH (231675), a 64-kD monomer integrated in the inner mitochondrial membrane, contains 1 molecule of FAD and a 4Fe-4S cluster. Both enzymes are required for electron transfer from at least 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Multiple acyl-CoA dehydrogenation deficiency (MADD; 231680), also known as glutaric acidemia II or glutaric aciduria II, can be caused by mutation in any of the 3 ETF genes. The disorders resulting from defects in the ETFA, ETFB, and ETFDH genes are referred to as glutaric acidemia IIA, IIB, and IIC, respectively, although there appears to be no difference in the clinical phenotypes.
Finocchiaro et al. (1988) cloned and sequenced cDNAs encoding the precursor of the alpha subunit of ETF. The cDNAs contained the entire coding region of 333 amino acids. The calculated molecular mass of the human precursor was 35,084.
Olsen et al. (2003) identified an alternatively spliced form of ETFA that lacks exon 2. The resulting protein has a 49-amino acid deletion compared with the full-length form.
Olsen et al. (2003) determined that the ETFA gene contains 12 exons.
By Southern analysis of somatic cell hybrid DNA and in situ hybridization using a cDNA clone, Finocchiaro et al. (1987) and Barton et al. (1987) showed that the ETFA gene is located on chromosome 15q23-q25.
White et al. (1996) demonstrated that the homologous gene in the mouse (Etfa) is located on chromosome 13.
Indo et al. (1991), Rhead et al. (1992), and Freneaux et al. (1992) identified mutations in the ETFA gene in patients with glutaric acidemia IIA (e.g., 608053.0001).
In a patient with glutaric acidemia IIA (231680), Indo et al. (1991) identified a transversion of T470 to G in the ETFA gene. The transversion caused substitution of glycine for valine-157 and resulted in an unstable ETFA. The patient was homozygous. Freneaux et al. (1992) found the same mutation in a compound heterozygote with neonatal onset.
In 4 unrelated patients with glutaric acidemia IIA (231680), Rhead et al. (1992) and Freneaux et al. (1992) found a substitution of methionine for threonine at codon 266. One of the patients was homozygous for the thr266-to-met mutation (T266M); the other 3 were compound heterozygotes. All 4 showed neonatal onset.
In a Belgian infant with glutaric acidemia IIA of the clinical form II (neonatal onset without congenital anomalies), Olsen et al. (2003) found compound heterozygosity for 2 mutations in the ETFA gene: the T266M mutation in exon 9 and a 1-bp deletion of the consensus G at the 5-prime donor splice site of intron 11 (IVS11+1delG; 608053.0005), resulting in an 81-bp deletion in the cDNA and deletion of thr295 to lys321 in the protein.
In a patient with neonatal-onset glutaric acidemia IIA (231680), Freneaux et al. (1992) found compound heterozygosity for the thr266-to-met mutation (231680.0002) and another mutation involving a G-to-A transition at nucleotide 346 resulting in a gly116-to-arg substitution.
In a patient with neonatal-onset glutaric acidemia IIA (231680), Freneaux et al. (1992) found compound heterozygosity for the thr266-to-met mutation (231680.0002) and a 3-bp deletion of nucleotides 808-810 (or 809-811), resulting in deletion of codon 270 (phenylalanine).
In a Belgian infant with glutaric acidemia IIA (231680) of the clinical form II (neonatal onset without congenital anomalies), Olsen et al. (2003) found compound heterozygosity for 2 mutations in the ETFA gene: the thr266-to-met mutation (T266M; 608053.0002) in exon 9 and a 1-bp deletion of the consensus G at the 5-prime donor splice site of intron 11 (IVS11+1delG), resulting in an 81-bp deletion in the cDNA and deletion of thr295 to lys321 in the protein.
Barton, D. E., Yang-Feng, T. L., Finocchiaro, G., Ozasa, H., Tanaka, K., Francke, U. Short chain acyl-CoA dehydrogenase (ACADS) maps to chromosome 12 (q22-qter) and electron transfer flavoprotein (ETFA) to 15 (q23-q25). (Abstract) Cytogenet. Cell Genet. 46: 577-578, 1987.
Finocchiaro, G., Ikeda, Y., Barton, D., Francke, U., Tanaka, K. Molecular cloning and gene mapping of alpha-subunit of human electron transfer flavoprotein. (Abstract) Am. J. Hum. Genet. 41: A214, 1987.
Finocchiaro, G., Ito, M., Ikeda, Y., Tanaka, K. Molecular cloning and nucleotide sequence of cDNAs encoding the alpha-subunit of human electron transfer flavoprotein. J. Biol. Chem. 263: 15773-15780, 1988. [PubMed: 3170610]
Freneaux, E., Sheffield, V. C., Molin, L., Shires, A., Rhead, W. J. 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. J. Clin. Invest. 90: 1679-1686, 1992. [PubMed: 1430199] [Full Text: https://doi.org/10.1172/JCI116040]
Indo, Y., Glassberg, R., Yokota, I., Tanaka, K. 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. Am. J. Hum. Genet. 49: 575-580, 1991. [PubMed: 1882842]
Olsen, R. K. J., Andresen, B. S., Christensen, E., Bross, P., Skovby, F., Gregersen, N. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum. Mutat. 22: 12-23, 2003. [PubMed: 12815589] [Full Text: https://doi.org/10.1002/humu.10226]
Rhead, W. J., Freneaux, E., Sheffield, V. C., Molin, L., Shires, A. Glutaric acidemia type II (GAII): heterogeneity in beta-oxidation flux, polypeptide synthesis and cDNA mutations in the alpha-subunit of electron transfer flavoprotein in 8 patients. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A175, 1992.
White, R. A., Dowler, L. L., Angeloni, S. V., Koeller, D. M. Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and 13: the mouse homologs of genes responsible for glutaric acidemia type II in human. Genomics 33: 131-134, 1996. [PubMed: 8617498] [Full Text: https://doi.org/10.1006/geno.1996.0170]