HGNC Approved Gene Symbol: ETFB
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38) : 19:51,345,155-51,366,388 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.41 | Glutaric acidemia IIB | 231680 | Autosomal recessive | 3 |
Electron transfer flavoprotein (ETF) exists in the mitochondrial matrix as a heterodimer of 30-kD alpha subunits (ETFA; 608053) and 28-kD beta subunits (ETFB) 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. (1989) cloned the gene for the beta subunit of human electron transfer flavoprotein.
Olsen et al. (2003) determined that the ETFB gene contains 6 exons.
Finocchiaro et al. (1989) mapped the ETFB gene to chromosome 19 by Southern analysis of somatic cell hybrid DNAs. Antonacci et al. (1994) assigned the ETFB gene to 19q13.3 by Southern analysis of somatic cell hybrids and fluorescence in situ hybridization. White et al. (1996) mapped the corresponding gene to mouse chromosome 7.
Rhein et al. (2014) determined that lys199 and lys202 of mature ETF-beta (i.e., ETF-beta lacking the N-terminal methionine) were trimethylated in bovine and human mitochondria. Affinity purification experiments showed interaction between ETF-beta and the lysine methyltransferase METTL20 (615256). Overexpression of METTL20 in HEK293T cells led to increased trimethylation of lys199 and lys202 of ETF-beta, whereas suppression of METTL20 via small interfering RNA (siRNA) in human 143B cells resulted in significant reduction in ETF-beta methylation. Suppression of trimethylation of Etf-beta via siRNA against Mettl20 in mouse C2C12 myoblasts oxidizing palmitate as an energy source reduced the consumption of oxygen by the cells. Rhein et al. (2014) concluded that oxidation of fatty acids in mitochondria and passage of electrons via ETF may be controlled by modulating interactions between reduced dehydrogenases and ETF-beta by trimethylation of lysine residues by METTL20.
Independently, Malecki et al. (2015) found that recombinant human METTL20 methylated ETF-beta in human cells. METTL20 specifically methylated lys200 and lys203 of full-length ETF-beta, both in vitro and in human cells. METTL20-mediated methylation of ETF-beta in vitro reduced the ability of ETF-beta to receive electrons from medium-chain acyl-CoA dehydrogenase (ACADM; 607008) and glutaryl-CoA dehydrogenase (GCDH; 608801). Malecki et al. (2015) proposed that METTL20 may regulate cellular metabolism by modulating interaction of ETF-beta and dehydrogenases.
Royal et al. (1991) demonstrated a 2-allele RFLP of the ETFB gene; the frequencies of the alternative alleles were 0.51 and 0.49.
Colombo et al. (1994) identified mutations in the ETFB gene in patients with glutaric acidemia IIB (e.g., 130410.0001).
In a series of 9 patients with glutaric acidemia II, Olsen et al. (2003) identified a defect in the ETFB gene in each of 3 patients representing the 3 different clinical forms of the disorder: the neonatal-onset form with congenital anomalies (type I), the neonatal-onset form without congenital anomalies (type II), and the late-onset form (type III).
In 2 Japanese brothers with glutaric acidemia IIB (231680), Colombo et al. (1994) demonstrated compound heterozygosity for mutations at the ETFB gene. One allele carried a G-to-A transition at nucleotide 518, causing a change of codon 164 from arginine to glutamine. The other allele carried a G-to-C transversion at the first nucleotide of the intron donor site (130410.0002), downstream of an exon that is skipped during the splicing event, and a deletion of 159 bp, spanning nucleotides 466 through 624 and leading to the removal of 53 amino acids and no interruption of the open reading frame.
For discussion of the splice site mutation in the ETFB gene that was found in compound heterozygous state in 2 Japanese brothers with glutaric acidemia IIB (231680) by Colombo et al. (1994), see 130410.0001.
In a patient with the late-onset form (type III) of multiple acyl-CoA dehydrogenase deficiency (MADD; 231680), Olsen et al. (2003) found homozygosity for an asp128-to-asn (D128N) mutation in exon 4 of the ETFB gene. The patient was born of consanguineous Kurdish parents and had been reported by Lundemose et al. (1997). Both parents were heterozygous for the mutation. The child died in its first episode during varicella infection at 21 months of age. A previous child had died unexpectedly at the age of 6 months. Slight stasis and edema of the lungs and notable fatty infiltration in the liver were found at autopsy.
Antonacci, R., Colombo, I., Archidiacono, N., Volta, M., DiDonato, S., Finocchiaro, G., Rocchi, M. Assignment of the gene encoding the beta-subunit of the electron-transfer flavoprotein (ETFB) to human chromosome 19q13.3. Genomics 19: 177-179, 1994. [PubMed: 8188225] [Full Text: https://doi.org/10.1006/geno.1994.1035]
Colombo, I., Finocchiaro, G., Garavaglia, B., Garbuglio, N., Yamaguchi, S., Frerman, F. E., Berra, B., DiDonato, S. Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaric acidemia type II. Hum. Molec. Genet. 3: 429-435, 1994. [PubMed: 7912128] [Full Text: https://doi.org/10.1093/hmg/3.3.429]
Finocchiaro, G., Archidiacono, N., Gellera, C., Bloisi, W., Colombo, I., Valdameri, G., Romeo, G., Tanaka, K., Di Donato, S. Molecular cloning and chromosomal localization of the beta-subunit of human electron transfer flavoprotein (ETF). (Abstract) Am. J. Hum. Genet. 45: A185, 1989.
Lundemose, J. B., Kolvraa, S., Gregersen, N., Christensen, E., Gregersen, M. Fatty acid oxidation disorders as primary cause of sudden and unexpected death in infants and young children: an investigation performed on cultured fibroblasts from 79 children who died aged between 0-4 years. Molec. Path. 50: 212-217, 1997. [PubMed: 9350306] [Full Text: https://doi.org/10.1136/mp.50.4.212]
Malecki, J., Ho, A. Y. Y., Moen, A., Dahl, H.-A., Falnes, P. O. Human METTL20 is a mitochondrial lysine methyltransferase that targets the beta subunit of electron transfer flavoprotein (ETF-beta) and modulates its activity. J. Biol. Chem. 290: 423-434, 2015. [PubMed: 25416781] [Full Text: https://doi.org/10.1074/jbc.M114.614115]
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]
Rhein, V. F., Carroll, J., He, J., Ding, S., Fearnley, I. M., Walker, J. E. Human METTL20 methylates lysine residues adjacent to the recognition loop of the electron transfer flavoprotein in mitochondria. J. Biol. Chem. 289: 24640-24651, 2014. [PubMed: 25023281] [Full Text: https://doi.org/10.1074/jbc.M114.580464]
Royal, V., Alberts, M. J., Pericak-Vance, M. A., Finocchiaro, G., Bebout, J., Yamaoka, L., Hung, W.-Y., Gaskell, P. C., Roses, A. D. RsaI RFLP for electron transport flavoprotein-beta (ETFB). Nucleic Acids Res. 19: 4021 only, 1991. [PubMed: 1677763] [Full Text: https://doi.org/10.1093/nar/19.14.4021]
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]