| *231675 | ||||||||||||||||||
| ELECTRON TRANSFER FLAVOPROTEIN DEHYDROGENASE; ETFDH | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| ELECTRON TRANSFER FLAVOPROTEIN:UBIQUINONE OXIDOREDUCTASE; ETFQO | ||||||||||||||||||
| HGNC Approved Gene Symbol: ETFDH | ||||||||||||||||||
| Cytogenetic location: 4q32.1 Genomic coordinates (GRCh37): 4:159,593,276 - 159,629,841 (from NCBI) | ||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||
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| TEXT | ||||||||||||||||||
| Description | ||||||||||||||||||
| 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; 130410) and contains 1 flavin adenine dinucleotide (FAD) and 1 adenosine 5-prime monophosphate (AMP) per heterodimer. ETFDH, 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. | ||||||||||||||||||
| Gene Structure | ||||||||||||||||||
| Olsen et al. (2003) determined that the ETFDH gene contains 13 exons. | ||||||||||||||||||
| Mapping | ||||||||||||||||||
| By analysis of mouse/human and CHO/human hybrid panels and by in situ hybridization, Beard et al. (1993) demonstrated that the ETFDH gene is located on 4q32-qter. White et al. (1996) demonstrated that the corresponding gene is located on mouse chromosome 3. | ||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||
| In 4 patients with multiple acyl-CoA dehydrogenase deficiency (MADD; 231680), also known as glutaric acidemia IIC, Beard et al. (1993) identified 5 mutations in the ETFDH gene (see, e.g., 231675.0001). All 5 mutations were rare and caused total lack of enzyme activity and antigen. In 4 Taiwanese patients from 3 unrelated families with MADD, Liang et al. (2009) identified homozygous or compound heterozygous mutations in the ETFDH gene (231675.0003-231675.0005). The A84T mutation (231675.0003) was present in all 4 patients. | ||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||
| Table View | ||||||||||||||||||
| .0001 GLUTARIC ACIDEMIA IIC | ||||||||||||||||||
| ETFDH, MET1THR [dbSNP:rs121964953] | ||||||||||||||||||
| In a patient with type IIC glutaric acidemia, also known as multiple acyl-CoA dehydrogenase deficiency (231680), Beard et al. (1993) identified a T-to-C transition in the triplet encoding the initiator methionine of the ETFDH gene. The mutation resulted in total loss of enzyme activity and antigen. | ||||||||||||||||||
| .0002 GLUTARIC ACIDEMIA IIC | ||||||||||||||||||
| ETFDH, 1-BP DEL, 36A | ||||||||||||||||||
| In an infant with the neonatal-onset form of glutaric acidemia IIC with congenital anomalies (231680), Olsen et al. (2003) found homozygosity for a 1-bp deletion of 36A in the ETFDH gene, causing a frameshift beginning with ala12, introducing a stop codon at amino acid 19. The parents were consanguineous. The child died 1 hour after birth and showed Potter face, enlarged polycystic kidneys, symmetrical warty dysplasia of the cerebral cortex, bile duct hypoplasia, cholestasis, fatty degeneration of the liver, siderosis, lung hypoplasia, and steatosis of the myocardium. A second child in the family presented at birth with similar clinical and morphologic findings. The patient had been previously reported by Lehnert et al. (1982) and Bohm et al. (1982). | ||||||||||||||||||
| .0003 GLUTARIC ACIDEMIA IIC | ||||||||||||||||||
| ETFDH, ALA84THR [dbSNP:rs121964954] | ||||||||||||||||||
| In 4 Taiwanese patients from 3 unrelated families with MADD (231680), Liang et al. (2009) identified a 250G-A transition in exon 3 of the ETFDH gene, resulting in an ala84-to-thr (A84T) substitution. One patient was homozygous for the mutation, whereas the other 3 were compound heterozygous for A84T and either a 524G-T transversion, resulting in an arg175-to-leu (R175L; 231675.0004) substitution (2 sibs) or a 380T-A transversion, resulting in a leu127-to-his (L127H; 231675.0005) substitution. All 3 mutations affected highly conserved residues in the FAD-binding domain. The R175L and L127H mutations were not identified in 200 Taiwanese control chromosomes. The A84T variant was identified in 1 of 200 Taiwanese control chromosomes but not in 100 Japanese, 100 Korean, and 100 Thai control chromosomes. No specific haplotype could be linked to the A84T variant. | ||||||||||||||||||
| .0004 GLUTARIC ACIDEMIA IIC | ||||||||||||||||||
| ETFDH, ARG175LEU [dbSNP:rs121964955] | ||||||||||||||||||
| See 231675.0003 and Liang et al. (2009). | ||||||||||||||||||
| .0005 GLUTARIC ACIDEMIA IIC | ||||||||||||||||||
| ETFDH, LEU127HIS [dbSNP:rs121964956] | ||||||||||||||||||
| See 231675.0003 and Liang et al. (2009). | ||||||||||||||||||
| REFERENCES | ||||||||||||||||||
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