Alternative titles; symbols
HGNC Approved Gene Symbol: ATP5F1E
Cytogenetic location: 20q13.32 Genomic coordinates (GRCh38) : 20:59,025,475-59,032,335 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.32 | Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 | 614053 | Autosomal recessive | 3 |
The mitochondrial F1Fo-ATP synthase complex (EC 3.6.1.34) uses energy derived from a proton gradient to synthesize ATP. The structure of this complex has been referred to as a 'lollipop,' as the soluble F1 catalytic unit is attached to the mitochondrial inner membrane via the Fo unit. The F1 unit consists of 5 subunit types assembled with a stoichiometry of 3 alpha, 3 beta, 1 gamma, 1 delta, and 1 epsilon (summary by Walker, 1995).
The ATP5E gene encodes the epsilon subunit of the mitochondrial ATPase F1 complex (Tu et al., 2000).
By EST database searching with the bovine ATP synthase epsilon subunit and screening of heart, skeletal muscle, and spleen cDNA libraries, Tu et al. (2000) constructed a full-length ATP5E cDNA encoding a 51-amino acid protein that shares 94% sequence identity with the bovine homolog. Northern blot analysis detected ubiquitous expression of a single transcript of approximately 0.6 kb, with highest expression in heart and skeletal muscle, intermediate or low expression in several other tissues, and barely detectable expression in lung and ovary. Tu et al. (2000) compared the sequence of ATP5E proteins in 10 different organisms and identified a conserved motif composed of 24 amino acids. The high degree of conservation indicates that this domain might be an important functional site.
Tu et al. (2000) determined that the ATP5E gene contains 3 exons and spans approximately 5 kb.
By radiation hybrid analysis, Tu et al. (2000) mapped the ATP5E gene to chromosome 20q13.3. They also mapped an ATP5E pseudogene (ATP5EP1) to chromosome 4q25.
Mayr et al. (2010) described a 22-year-old Austrian woman (P3), previously reported by Cizkova et al. (2008), with mitochondrial complex V deficiency (MC5DN3; 614053). She had a history of neonatal-onset lactic acidosis, 3-methylglutaconic aciduria, mildly impaired intellectual development, and peripheral neuropathy. Her fibroblasts showed a 60 to 70% decrease in both oligomycin-sensitive ATPase activity and mitochondrial ATP synthesis. The mitochondrial content of the ATP synthase complex was equally reduced, but its size was normal. The patient was found to be homozygous for a tyr12-to-cys (Y12C) missense mutation in the ATP5E gene (606153.0001). Mayr et al. (2010) concluded that the epsilon subunit plays an essential role in the biosynthesis and assembly of the F1 part of the ATP synthase. They also suggested that the epsilon subunit may be involved in the incorporation of subunit c to the rotor structure of the mammalian enzyme.
In 2 unrelated patients (P2 and P3) with MC5DN3, Zech et al. (2022) identified a homozygous Y12C mutation in the ATP5F1E gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Fibroblasts from patient 2 showed decreased amounts of the ATPase marker ATP5F1A (164360) and reduced oxygen consumption rate, consistent with a mitochondrial defect. These patients were ascertained from a large cohort of 2,962 individuals with mitochondrial disease or dystonia who underwent whole-exome sequencing.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human ATP5E is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a 22-year-old Austrian woman with mitochondrial complex V deficiency (MC5DN3; 614053), Mayr et al. (2010) identified a homozygous c.35A-G transition in exon 2 of the ATP5E gene, resulting in a tyr12-to-cys (Y12C) substitution at a highly conserved position. The healthy, nonconsanguineous parents were heterozygous for the mutation, which was not found in 180 Austrian control chromosomes.
In 2 unrelated patients (P2 and P3) with MC5DN3, Zech et al. (2022) identified a homozygous Y12C mutation (c.35A-G, NM_006886.4) in the ATP5F1E gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Fibroblasts from patient 2 showed decreased amounts of the ATPase marker ATP5F1A (164360) and reduced oxygen consumption rate, consistent with a mitochondrial defect.
Cizkova, A., Stranecky, V., Mayr, J. A., Tesarova, M., Havlickova, V., Paul, J., Ivanek, R., Kuss, A. W., Hansikova, H., Kaplanova, V., Vrbacky, M., Hartmannova, H., and 9 others. TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nature Genet. 40: 1288-1290, 2008. [PubMed: 18953340] [Full Text: https://doi.org/10.1038/ng.246]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Mayr, J. A., Havlickova, V., Zimmermann, F., Magler, I., Kaplanova, V., Jesina, P., Pecinova, A., Nuskova, H., Koch, J., Sperl, W., Houstek, J. Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum. Molec. Genet. 19: 3430-3439, 2010. [PubMed: 20566710] [Full Text: https://doi.org/10.1093/hmg/ddq254]
Tu, Q., Yu, L., Zhang, P., Zhang, M., Zhang, H., Jiang, J., Chen, C., Zhao, S. Cloning, characterization and mapping of the human ATP5E gene, identification of pseudogene ATP5EP1, and definition of the ATP5E motif. Biochem. J. 347: 17-21, 2000. [PubMed: 10727396]
Walker, J. E. Determination of the structures of respiratory enzyme complexes from mammalian mitochondria. Biochim. Biophys. Acta 1271: 221-227, 1995. [PubMed: 7599212] [Full Text: https://doi.org/10.1016/0925-4439(95)00031-x]
Zech, M., Kopajtich, R., Steinbrucker, K., Bris, C., Gueguen, N., Feichtinger, R. G., Achleitner, M. T., Duzkale, N., Perivier, M., Koch, J., Engelhardt, H., Freisinger, P., and 22 others. Variants in mitochondrial ATP synthase cause variable neurologic phenotypes. Ann. Neurol. 91: 225-237, 2022. [PubMed: 34954817] [Full Text: https://doi.org/10.1002/ana.26293]