Alternative titles; symbols
HGNC Approved Gene Symbol: COX8A
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:63,974,620-63,976,543 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | ?Mitochondrial complex IV deficiency, nuclear type 15 | 619059 | Autosomal recessive | 3 |
The COX8A gene encodes the smallest structural component of cytochrome c oxidase (COX; EC 1.9.3.1), the terminal enzyme of the mitochondrial respiratory chain (summary by Hallmann et al., 2016). The COX enzyme couples the transfer of electrons from cytochrome c to molecular oxygen with the concomitant production of a proton electrochemical gradient across the inner mitochondrial membrane. In addition to 3 mitochondrially encoded subunits, which correspond to the 3 subunits of the prokaryotic enzyme and which perform the catalytic function, the eukaryotic enzyme contains additional nuclear-encoded smaller subunits, ranging in number from 4 in some organisms to 10 in mammals. In unicellular organisms, alternative forms of COX subunits are expressed in different phases of the cell cycle. In higher organisms, the specificity of COX appears to reside in the nuclear-encoded subunits, thus accounting for different kinetic and biochemical properties of the enzyme isolated from different tissues, and for the fact that in human COX deficiency diseases the biochemical defect and clinical involvement may be limited to 1 or a few tissues (summary by Rizzuto et al., 1989).
Rizzuto et al. (1989) isolated a full-length cDNA specifying subunit VIII of human COX from a human liver cDNA library. In cows and pigs, the COX VIII of liver is apparently distinct from the COX VIII of heart. Consistent with this, Rizzuto et al. (1989) found that the deduced human polypeptide is 58% identical with COX VIII isolated from beef liver, but only 38% identical with COX VIII isolated from beef heart. Transcriptional analysis, however, showed that an mRNA identical with the isolated cDNA is present in abundance not only in human and monkey liver tissue, but also in heart and skeletal muscle, tissues not known previously to contain this isoform. Since the only COX VIII subunit found in human heart agrees 100% with the polypeptide deduced from this COX8, in distinction to what has been observed in other mammals, only 1 form of COX VIII exists in primates. This suggests that the putative gene duplication event that gave rise to 2 COX VIII isoforms occurred after the divergence of primates from other mammals, or, more likely, that the duplication event occurred before the mammalian radiation, but that in primates the heart isoform gene was silenced in a manner similar to the silencing of the delta-globin gene (142000) in Old World monkeys.
By genomic Southern hybridization analysis, Rizzuto et al. (1989) detected a single hybridizing human band and showed in Chinese hamster x human somatic cell hybrids that the human-specific COX8 restriction fragment was concordant with human chromosome 11. By in situ hybridization to human metaphase chromosomes, they were able to regionalize the gene to 11q12-q13. Richard et al. (1991) described a high resolution radiation hybrid map of 11q12-q13, which placed COX8 between FTH1 (134770) and PYGM (608455).
Courseaux et al. (1996) used a combination of methods to refine maps of an approximately 5-Mb region of 11q13. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel.
In a 12.5-year old girl, born of Turkish parents who were likely distantly related, with mitochondrial complex IV deficiency nuclear type 15 (MC4DN15; 619059), Hallmann et al. (2016) identified a homozygous splice site mutation in the COX8A gene (123870.0001). The mutation was found by exome sequencing. Patient skeletal muscle and fibroblasts showed about 10% residual complex IV activity and a marked reduction of the fully assembled COX complex, consistent with a loss of function. The patient had infantile primary pulmonary hypertension, microcephaly, global developmental delay, poor feeding, scoliosis, drug-resistant seizures, and hypotonia with spasticity, and was nonambulatory. Brain imaging showed abnormal T2-weighted signals and enlarged ventricles. She died at age 12.5 from cardiorespiratory failure associated with infection and metabolic crisis.
In a 12.5-year old girl, born of Turkish parents who were likely distantly related, with mitochondrial complex IV deficiency nuclear type 15 (MC4DN15; 619059), Hallmann et al. (2016) identified a homozygous G-to-C transversion in intron 1 of the COX8A gene (c.115-1G-C), resulting in a splice site mutation. The mutation, which was found by exome sequencing, was filtered against the dbSNP (build 135), 1000 Genomes Project, and Exome Variant Server databases, and an in-house database of 511 epilepsy patients. Patient cells showed decreased amounts of an aberrantly spliced COX8A transcript. Patient skeletal muscle and fibroblasts showed about 10% residual complex IV activity, consistent with a loss of function. Patient cells also showed a marked reduction of the fully assembled COX complex. Expression of wildtype COX8A in patient fibroblasts restored the deficient COX activity.
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
Hallmann, K., Kudin, A. P., Zsurka, G., Kornblum, C., Reimann, J., Stuve, B., Waltz, S., Hattingen, E., Thiele, H., Nurnberg, P., Rub, C., Voos, W., Kopatz, J., Neumann, H., Kunz, W. S. Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. Brain 139: 338-345, 2016. [PubMed: 26685157] [Full Text: https://doi.org/10.1093/brain/awv357]
Richard, C. W., Withers, D. A., Meeker, T. C., Myers, R. M. A radiation hybrid map of the proximal long arm of human chromosome 11 containing the MEN-1 and bcl-1 disease locus. (Abstract) Cytogenet. Cell Genet. 58: 1970 only, 1991.
Rizzuto, R., Nakase, H., Darras, B., Francke, U., Fabrizi, G. M., Mengel, T., Walsh, F., Kadenbach, B., DiMauro, S., Schon, E. A. A gene specifying subunit VIII of human cytochrome c oxidase is localized to chromosome 11 and is expressed in both muscle and non-muscle tissues. J. Biol. Chem. 264: 10595-10600, 1989. [PubMed: 2543673]