Alternative titles; symbols
HGNC Approved Gene Symbol: COX6A1
SNOMEDCT: 1187567002;
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38): 12:120,438,113-120,440,730 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | Charcot-Marie-Tooth disease, recessive intermediate D | 616039 | Autosomal recessive | 3 |
Mammalian cytochrome c oxidase (COX) is a multimeric protein complex comprising 13 different polypeptides, 3 of which are encoded by the mitochondrial genome and the remaining 10 by nuclear genes. COX is the terminal enzyme of the respiratory chain, and the expression of mRNAs encoding all subunits varies during development. For further information on COX, see 123870.
Schlerf et al. (1988) cloned rat Cox6a1 and Cox6a2 (602009). Northern blot analysis of rat tissues showed that Cox6a2 was expressed only in heart and skeletal muscle, whereas Cox6a1 was expressed in liver, kidney, brain, and heart, with weak expression in muscle.
By screening liver and endothelial cell libraries with a rat COX VIa cDNA, Fabrizi et al. (1989) isolated human COX VIa cDNAs. The predicted 86-amino acid human protein shares 87% and 51% identity with rat liver COX VIa and rat heart COX VIa (COX6A2), respectively.
By genomic sequence analysis, Wong-Riley et al. (2000) determined that the COX6A1 gene encodes a 109-amino acid preprotein containing a 24-amino acid presequence followed by an 85-amino acid mature protein. They isolated a full-length COX6A1 cDNA from a brain cDNA library. The brain cDNA encodes a mature protein identical to that encoded by the liver cDNA. In situ hybridization of monkey brain sections using the human brain cDNA detected staining in neuronal cell bodies in all brain regions examined. In cerebellum, Purkinje cell bodies were densely labeled, as were some Golgi cells in the granule cell layer and basket/stellate cells in the molecular layer, while granule cells were only lightly labeled. In the primary visual cortex, COX6A1 mRNA was localized to neuronal cell bodies in various layers. Monocular impulse blockade in adult monkeys induced a downregulation of COX6A1 mRNA in deprived visual neurons, indicating that COX6A1 is regulated by neuronal activity.
Wong-Riley et al. (2000) determined that the COX6A1 gene contains 3 exons. It exhibits several characteristics of a housekeeping gene, including a GC-rich 5-prime end; no closely linked TATA box, although 2 potential CCAAT sequences are present; multiple transcription start sites; and binding sites for several transcription factors, including Sp1 (189906), NRF1 (600879), NRF2 (GABPA; 600609), and YY1 (600013).
Hey et al. (1997) isolated Zeneca YACs corresponding to the COX6A1 gene. PCR primers were designed that distinguished between COX6A1 and its pseudogene (COX6A1P). Somatic cell hybrid analysis and in situ hybridization indicated that COX6A1 maps to chromosome 6p21 and COX6A1P to chromosome 1p31.1.
By Southern blot analysis of liver genomic DNA and by library screening, Merante et al. (1997) identified a total of 4 COX6AL-related sequences, at least 3 of which were pseudogenes. Using in situ hybridization and somatic cell hybrid analysis, they mapped COX6AL-related sequences to chromosomes 12q24.3 and 6p21.1. Merante et al. (1997) determined that there are 2 COX6AL-related sequences on chromosome 6, at least 1 of which is a pseudogene.
By genomic sequence analysis, Wong-Riley et al. (2000) determined that the expressed COX6A1 gene is located in a CpG island on chromosome 12q24.2. They identified 2 additional COX6A1 pseudogenes on chromosomes 7q21 and 7q31-q32.
In 3 Japanese patients from 2 unrelated consanguineous families with autosomal recessive intermediate Charcot-Marie-Tooth disease D (CMTRID; 616039), Tamiya et al. (2014) identified a homozygous 5-bp deletion in the COX6A1 gene (602072.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing, segregated with the disorder in both families, but haplotype analysis did not suggest a founder effect.
Tamiya et al. (2014) found that Cox6a1-null mice had walking difficulties. Histologic examination showed thinned sciatic nerves and neurogenic muscular changes, including small angular fibers and small group atrophy. Electrophysiologic studies showed delayed motor nerve conduction velocities compared to controls. COX activity and ATP contents in liver cells were decreased.
In 3 Japanese patients from 2 unrelated consanguineous families with autosomal recessive intermediate Charcot-Marie-Tooth disease D (CMTRID; 616039), Tamiya et al. (2014) identified a 5-bp deletion (c.247-10_247-6delCACTC, NM_004373.3) in a pyrimidine tract within a splicing element of intron 2 adjacent to the third exon of the COX6A1 gene. The mutation, which was found by a combination of linkage analysis and whole-genome sequencing, segregated with the disorder in both families. The mutation was not found in 1,452 control chromosomes from diverse ethnic groups. Haplotype analysis suggested that the mutation occurred independently in the 2 families, perhaps representing a mutation hotspot. Patient cells showed significantly decreased levels of COX6A1 mRNA and protein, consistent with potential nonsense-mediated mRNA decay. Mitochondrial COX activity and ATP content were also decreased in patient cells.
Lassuthova et al. (2015) identified homozygosity for the same 5-bp deletion, which they referred to as c.247-7_247-3delCACTC (c.247-7_247-3delCACTC, NM_004373.2), in a 37-year-old woman of Czech origin with severe diffuse axonal neuropathy. Her parents were not known to be related. Haplotype analysis showed different haplotypes compared to the Japanese cases reported by Tamiya et al. (2014), suggesting that this is a mutational hotspot.
Fabrizi, G. M., Rizzuto, R., Nakase, H., Mita, S., Kadenbach, B., Schon, E. A. Sequence of a cDNA specifying subunit VIa of human cytochrome c oxidase. Nucleic Acids Res. 17: 6409 only, 1989. [PubMed: 2549515] [Full Text: https://doi.org/10.1093/nar/17.15.6409]
Hey, Y., Hoggard, N., Burt, E., James, L. A., Varley, J. M. Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1p31.1 by in situ hybridization and somatic cell hybrids. Cytogenet. Cell Genet. 77: 167-168, 1997. [PubMed: 9284905] [Full Text: https://doi.org/10.1159/000134565]
Lassuthova, P., Beharka, R., Krutova, M., Neupauerova, J., Seeman, P. COX6A1 mutation causes axonal hereditary motor and sensory neuropathy--the confirmation of the primary report. (Letter) Clin. Genet. 89: 512-514, 2015. [PubMed: 26302975] [Full Text: https://doi.org/10.1111/cge.12649]
Merante, F., Ling, M., Duncan, A. M. V., Duff, C., Robinson, B. H. Cloning, characterization, and chromosomal localization of human liver form cytochrome c oxidase subunit VIa related genes. Genome 40: 325-331, 1997. [PubMed: 9202413] [Full Text: https://doi.org/10.1139/g97-045]
Schlerf, A., Droste, M., Winter, M., Kadenbach, B. Characterization of two different genes (cDNA) for cytochrome c oxidase subunit VIa from heart and liver of the rat. EMBO J. 7: 2387-2391, 1988. [PubMed: 2461293] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03083.x]
Tamiya, G., Makino, S., Hayashi, M., Abe, A., Numakura, C., Ueki, M., Tanaka, A., Ito, C., Toshimori, K., Ogawa, N., Terashima, T., Maegawa, H., Yanagisawa, D., Tooyama, I., Tada, M., Onodera, O., Hayasaka, K. A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 95: 294-300, 2014. [PubMed: 25152455] [Full Text: https://doi.org/10.1016/j.ajhg.2014.07.013]
Wong-Riley, M., Guo, A., Bachman, N. J., Lomax, M. I. Human COX6A1 gene: promoter analysis, cDNA isolation and expression in the monkey brain. Gene 247: 63-75, 2000. [PubMed: 10773445] [Full Text: https://doi.org/10.1016/s0378-1119(00)00121-9]