Alternative titles; symbols
HGNC Approved Gene Symbol: COX11
Cytogenetic location: 17q22 Genomic coordinates (GRCh38): 17:54,951,902-54,968,785 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q22 | Mitochondrial complex IV deficiency, nuclear type 23 | 620275 | Autosomal recessive | 3 |
COX11 is a nuclear-encoded subunit of cytochrome c oxidase (COX; EC 1.9.3.1), the terminal component of the mitochondrial respiratory chain.
By searching an EST database for sequences related to S. cerevisiae cox11, Petruzzella et al. (1998) identified cDNAs encoding human COX11. The predicted 276-amino acid protein is 41% identical to yeast cox11. Sequence analysis indicated that COX11 contains a mitochondrial leader peptide and a putative transmembrane domain. Using in vitro mitochondrial import and trypsin-protection assays, Petruzzella et al. (1998) demonstrated that the COX11 protein is targeted to mitochondria. Northern blot analysis revealed that COX11 was expressed as 1.7- and 2.7-kb mRNAs in all tissues tested.
Based on sequence similarity to ESTs and analysis of somatic cell hybrids, Petruzzella et al. (1998) mapped the COX11 gene to chromosome 17q22 and a COX11 pseudogene to 6p23-p22.
In 2 unrelated patients, born to consanguineous parents, with mitochondrial complex IV deficiency nuclear type 23 (MC4DN23; 620275), Rius et al. (2022) identified homozygous mutations in the COX11 gene (603648.0001; 603648.0002). The mutations, which were identified by trio whole-exome sequencing, were present in heterozygous state in both sets of parents. Analysis of mitochondria from fibroblasts from patient X1 demonstrated a modest reduction in complex IV assembly and a reduction of respiration-derived ATP. The reduction in respiration-derived ATP was corrected in vitro by treatment with coenzyme Q10.
Caron-Godon et al. (2023) identified compound heterozygous mutations in the COX11 gene (c.766dupA, 603648.0003 and P247T, 603648.0004) in a patient with MC4DN23. cDNA analysis in fibroblasts from the patient demonstrated that the mutations resulted in a relative decrease in complex IV function and were not subject to nonsense-mediated decay. Studies in patient muscle tissue demonstrated decreased COX11 protein expression. Caron-Godon et al. (2023) generated S. cerevisiae with compound heterozygous mutations in cox11: a c.238T mutation corresponding to the human P247T mutation, and a Y250X mutation to mimic the effects of the human c.766dupA mutation. The Y250X mutation resulted in increased sensitivity to oxidative stress and complete respiratory deficiency when grown on glycerol and ethanol carbon sources.
In a patient (patient X1), born to consanguineous parents, with mitochondrial complex IV deficiency nuclear type 23 (MC4DN23; 620275), Rius et al. (2022) identified homozygosity for a c.730G-C transversion (c.730G-C, NM_004375.4) in the COX11 gene, resulting in an ala244-to-pro (A244P) substitution at a conserved residue. The mutation, which was identified by trio genome sequencing, was present in heterozygous state in the parents. Sanger sequencing identified the mutation in heterozygosity in the patient's unaffected sibs. The variant was not present in the gnomAD database (v3.1.2). Analysis of mitochondria from patient fibroblasts demonstrated a modest reduction in complex IV assembly and a reduction of respiration-derived ATP.
In a patient (patient X2), born to consanguineous parents, with mitochondrial complex IV deficiency nuclear type 23 (MC4DN23; 620275), Rius et al. (2022) identified homozygosity for a c.35_36delinsG (c.35_36delinsG, NM_004375.4) in the COX11 gene, resulting in a frameshift and premature termination (Val12GlyfsTer21). The mutation was identified by trio exome sequencing, and Sanger sequencing showed that the parents and an unaffected sib were heterozygous for the mutation. The mutation was not present in the gnomAD database (v2.1.1). Transcript analysis in patient blood demonstrated that the mutant COX11 transcript was expressed, leading Rius et al. (2022) to conclude that the mutation resulted in a truncated protein rather than nonsense-mediated mRNA decay.
In a patient with mitochondrial complex IV deficiency nuclear type 23 (MC4DN23; 620275), Caron-Godon et al. (2023) identified compound heterozygous mutations in the COX11 gene: a 1-bp duplication (c.766dupA, NM004375.5) in the final exon of the gene, predicted to result in a frameshift (Thr256AsnfsTer8) in the C-terminal region, replacing the last 21 amino acids with 7 alternative residues, and a c.739C-A transversion (c.739C-A, NM_004375.5), resulting in a pro247-to-thr (P247T; 603648.0004) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were confirmed to be in the carrier state in the parents. The P247T mutation was not present in the gnomAD database (v4.0), and the c.766dupA mutation was present at an allele frequency of 4x10(-6) with no homozygotes. cDNA analysis in fibroblasts from patients demonstrated that both mutations resulted in a relative decrease in complex IV function and were not subject to nonsense-mediated decay. Studies in patient muscle tissue demonstrated decreased COX11 protein expression.
For a discussion of the c.739C-A transversion (c.739C-A, NM_004375.5) in the COX11 gene, resulting in a pro247-to-thr (P247T) substitution, that was identified in compound heterozygous state in a patient with mitochondrial complex IV deficiency nuclear type 23 (MC4DN23; 620275) by Caron-Godon et al. (2023), see 603648.0003.
Caron-Godon, C. A., Della Vecchia, S., Romano, A., Doccini, S., Dal Canto, F., Pasquariello, R., Rubegni, A., Battini, R., Santorelli, F. M., Glerum, D. M., Nesti, C. Novel COX11 mutations associated with mitochondrial disorder: functional characterization in patient fibroblasts and Saccharomyces cerevisiae. Int. J. Molec. Sci. 24: 16636, 2023. [PubMed: 38068960] [Full Text: https://doi.org/10.3390/ijms242316636]
Petruzzella, V., Tiranti, V., Fernandez, P., Ianna, P., Carrozzo, R., Zeviani, M. Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain. Genomics 54: 494-504, 1998. [PubMed: 9878253] [Full Text: https://doi.org/10.1006/geno.1998.5580]
Rius, R., Bennett, N. K., Bhattacharya, K., Riley, L. G., Yuksel, Z., Formosa, L. E., Compton, A. G., Dale, R. C., Cowley, M. J., Gayevskiy, V., Al Tala, S. M., Almehery, A. A., Ryan, M. T., Thorburn, D. R., Nakamura, K., Christodoulou, J. Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy. Hum. Mutat. 43: 1970-1978, 2022. [PubMed: 36030551] [Full Text: https://doi.org/10.1002/humu.24453]