Alternative titles; symbols
HGNC Approved Gene Symbol: COA7
Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38) : 1:52,684,449-52,698,347 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32.3 | Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 | 618387 | Autosomal recessive | 3 |
The COA7 gene encodes a protein that localizes to the mitochondria and is involved in the assembly of mitochondrial complex IV, which is the terminal component of the mitochondrial respiratory chain (summary by Martinez Lyons et al., 2016).
COA7 is predicted to have a role in assembling mitochondrial complexes that function in oxidative phosphorylation (Kozjak-Pavlovic et al., 2014).
Kozjak-Pavlovic et al. (2014) reported that human COA7, which they called C1ORF163, encodes a 231-amino acid protein that shares sequence similarity with beta-lactamase (LACTB; 608440). The protein is rich in cysteine and has 5 predicted Sel1-like repeats (SLRs). SLRs share similarity with C. elegans Sel1 (see 602329) and are predicted to be involved in protein-protein interactions. C1ORF163 localized to mitochondria in HeLa cells. Extraction and swelling experiments revealed that C1ORF163 is a soluble protein of the inner mitochondrial space. Database analysis found conservation of C1ORF163 from bacteria to human.
Higuchi et al. (2018) found expression of the COA7 gene in the cytoplasm of Schwann cells of human sural nerve.
Kozjak-Pavlovic et al. (2014) found that knockdown of SAM50 (SAMM50; 612058) or mitofilin (IMMT; 600378) in HeLa cells reduced the protein content of C1ORF163. Knockdown of C1ORF163 via short hairpin RNA reduced the content of mitochondrial complex IV proteins and the number of mature complex IV complexes. Knockdown of C1ORF163 had weaker effects on complex I, III, and V proteins, and had no effect on complex II proteins. Knockdown of C1ORF163 reduced complex IV activity, with weaker effects on the activities of complexes I and V. Knockdown of C1ORF163 had no effect on mitochondrial morphology, membrane potential, or protein import. Native gel electrophoresis detected C1ORF163 in several soluble protein complexes of the inner mitochondrial space, and knockdown experiments showed that the endogenous protein was present in complexes with apparent molecular masses of 60 and 150 kD.
Martinez Lyons et al. (2016) determined that the COA7 is a soluble protein that predominantly localizes to the mitochondrial matrix, although some appeared to be associated with the inner mitochondrial membrane.
Using affinity purification, mass spectrometry, and Western blot analyses in human Flp-In T-Rex 293 cells, Mohanraj et al. (2019) found that COA7 interacted with MIA40 (CHCHD4; 611077) through disulfide bonds. COA7 was a substrate of MIA40 that was synthesized in the cytosol and imported to the mitochondrial intermembrane space in a manner dependent on MIA40.
Kozjak-Pavlovic et al. (2014) reported that the COA7 gene maps to chromosome 1p32.3.
In a 19-year-old woman with autosomal recessive spinocerebellar ataxia with axonal neuropathy-3 (SCAN3; 618387), Martinez Lyons et al. (2016) identified compound heterozygous mutations in the COA7 gene (615623.0001 and 615623.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed no detectable COA7 protein, decreased amounts of COX structural subunits MTCO2 (516040) and MTCO3 (516050), and decreased levels of fully assembled complex IV.
In 4 unrelated Japanese patients with SCAN3, Higuchi et al. (2018) identified homozygous or compound heterozygous mutations in the COA7 gene (see, e.g., 615623.0003-615623.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Expression of some of the variants in HeLa cells showed that they localized normally to the mitochondria. The mutations were postulated to result in a loss of function with a neurodegenerative effect. The patients were ascertained from 1,396 Japanese patients with peripheral neuropathy who underwent genetic analysis.
Higuchi et al. (2018) found that knockdown of the Drosophila Coa7 gene caused morphologically aberrant rough eyes with fusion of ommatidia and lack of bristles compared to controls. Mutant flies also showed a shorter life span and locomotor defects, which were associated with abnormalities in the formation of motor neurons at presynaptic terminals at the neuromuscular junction (NMJ). However, Higuchi et al. (2018) suggested that the NMJ abnormalities may be a secondary effect of axonal changes in the peripheral nervous system.
In a 19-year-old woman with autosomal recessive spinocerebellar ataxia with axonal neuropathy-3 (SCAN3; 618387), Martinez Lyons et al. (2016) identified compound heterozygous mutations in the COA7 gene: a c.410A-G transition (c.410A-G, NM_023077), resulting in a tyr137-to-cys (Y137C) substitution at a highly conserved residue, and a G-to-T transversion in intron 2 (c.287+1G-T; 615623.0002), resulting in an in-frame deletion of the 47 amino acids encoded by exon 2. This deletion spans almost all of the first conserved Sel1-like domain and half of the second domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was reported in the ExAC database. Patient cells showed no detectable COA7 protein, decreased amounts of COX structural subunits MTCO2 (516040) and MTCO3 (516050), and decreased levels of fully assembled complex IV. These defects could be rescued by expression of wildtype COA7.
Mohanraj et al. (2019) found that COA7 with the Y137C mutation could interact with MIA40 (CHCHD4; 611077), but its import into mitochondria was impaired. Inefficient import of mutant COA7 into mitochondria exposed it to excessive degradation by the proteasome, resulting in impaired mitochondrial respiratory chain assembly. Inhibition of the proteasome increased mitochondrial levels of mutant COA7 and restored respiratory complex activity and assembly in patient-derived fibroblasts.
For discussion of a G-to-T transversion in intron 2 (c.287+1G-T, NM_023077) of the COA7 gene, resulting in an in-frame deletion of the 47 amino acids encoded by exon 2, that was found in compound heterozygous state in a patient with autosomal recessive spinocerebellar ataxia with axonal neuropathy-3 (SCAN3; 618387) by Martinez Lyons et al. (2016), see 615623.0001.
Mohanraj et al. (2019) found that COA7 with the exon 2 deletion could interact with MIA40 (CHCHD4; 611077), but its import into mitochondria was impaired. Inefficient import of mutant COA7 into mitochondria exposed it to excessive degradation by the proteasome, resulting in impaired mitochondrial respiratory chain assembly. Inhibition of the proteasome increased mitochondrial levels of mutant COA7 and restored respiratory complex activity and assembly in patient-derived fibroblasts.
In a 63-year-old Japanese man (patient 1), born of consanguineous parents, with autosomal recessive spinocerebellar ataxia with axonal neuropathy-3 (SCAN3; 618387), Higuchi et al. (2018) identified a homozygous c.17A-G transition in the COA7 gene, resulting in an asp6-to-gly (D6G) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found at a low frequency in heterozygous state in the ExAC database (1 in 120,268 alleles), but was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Two additional unrelated Japanese patients with a similar disorder were found to be compound heterozygous for D6G and a different mutation in the COA7 gene: a 28-year-old man (patient 3) carried a c.446G-T transversion, resulting in a ser149-to-ile (S149I; 615623.0004) substitution at a conserved residue on the other allele, and a 27-year-old man (patient 4) carried a 1-bp deletion (c.430delG; 615623.0005), resulting in a frameshift and premature termination (Gly144fs), on the other allele. The 2 additional variants were not found in any of the public databases.
For discussion of the c.446G-T transversion in the COA7 gene, resulting in a ser149-to-ile (S149I) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spinocerebellar ataxia with axonal neuropathy-3 (SCAN3; 618387) by Higuchi et al. (2018), see 615623.0003.
For discussion of the 1-bp deletion (c.430delG) in the COA7 gene, resulting in a frameshift and premature termination (Gly144fs), that was found in compound heterozygous state in a patient with autosomal recessive spinocerebellar ataxia with axonal neuropathy-3 (SCAN3; 618387) by Higuchi et al. (2018), see 615623.0003.
Higuchi, Y., Okunushi, R., Hara, T., Hashiguchi, A., Yuan, J., Yoshimura, A., Murayama, K., Ohtake, A., Ando, M., Hiramatsu, Y., Ishihara, S., Tanabe, H. and 18 others. Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy. Brain 141: 1622-1636, 2018. [PubMed: 29718187] [Full Text: https://doi.org/10.1093/brain/awy104]
Kozjak-Pavlovic, V., Prell, F., Thiede, B., Gotz, M., Wosiek, D., Ott, C., Rudel, T. C1ORF163/RESA1 is a novel mitochondrial intermembrane space protein connected to respiratory chain assembly. J. Molec. Biol. 426: 908-920, 2014. [PubMed: 24333015] [Full Text: https://doi.org/10.1016/j.jmb.2013.12.001]
Martinez Lyons, A., Ardissone, A., Reyes, A., Robinson, A. J., Moroni, I., Ghezzi, D., Fernandez-Vizarra, E., Zeviani, M. COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency. J. Med. Genet. 53: 846-849, 2016. [PubMed: 27683825] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104194]
Mohanraj, K., Wasilewski, M., Beninca, C., Cysewski, D., Poznanaski, J., Sakowska, P., Bugajska, Z., Deckers, M., Dennerlein, S., Fernandez-Vizarra, E., Rehling, P., Dadlez, M., Zeviani, M., Chacinska, A. Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7. EMBO Molec. Med. 11: e9561, 2019. [PubMed: 30885959] [Full Text: https://doi.org/10.15252/emmm.201809561]