CYTOCHROME c OXIDASE ASSEMBLY FACTOR COX15; COX15

Alternative titles; symbols

• COX15, S. CEREVISIAE, HOMOLOG OF

HGNC Approved Gene Symbol: COX15

Cytogenetic location: 10q24.2 Genomic coordinates (GRCh38): 10:99,694,292-99,732,130 (from NCBI)

▼ Description
Cytochrome c oxidase (COX; EC 1.9.3.1), the terminal component of the mitochondrial respiratory chain, is a multiheteromeric enzyme embedded in the mitochondrial inner membrane. COX consists of a protein backbone bound to 2 copper-containing prosthetic groups, the cytochromes a and a-3. See 123864. The S. cerevisiae cox15 protein is a constituent of the inner mitochondrial membrane and may be involved in the assembly of the COX protein backbone (Petruzzella et al., 1998).

▼ Cloning and Expression
By searching an EST database for sequences related to cox15, Petruzzella et al. (1998) identified cDNAs encoding human COX15. The cDNAs encoded 2 COX15 isoforms, COX15.1 and COX15.2, with different C termini. The amino acid sequences of both isoforms are 42% identical to that of yeast cox15. Sequence analysis indicated that COX15 contains a mitochondrial leader peptide and 5 transmembrane domains. Using in vitro mitochondrial import and trypsin-protection assays, the authors demonstrated that the COX15 protein is targeted to mitochondria. Northern blot analysis revealed that COX15 is expressed as 1.5-, 1.8-, and 3-kb mRNAs predominantly in tissues characterized by high rates of oxidative phosphorylation (OXPHOS), including muscle, heart, and brain.

▼ Mapping
Based on sequence similarity to ESTs, Petruzzella et al. (1998) tentatively mapped the COX15 gene to 10q24.

▼ Molecular Genetics
Antonicka et al. (2003) used a panel of retroviral vectors expressing COX assembly factors in a patient with COX deficiency (MC4DN6; 615119) reported by Kennaway et al. (1990) to identify the molecular basis of the deficiency by functional complementation. They showed that overexpression of COX15, a protein involved in the synthesis of heme A, the heme prosthetic group for COX, could functionally complement the isolated COX deficiency in fibroblasts from the patient. Mutation analysis of COX15 in the patient identified compound heterozygous mutations: a missense mutation (R217W; 603646.0001) and a splice site mutation (447-3C-G; 603646.0002). In the patient, mitochondrial heme A content was reduced in heart and fibroblast mitochondria, and levels of heme O were increased in heart. COX activity and the total amount of fully assembled enzyme were reduced by 50 to 70% in fibroblasts. Expression of COX15 increased heme A content and rescued COX activity. Thus, it appeared that reduced availability of heme A stalls the assembly of COX. This study established COX15 as an additional cause, along with SCO2 (604272), of fatal infantile hypertrophic cardiomyopathy associated with isolated COX deficiency.

In a patient with cytochrome c deficiency presenting as Leigh syndrome (see 256000), Oquendo et al. (2004) identified homozygosity for the R217W mutation in the COX15 gene.

Bugiani et al. (2005) reported a 16-year-old Italian boy with Leigh syndrome who was compound heterozygous for a nonsense mutation (S151X; 603646.0003) and a missense mutation (S344P; 603646.0004) in the COX15 gene. The authors noted that defects in the COX15 gene appear to be associated with considerable clinical and biochemical heterogeneity.

In an infant girl with isolated complex IV deficiency that was more marked in cardiac than skeletal muscle, who died at day 9 of life with encephalopathy, respiratory depression, and marked cardiac hypertrophy of all walls, Alfadhel et al. (2011) analyzed 6 candidate genes and identified compound heterozygosity for the R217W missense mutation and a nonsense mutation (S151X; 603646.0003) in the COX15 gene.

▼ ALLELIC VARIANTS ( 4 Selected Examples):

.0001 MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 6
COX15, ARG217TRP
In a female infant with mitochondrial complex IV deficiency nuclear type 6 (MC4DN6; 615119) with predominantly cardiac involvement and relative sparing of skeletal muscle, who was originally reported by Kennaway et al. (1990), Antonicka et al. (2003) identified compound heterozygosity for a 700C-T transition on 1 allele, resulting in an arg217-to-trp (R217W) substitution, and a splice site mutation in intron 3 on the other allele (447-3C-G), resulting in deletion of exon 4 (603646.0002). The splicing error introduced a frameshift and a premature stop codon, resulting in an unstable mRNA and, likely, a null allele.

In an infant girl with isolated complex IV deficiency that was more marked in cardiac than skeletal muscle, who died at day 9 of life with encephalopathy, respiratory depression, and marked cardiac hypertrophy, Alfadhel et al. (2011) identified compound heterozygosity for the R217W missense mutation and a nonsense mutation (S151X; 603646.0003) in the COX15 gene.

In a patient with cytochrome c oxidase deficiency presenting as Leigh syndrome, Oquendo et al. (2004) identified homozygosity for the R217W mutation. Both parents were heterozygous for the mutation. The authors noted the phenotypic variation associated with this mutation.

.0002 MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 6
COX15, IVS3, C-G, -3
For discussion of the splice site mutation in the COX15 gene (447-3C-G) that was found in compound heterozygous state in a patient with mitochondrial complex IV deficiency nuclear type 6 (MC4DN6; 615119) by Antonicka et al. (2003), see 603646.0001.

.0003 MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 6
COX15, SER151TER
In a 16-year-old Italian boy with mitochondrial complex IV deficiency nuclear type 6 (MC4DN6; 615119) presenting as Leigh syndrome, Bugiani et al. (2005) identified compound heterozygosity for a 452C-G transversion in exon 4 of the COX15 gene, resulting in a ser151-to-ter (S151X) substitution, and a 1030T-C transition in exon 8, resulting in a ser344-to-pro (S344P; 603646.0004) substitution at a conserved residue in the C-terminal end of the fifth predicted transmembrane domain.

For discussion of the S151X mutation in the COX15 gene that was found in compound heterozygous state in a patient with isolated complex IV deficiency by Alfadhel et al. (2011), see 603646.0001.

.0004 MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 6
COX15, SER344PRO
For discussion of the ser344-to-pro (S344P) mutation in the COX15 gene that was found in compound heterozygous state in a patient with mitochondrial complex IV deficiency nuclear type 6 (MC4DN6; 615119) by Bugiani et al. (2005), see 603646.0003.