Alternative titles; symbols
HGNC Approved Gene Symbol: SCO2
Cytogenetic location: 22q13.33 Genomic coordinates (GRCh38): 22:50,523,568-50,526,442 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
22q13.33 | Mitochondrial complex IV deficiency, nuclear type 2 | 604377 | Autosomal recessive | 3 |
Myopia 6 | 608908 | Autosomal dominant | 3 |
Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA encodes 3 COX subunits, I-III (see COXI, 516030), and nuclear DNA encodes 10 (see 123870). In addition, ancillary proteins are required for the correct assembly and function of COX. Although pathogenetic mutations in mitochondrial DNA-encoded subunits had been described, no mutations in the nuclear DNA-encoded subunits had been uncovered in any mendelian inherited COX deficiency disorder. In yeast, 2 related COX assembly genes, SCO1 (603644) and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. Papadopoulou et al. (1999) isolated the human SCO2 gene. The deduced human SCO2 protein of 266 amino acids predicts an N-terminal mitochondrial targeting presequence of 41 amino acids. Human and yeast SCO polypeptides share the greatest identity in a core region, which lies between glycine-102 and glycine-242 in human SCO2. In this region the amino acid identity between the 2 human proteins (54%) is less than that between the 2 yeast proteins (73%). Moreover, human SCO2 and SCO1 show similar divergence from both yeast proteins suggesting that the 2 human genes are not orthologous to the 2 yeast genes, but rather are paralogous genes. Northern blot analysis detected SCO2 expression as a 0.9-kb transcript in all 12 human tissues examined, with strongest signals in heart, skeletal muscle, brain, liver, and kidney.
By immunohistochemistry in mouse ocular tissues, Tran-Viet et al. (2013) observed Sco2 protein localization in the retina, retinal pigment epithelium (RPE), and scleral wall. RT-PCR in fetal and adult human ocular tissues confirmed expression of SCO2 in choroid, sclera, retina, and RPE.
Papadopoulou et al. (1999) determined that the human SCO2 gene contains 2 exons and 1 intron. Exon 1 encodes part of the 5-prime untranslated region. Exon 2 contains the remaining 13 basepairs of the 5-prime untranslated region, an 801-basepair coding region, and a 41-basepair 3-prime untranslated region containing a polyadenylation signal for a total length of 918 nucleotides.
Papadopoulou et al. (1999) mapped the SCO2 gene to chromosome 22q13 by genomic sequence analysis.
Leary et al. (2004) characterized the mitochondrial copper delivery pathway in SCO1 and SCO2 patient backgrounds. Immunoblot analysis of patient cell lines showed reduced levels of the mutant proteins, resulting in a defect in COX assembly, and the appearance of a common assembly intermediate. Overexpression of the metallochaperone COX17 (604813) rescued the COX deficiency in SCO2 patient cells but not in SCO1 patient cells. Overexpression of either wildtype SCO protein in the reciprocal patient background resulted in a dominant-negative phenotype, suggesting a physical interaction between SCO1 and SCO2. Chimeric proteins, constructed from the C-terminal copper-binding and N-terminal matrix domains of the 2 SCO proteins, failed to complement the COX deficiency in either patient background, but mapped the dominant-negative phenotype in the SCO2 background to the N-terminal domain of SCO1, the most divergent part of the 2 SCO proteins. Leary et al. (2004) concluded that the human SCO proteins have nonoverlapping, cooperative functions in mitochondrial copper delivery.
Matoba et al. (2006) showed that p53 (191170) modulates the balance between the utilization of respiratory and glycolytic pathways. They identified SCO2 as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the COX complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wildtype p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. Matoba et al. (2006) concluded that the fact that SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect, i.e., cancer cells preferentially utilize glycolytic pathways for energy generation while downregulating their aerobic respiratory activity, and offers new clues as to how p53 might affect aging and metabolism.
Human SCO1 and SCO2 code for essential metallochaperones with ill-defined functions in the biogenesis of the CuA site of cytochrome c oxidase subunit II (COII) (MTCO2; 516040). Leary et al. (2009) used patient cell lines to demonstrate that the synthesis of COII was reduced in SCO2-mutant, but not in SCO1-mutant, cells. Despite this biosynthetic defect, newly synthesized COII was more stable in SCO2-mutant cells than in control cells. RNAi-mediated knockdown of mutant SCO2 abolished COII labeling in a translation assay, whereas knockdown of mutant SCO1 did not affect COII synthesis. These results indicated that SCO2 acts upstream of SCO1 and that SCO2 is indispensable for COII synthesis. The subsequent maturation of COII was contingent upon the formation of a complex that included both SCO proteins, each with a functional CxxxC copper-coordinating motif. In control cells, the cysteines in this motif in SCO1 existed as a mixed population composed of oxidized disulfides and reduced thiols; however, the relative ratio of oxidized to reduced cysteines in SCO1 was perturbed in cells from both SCO backgrounds. Overexpression of wildtype SCO2, or knockdown of mutant SCO2, in SCO2-mutant cells altered the ratio of oxidized to reduced cysteines in SCO1, suggesting that SCO2 acts as a thiol-disulfide oxidoreductase to oxidize the copper-coordinating cysteines in SCO1 during COII maturation. Leary et al. (2009) presented a model in which each SCO protein fulfills distinct, stage-specific functions during COII synthesis and CuA site maturation.
Using SCO1 and SCO2 patient fibroblasts, Leary et al. (2013) showed that both the redox state of the copper-binding cysteines of SCO1 and the abundance of SCO2 correlated with cellular copper content. COX19 (610429), which distributes between the mitochondrial intermembrane space and the cytosol in a copper-dependent manner, transduced the SCO1-dependent redox signal to the plasma membrane copper transporter ATP7A (300011), resulting in copper efflux.
Tran-Viet et al. (2013) observed significant reduction of Sco2 immunostaining intensity in myopic retinal tissues of experimentally induced myopic mice compared to nonmyopic controls, and noted significantly increased intensity in myopic sclerae. RT-PCR confirmed Sco2 mRNA levels to be significantly reduced in myopic retinae compared to controls, with increased Sco2 mRNA levels in myopic sclerae.
Mitochondrial Complex IV Deficiency, Nuclear Type 2
Papadopoulou et al. (1999) identified SCO2 mutations in 3 patients with mitochondrial complex IV (COX) deficiency nuclear type 2 (MC4DN2; 604377); all presented with a fatal infantile cardioencephalomyopathy. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mitochondrial DNA-encoded subunits. There was decreased COX activity in heart and skeletal muscle but no ragged-red fibers were observed. The clinical phenotype caused by mutations in human SCO2 differed from that caused by mutations in SURF1 (185620), another COX assembly gene, associated with Leigh syndrome (see 256000).
Based on studies of yeast homologs, Glerum et al. (1996) had suggested that human SCO2 may act as a copper chaperone, transporting copper to the Cu(A) site on the COX II subunit. Jaksch et al. (2001) showed that a recombinant SCO2 segment, bearing the putative CxxxC metal-binding motif, bound copper with a 1:1 stoichiometry. Immunoblot analysis showed that SCO2 was severely reduced in fibroblasts and myoblasts from patients with known SCO2 mutations. Patient fibroblasts showed increased (64)Cu uptake but normal retention values and, consistent with this, Cu(2++) concentration was 4 times higher in Sco2-deficient myoblasts than in controls. COX activity in patient myoblasts was completely rescued by transduction with a retroviral vector expressing the human SCO2 coding sequence, as well as by addition of copper-histidine to the culture medium. Whether the latter was accomplished by the very low residual levels of SCO2 in the patient cells, direct addition of copper to the Cu(A) site, or by another copper-binding protein remained unknown.
Tarnopolsky et al. (2004) noted that a classic phenotypic presentation for spinal muscular atrophy type I (SMA1; 253300) can be seen in patients with mutation in the SCO2 gene, who they suggested should be tested for changes in the SMN1 gene (600354) when SMN deletion testing is negative and any of the following is present: cardiomyopathy, lactic acidosis, or COX deficiency in muscle. They described a patient with COX deficiency who died at the age of 30 days of progressive cardiomyopathy; sequencing of exon 2 of the SCO2 gene revealed compound heterozygosity for the common glu140-to-lys mutation (E140K; 604272.0002) and a cys133-to-tyr mutation (C133Y; 604272.0007) in the copper-binding region of the protein. The father was heterozygous for the first and the mother for the second of these mutations. These findings supported the notion that mutations in close proximity to or involving the copper-binding region of the SCO2 protein result in fatal outcomes within the first few months of life.
Leary et al. (2013) presented evidence that defective copper handling in SCO1 and SCO2 patient fibroblasts results in both inappropriate mitochondrial redox signaling in response to oxidative stress and altered cellular copper homeostasis, resulting in copper deficiency.
Myopia 6
By exome sequencing in a large 4-generation family with high-grade myopia (MYP6; 608908), Tran-Viet et al. (2013) identified a heterozygous nonsense mutation in the SCO2 gene (Q53X; 604272.0001) that segregated with disease. Sequencing of SCO2 in an additional 140 high-grade myopia patients revealed 3 heterozygous variants in 3 patients (e.g., 604272.0002 and 604272.0009). Noting that compound heterozygosity for SCO2 mutations has been shown to cause a COX-deficient form of fatal infantile cardioencephalomyopathy, Tran-Viet et al. (2013) commented that neonatal death precludes investigation of an associated clinical ocular phenotype such as refractive error, and that further investigation of the phenotypic intersection of myopia and cardioencephalopathy was warranted.
Yang et al. (2010) generated mice harboring a Sco2 knockout allele and a Sco2 knockin allele expressing a E140K mutation, corresponding to the E140K (604272.0002) mutation found in almost all human SCO2-mutated patients. Whereas homozygous knockout mice were embryonic lethals, homozygous knockin and compound heterozygous knockout/knockin mice were viable, but had muscle weakness. Biochemical assay of viable mice showed respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues. There was a concomitant reduction in mitochondrial copper content, but the total amount of copper in examined tissues was not reduced.
Mitochondrial Complex IV Deficiency, Nuclear Type 2
In 2 unrelated patients with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377), Papadopoulou et al. (1999) identified compound heterozygosity for a C-to-T transition at nucleotide 1280 of the SCO2 gene, creating a stop codon at glutamine-53, and for a glu140-to-lys substitution (604272.0002). The patients had a fatal infantile cardioencephalomyopathy. Heart and skeletal muscle showed reductions in COX activity, with less severe reductions in liver and fibroblasts.
Myopia 6
In 8 affected members of large 4-generation family of European descent with high-grade myopia (MYP6; 608908), Tran-Viet et al. (2013) identified heterozygosity for a 157C-T transition in exon 2 of the SCO2 gene, resulting in the Q53X substitution in the functional catalytic domain. The mutation segregated with disease in the family and was not found in 1,000 control DNA samples.
Mitochondrial Complex IV Deficiency, Nuclear Type 2
In 3 unrelated patients with COX deficiency (MC4DN2; 604377), Papadopoulou et al. (1999) identified compound heterozygous mutations in the SCO2 gene: all 3 carried a glu140-to-lys substitution, 2 carried the Q53X mutation (604272.0001), and 1 carried a c.1797C-T transition, resulting in a ser225-to-phe substitution (604272.0003). The patients had a fatal infantile cardioencephalomyopathy. Heart and skeletal muscle showed reductions in COX activity, with less severe reductions in liver and fibroblasts.
Jaksch et al. (2001) reported 3 unrelated infants with a distinctive phenotype of Leigh-like syndrome, neurogenic muscular atrophy, and hypertrophic obstructive cardiomyopathy. The patients all had a homozygous missense mutation in SCO2: E140K. The disease onset and symptoms differed significantly from those in compound heterozygotes. MRI and muscle morphology demonstrated an age-dependent progression of disease with predominant involvement of white matter, late appearance of basal ganglia lesions, and neurogenic muscular atrophy in addition to the relatively late onset of hypertrophic cardiomyopathy. The copper uptake of cultured fibroblasts was significantly increased. Thus, the clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy. The observed increased copper uptake in patients' fibroblasts indicated that the 1541G-A transition in SCO2 affects cellular copper metabolism.
Salviati et al. (2002) reported an infant girl who presented at birth with generalized weakness, hypotonia, and lactic acidosis, and later developed fatal hypertrophic cardiomyopathy. Muscle biopsy showed neurogenic abnormalities and severe COX deficiency, and spinal cord examination showed severe loss of motor neurons and astrocytosis in the ventral horn, similar to Werdnig-Hoffmann disease (253300). Sequencing of the SCO2 gene revealed the E140K mutation and a 10-bp duplication of nucleotides 1302-1311 (604272.0006) that disrupted the reading frame of the mRNA and resulted in a truncated protein. The patient's father carried the E140K mutation and the mother carried the 10-bp duplication.
Among 9 children with encephalomyopathy and/or cardiomyopathy associated with mutations in the SCO2 gene, Bohm et al. (2006) identified the 1541G-A transition in 83% of independent alleles. All patients died before age 2 years.
Freisinger et al. (2004) reported a patient with the E140K SCO2 mutation in homozygosity who had resolution of severe hypertrophic cardiomyopathy due to subcutaneous application of copper histidine (Cu-his).
Myopia 6
In an individual of European descent with high-grade myopia (MYP6; 608908), Tran-Viet et al. (2013) identified heterozygosity for a 418G-A transition in exon 2 of the SCO2 gene, resulting in the E140K substitution at a highly conserved residue in the functional catalytic domain. The mutation was not found in 1,000 control DNA samples.
For discussion of the c.1797C-T transition in the SCO2 gene, resulting in a ser225-to-phe substitution, that was found in compound heterozygous state in a patient with COX deficiency manifesting as infantile cardioencephalomyopathy (MC4DN2; 604377) by Papadopoulou et al. (1999), see 604272.0002.
Jaksch et al. (2000) sequenced the SCO2 gene in 10 patients with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377) manifesting as fatal infantile cardioencephalopathy in 9 families; mutations were found in 3 individuals. All 3 individuals were heterozygous for the glu140-to-lys mutation (604272.0002); 1 individual (family A) also carried a c.1634C-T transition, resulting in an arg171-to trp (R171W) substitution, and 2 sibs also carried an arg90-to-ter substitution (604272.0005). The COX deficiency in patient fibroblasts (approximately 50%) did not result in a measurable decrease in the steady-state levels of COX complex polypeptide subunits and could be rescued by microcell-mediated transfer of chromosome 22, but not other chromosomes. The authors speculated that another gene in the copper delivery pathway may lie on chromosome 22 and may contribute to the genetic heterogeneity of this disorder.
In a pair of sibs (family B) with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377) manifesting as fatal infantile cardioencephalomyopathy, Jaksch et al. (2000) detected a c.1391C-T transition in the SCO2 gene, resulting in an amino acid change of arg90 to ter (R90X). The sibs also were heterozygous for the glu140 to lys (604272.0002) mutation, present in the father. The mother carried the R90X mutation.
For discussion of the 10-bp duplication (c.1302_1311dup) in the SCO2 gene that was found in compound heterozygous state in a patient with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377) by Salviati et al. (2002), see 604272.0002.
In a male neonate with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377), Tarnopolsky et al. (2004) found compound heterozygosity for 2 mutations in exon 2 of the SCO2 gene: the common E140K mutation (604272.0002) and a 1521G-A transition, converting a highly conserved cysteine to tyrosine at codon 133 (C133Y) in the copper-binding region of the protein, which they incorrectly reported as C133S. The father was heterozygous for the first and the mother for the second of these mutations. The patient was born with hypotonia, persistent lactic acidosis, and spontaneous activity with EMG testing and developed respiratory distress in the first few hours of life, followed by death at 30 days of age with progressive cardiomyopathy. The phenotype strongly resembled spinal muscular atrophy type I (253300).
In a male infant with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377) manifesting as fatal infantile cardioencephalomyopathy, Verdijk et al. (2008) identified compound heterozygosity for 2 mutations in the SCO2 gene: the common E140K mutation (604272.0002) and a 107G-A transition resulting in a trp36-to-ter (W36X) substitution predicted to lead to a nonfunctioning protein product. Genetic analysis of amniocytes from a subsequent pregnancy identified both mutations, and the pregnancy was terminated at 23 weeks' gestation. Postmortem examination showed antenatal onset of cardiac and brain anomalies.
In an individual of Middle Eastern descent with high-grade myopia (MYP6; 608908), Tran-Viet et al. (2013) identified heterozygosity for a 341G-A transition in exon 2 of the SCO2 gene, resulting in an arg114-to-his (R114H) substitution at a conserved residue in the functional catalytic domain. The mutation was not found in 1,000 control DNA samples.
Bohm, M., Pronicka, E., Karczmarewicz, E., Pronicki, M., Piekutowska-Abramczuk, D., Sykut-Cegielska, J., Mierzewska, H., Hansikova, H., Vesela, K., Tesarova, M., Houstkova, H., Houstek, J., Zeman, J. Retrospective, multicentric study of 180 children with cytochrome c oxidase deficiency. Pediat. Res. 59: 21-26, 2006. [PubMed: 16326995] [Full Text: https://doi.org/10.1203/01.pdr.0000190572.68191.13]
Freisinger, P., Horvath, R., Macmillan, C., Peters, J., Jaksch, M. Reversion of hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial copper binding protein Sco2: is there a potential effect of copper? J. Inherit. Metab. Dis. 27: 67-79, 2004. [PubMed: 14970747] [Full Text: https://doi.org/10.1023/B:BOLI.0000016614.47380.2f]
Glerum, D. M., Shtanko, A., Tzagoloff, A. SCO1 and SCO2 act as high copy suppressors of a mitochondrial copper recruitment defect in Saccharomyces cerevisiae. J. Biol. Chem. 271: 20531-20535, 1996. [PubMed: 8702795] [Full Text: https://doi.org/10.1074/jbc.271.34.20531]
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Jaksch, M., Ogilvie, I., Yao, J., Kortenhaus, G., Bresser, H.-G., Gerbitz, K.-D., Shoubridge, E. A. Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum. Molec. Genet. 9: 795-801, 2000. [PubMed: 10749987] [Full Text: https://doi.org/10.1093/hmg/9.5.795]
Jaksch, M., Paret, C., Stucka, R., Horn, N., Muller-Hocker, J., Horvath, R., Trepesch, N., Stecker, G., Freisinger, P., Thirion, C., Muller, J., Lunkwitz, R., Rodel, G., Shoubridge, E. A., Lochmuller, H. Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts. Hum. Molec. Genet. 10: 3025-3035, 2001. [PubMed: 11751685] [Full Text: https://doi.org/10.1093/hmg/10.26.3025]
Leary, S. C., Cobine, P. A., Nishimura, T., Verdijk, R. M., de Krijger, R., de Coo, R., Tarnopolsky, M. A., Winge, D. R., Shoubridge, E. A. Cox19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux. Molec. Biol. Cell 24: 683-691, 2013. [PubMed: 23345593] [Full Text: https://doi.org/10.1091/mbc.E12-09-0705]
Leary, S. C., Kaufman, B. A., Pellecchia, G., Guercin, G.-H., Mattman, A., Jaksch, M., Shoubridge, E. A. Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase. Hum. Molec. Genet. 13: 1839-1848, 2004. [PubMed: 15229189] [Full Text: https://doi.org/10.1093/hmg/ddh197]
Leary, S. C., Sasarman, F., Nishimura, T., Shoubridge, E. A. Human SCO2 is required for the synthesis of CO II and as a thiol-disulphide oxidoreductase for SCO1. Hum. Molec. Genet. 18: 2230-2240, 2009. [PubMed: 19336478] [Full Text: https://doi.org/10.1093/hmg/ddp158]
Matoba, S., Kang, J.-G., Patino, W. D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P. J., Bunz, F., Hwang, P. M. p53 regulates mitochondrial respiration. Science 312: 1650-1653, 2006. [PubMed: 16728594] [Full Text: https://doi.org/10.1126/science.1126863]
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Salviati, L., Sacconi, S., Rasalan, M. M., Kronn, D. F., Braun, A., Canoll, P., Davidson, M., Shanske, S., Bonilla, E., Hays, A. P., Schon, E. A., DiMauro, S. Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease. Arch. Neurol. 59: 862-865, 2002. Note: Erratum: Arch. Neurol. 60: 749 only, 2003. [PubMed: 12020273] [Full Text: https://doi.org/10.1001/archneur.59.5.862]
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Tran-Viet, K.-N., Powell, C., Barathi, V. A., Klemm, T., Maurer-Stroh, S., Limviphuvadh, V., Soler, V., Ho, C., Yanovitch, T., Schneider, G., Li, Y.-J., Nading, E., Metlapally, R., Saw, S.-M., Goh, L., Rozen, S., Young, T. L. Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am. J. Hum. Genet. 92: 820-826, 2013. [PubMed: 23643385] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.005]
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Yang, H., Brosel, S., Acin-Perez, R., Slavkovich, V., Nishino, I., Khan, R., Goldberg, I. J., Graziano, J., Manfredi, G., Schon, E. A. Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2. Hum. Molec. Genet. 19: 170-180, 2010. [PubMed: 19837698] [Full Text: https://doi.org/10.1093/hmg/ddp477]