HGNC Approved Gene Symbol: UQCRC2
Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38): 16:21,953,361-21,983,660 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.2 | Mitochondrial complex III deficiency, nuclear type 5 | 615160 | Autosomal recessive | 3 |
The UQCRC2 gene encodes a subunit of mitochondrial complex III (Duncan et al., 1993). See also UQCRC1 (191328).
By in situ hybridization to metaphase chromosomes, Duncan et al. (1993) assigned the UQCRC2 gene to human chromosome 16p12, thus confirming that it is encoded by the nuclear rather than the mitochondrial genome. Two other subunits of mitochondrial complex III (CYC1, 123980; UQPC, 191330) map to chromosome 8.
Wisloff et al. (2005) hypothesized that artificial selection of rats based on low and high intrinsic exercise capacity would yield models that also contrast for cardiovascular disease risk. After 11 generations, rats with low aerobic capacity scored higher on cardiovascular risk factors that constitute the metabolic syndrome. The decrease in aerobic capacity was associated with decreases in the amounts of transcription factors required for mitochondrial biogenesis and in the amounts of oxidative enzymes in skeletal muscle. Wisloff et al. (2005) found that the amount of PPARG (601487), PPARG coactivator-1-alpha (PPARGC1A; 604517), ubiquinol-cytochrome c oxidoreductase core 2 subunit (UQCRC2), cytochrome c oxidase subunit I (MTCO1; 516030), uncoupling protein-2 (UCP2; 601693), and ATP synthase H(+)-transporting mitochondrial F1 complex (F1-ATP synthase; see 108729) were markedly reduced in the low capacity runner rats in comparison with the high capacity runners. The uniform decline in these proteins was consistent with the hypothesis that reduced aerobic metabolism plays a causal role in the development of the differences between the low capacity runner and high capacity runner rats. Wisloff et al. (2005) concluded that impairment of mitochondrial function may link reduced fitness to cardiovascular and metabolic disease.
In 3 affected individuals from a large consanguineous Mexican kindred with mitochondrial complex III deficiency nuclear type 5 (MC3DN5; 615160), Miyake et al. (2013) identified a homozygous mutation in the UQCRC2 gene (R183W; 191329.0001). Structural analysis indicated that the substitution would disrupt the hydrophobic core at the interface of the UQCRC2-containing complex, resulting in destabilization of complex III. In vitro studies showed that the mutant protein localized properly to the mitochondria but had decreased expression compared to wildtype, suggesting protein instability. Complex III activity in one of the patient's cells was decreased to 50% of normal, whereas complex I activity was increased and complex IV activity was normal. The patient's cells also showed severely decreased levels of complex III assembly and decreased levels of the supercomplex formed from complexes I, III, and IV. The patients had neonatal onset of severe metabolic acidosis associated with hyperammonemia and hypoglycemia. Physical signs included tachypnea and poor sucking. Two of the patients showed normal growth and development by early childhood despite multiple episodes of metabolic decompensation, usually associated with illness. The third patient had a similar disease course, but showed mild development delay at age 18 months.
In a boy of French Canadian descent with MC3DN5, Gaignard et al. (2017) identified a homozygous R183W mutation. The mutation, which was found by targeted resequencing of nuclear genes involved in mitochondrial defects and confirmed by Sanger sequencing, segregated with the disorder in the family.
In a 6-year-old girl with MC3DN5, Burska et al. (2021) identified homozygosity for a missense mutation (G222A; 191329.0002) in the UQCRC2 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Microscopic analysis of patient fibroblasts showed fragmentation of the mitochondrial network and swollen mitochondria with low christae number. Analysis in patient muscle and fibroblasts showed impaired complex I+III activity. Steady-state levels of respiratory chain complexes I and III were severely decreased in patient fibroblasts. Analysis of patient fibroblasts also showed accumulation of complex III assembly units that were devoid of the subunits UQCRC1, UQCRC2 and UQCRFS1 (191327). Burska et al. (2021) identified increased expression of the matrix protease CLPP (601119) in patient fibroblasts, suggesting activation of the mitochondrial protein quality control machinery.
In 3 affected individuals from a large consanguineous Mexican kindred with mitochondrial complex III deficiency, nuclear type 5 (MC3DN5; 615160), Miyake et al. (2013) identified a homozygous c.547C-T transition in the UQCRC2 gene, resulting in an arg183-to-trp (R183W) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in 80 Mexican or 750 Japanese control alleles. Three unaffected family members were heterozygous for the mutation. Structural analysis indicated that the substitution would disrupt the hydrophobic core at the interface of the UQCRC2-containing complex, resulting in destabilization of complex III. In vitro studies showed that the mutant protein localized properly to the mitochondria but had decreased expression compared to wildtype, suggesting protein instability. Complex III activity in one of the patient's cells was decreased to 50% of normal, whereas complex I activity was increased and complex IV activity was normal. Patients cells also showed severely decreased levels of complex III assembly and decreased levels of the supercomplex formed from complexes I, III, and IV.
In a boy of French Canadian descent with MC3DN5, Gaignard et al. (2017) identified homozygosity for the R183W mutation. The mutation, which was found by targeted resequencing of nuclear genes involved in mitochondrial defects and confirmed by Sanger sequencing, segregated with the disorder in the family. The minor allele frequency of this variant was 1 in 121,054 in the ExAC database; it was not found in the Exome Sequencing Project database. Patients cells showed decreased levels and activities of complexes III and I.
In a 6-year-old girl with mitochondrial complex III deficiency nuclear type 5 (MC3DN5; 615160), Burska et al. (2021) identified homozygosity for a c.665G-C transversion (c.665G-C, NM_003366) in the UQCRC2 gene, resulting in a gly222-to-ala (G222A) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the gnomAD database or in a control population from the Czech Republic. Analysis in patient muscle and fibroblast cells showed impaired complex I+III activity. Steady-state levels of respiratory chain complexes I and III were severely decreased in patient fibroblasts. Analysis of patient fibroblasts also showed accumulation of complex III assembly units that were devoid of the subunits UQCRC1, UQCRC2, and UQCRFS1 (191327). Burska et al. (2021) identified increased expression of the matrix protease CLPP (601119) in patient fibroblasts, suggesting activation of the mitochondrial protein quality control machinery. Expression of wildtype UQCRC2 in patient fibroblasts increased maximal respiration rate.
Burska, D., Stiburek, L., Krizova, J., Vanisova, M., Martinek, V., Sladkova, J., Zamecnik, J., Honzik, T., Zeman, J., Hansikova, H., Tesarova, M. Homozygous missense mutation in UQCRC2 associated with severe encephalomyopathy, mitochondrial complex III assembly defect and activation of mitochondrial protein quality control. Biochim. Biophys. Acta Molec. Basis Dis. 1867: 166147, 2021. [PubMed: 33865955] [Full Text: https://doi.org/10.1016/j.bbadis.2021.166147]
Duncan, A. M. V., Ozawa, T., Suzuki, H., Rozen, R. Assignment of the gene for the core protein II (UQCRC2) subunit of the mitochondrial cytochrome bc1 complex to human chromosome 16p12. Genomics 18: 455-456, 1993. [PubMed: 8288258] [Full Text: https://doi.org/10.1006/geno.1993.1500]
Gaignard, P., Eyer, D., Lebigot, E., Oliveira, C., Therond, P., Boutron, A., Slama, A. UQCRC2 mutation in a patient with mitochondria complex III deficiency causing recurrent liver failure lactic acidosis and hypoglycemia. J. Hum. Genet. 62: 729-731, 2017. [PubMed: 28275242] [Full Text: https://doi.org/10.1038/jhg.2017.22]
Miyake, N., Yano, S., Sakai, C., Hatakeyama, H., Matsushima, Y., Shiina, M., Watanabe, Y., Bartley, J., Abdenur, J. E., Wang, R. Y., Chang, R., Tsurusaki, Y., Doi, H., Nakashima, M., Saitsu, H., Ogata, K., Goto, Y., Matsumoto, N. Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation. Hum. Mutat. 34: 446-452, 2013. [PubMed: 23281071] [Full Text: https://doi.org/10.1002/humu.22257]
Wisloff, U., Najjar, S. M., Ellingsen, O., Haram, P. M., Swoap, S., Al-Share, Q., Fernstrom, M., Rezaei, K., Lee, S. J., Koch, L. G., Britton, S. L. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307: 418-420, 2005. [PubMed: 15662013] [Full Text: https://doi.org/10.1126/science.1108177]