Alternative titles; symbols
HGNC Approved Gene Symbol: COQ2
Cytogenetic location: 4q21.23 Genomic coordinates (GRCh38): 4:83,263,824-83,285,134 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q21.23 | {Multiple system atrophy, susceptibility to} | 146500 | Autosomal dominant; Autosomal recessive | 3 |
| Coenzyme Q10 deficiency, primary, 1 | 607426 | Autosomal recessive | 3 |
CoQ (ubiquinone) serves as a redox carrier in the mitochondrial respiratory chain and is a lipid-soluble antioxidant. COQ2, or parahydroxybenzoate-polyprenyltransferase (EC 2.5.1.39), catalyzes one of the final reactions in the biosynthesis of CoQ, the prenylation of parahydroxybenzoate with an all-trans polyprenyl group (Forsgren et al., 2004).
By database analysis, followed by RT-PCR and RACE of human liver and skeletal muscle cDNA libraries, Forsgren et al. (2004) cloned COQ2. The deduced 421-amino acid protein contains a central polyprenyl diphosphate-binding site, followed by 6 C-terminal transmembrane regions. COQ2 was predicted to localize to mitochondria. Northern blot analysis detected abundant expression of a 1.8-kb transcript in skeletal muscle. RNA dot-blot analysis detected COQ2 in all adult and fetal tissues examined, with highest levels in skeletal muscle, adrenal gland, and heart.
Forsgren et al. (2004) found that human COQ2 rescued the growth of Coq2-null yeast cells and restored CoQ biosynthesis. CoQ formed when cells were incubated with labeled decaprenyl pyrophosphate and nonaprenyl pyrophosphate, indicating that human COQ2 participates in the biosynthesis of CoQ.
Forsgren et al. (2004) determined that the COQ2 gene contains 7 exons and spans more than 20.7 kb.
By genomic sequence analysis, Forsgren et al. (2004) mapped the COQ2 gene to chromosome 4q21-q22.
Primary Coenzyme Q10 Deficiency 1
Using homozygosity mapping and sequence analysis, Quinzii et al. (2006) detected a homozygous A-to-G transition at nucleotide 890 of the COQ2 gene in a patient with coenzyme Q10 deficiency-1 (COQ10D1; 607426). The mutation was predicted to change amino acid 297 from tyrosine to cysteine (Y297C; 609825.0001) in the third of 6 predicted transmembrane domains of the COQ2 protein. The transition was heterozygous in both parents and absent in healthy individuals.
Mollet et al. (2007) reported a French family with COQ10 deficiency that manifested as fatal infantile multiorgan disease. Enzymologic analysis showed low quinone-dependent oxidative phosphorylation activity, and COQ10 deficiency was confirmed by restoration of oxidative phosphorylation activity after quinone addition. In the affected family members, Mollet et al. (2007) identified a homozygous 1-bp deletion in the COQ2 gene that resulted in a frameshift (609825.0002). Transformation of yeast lacking Coq2 with human COQ2 containing the mutation resulted in defective growth on respiratory medium.
Diomedi-Camassei et al. (2007) reported 2 patients with COQ10 deficiency who had primarily renal involvement. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months with no extrarenal symptoms, and the second patient presented at 5 days of life with oliguria and developed end-stage renal disease to which he succumbed at 6 months of age after a course complicated by progressive epileptic encephalopathy. Both patients carried 2 mutations in the COQ2 gene. The mutations (609825.0003, 609825.0004, and 609825.0005) were all missense mutations occurring in residues highly conserved from yeast to human.
Multiple System Atrophy 1, Susceptibility to
The association between variation in the COQ2 gene and susceptibility to multiple system atrophy is controversial.
In affected members of 2 unrelated Japanese families with multiple system atrophy-1 (MSA1; 146500), The Multiple-System Atrophy Research Collaboration (2013) identified homozygous or compound heterozygous mutations in the COQ2 gene (609825.0006-609825.0008). The mutations were found in the first family by linkage analysis combined by whole-genome sequencing. Subsequent sequencing of the COQ2 gene in 363 Japanese patients with sporadic MSA and 2 sets of controls (520 individuals and 2,383 individuals) identified putative heterozygous or biallelic pathogenic variants in 33 patients (see, e.g., 609825.0009). The most common variant was V393A (609825.0007), which was also found in heterozygous state in 17 Japanese controls. Statistical analysis in the Japanese population yielded an odds ratio for disease development of 2.23 (p = 6.0 x 10(-5)) in COQ2 carriers. Rare pathogenic variants were also found in 4 of 223 European patients with sporadic disease and in 1 of 172 North American patients with sporadic disease. None of 315 European controls carried a variant, but 1 of 294 North American controls carried a variant. In vitro functional expression assays in yeast Coq2-null strains demonstrated that the mutations caused variable growth defects and variably low COQ2 activities in patient cell lines. The findings suggested that mutations in the COQ2 gene may cause susceptibility to the disorder. Patients with COQ2 mutations had increased frequency of the cerebellar variant compared to the parkinsonism variant. Four additional families with MSA, including a German family reported by Wullner et al. (2009), did not have COQ2 mutations, indicating genetic heterogeneity.
Jeon et al. (2014) did not find an association between the V393A variant in the COQ2 gene (609825.0007) and multiple system atrophy among 299 Korean patients with the disorder and 365 controls (minor allele frequency 2.7% of cases vs 2.6% of controls). Sharma et al. (2014) did not find the V393A variant in a large cohort of 788 European patients with MSA or 600 European controls. Schottlaender and Houlden (2014) did not find the V393A variant in more than 300 European patients with MSA or 262 European controls. These authors suggested that variation in the COQ2 gene may not represent a risk factor for the development of multiple system atrophy.
Associations Pending Confirmation
In a 27-year-old Japanese man with features of both retinitis pigmentosa (RP; see 268000) and Leber hereditary optic neuropathy (LHON; see 535000), who was negative for mutation in known RP-associated genes or LHON-associated mtDNA, Kurata et al. (2022) performed trio whole-exome sequencing and identified compound heterozygosity for missense mutations in the COQ2 gene: c.469C-T (P157S) and c. 518G-A (R173H). His unaffected parents were each heterozygous for one of the variants, both of which had previously been reported in patients with multiple system atrophy. Physical examination of the proband revealed no renal or neurologic abnormalities. The authors noted that this was the first report of COQ2 mutations associated with isolated eye anomalies.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human COQ2 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a boy, born of consanguineous parents, with infantile encephalomyopathy, nephropathy, and primary coenzyme Q10 deficiency-1 (COQ10D1; 607426), originally reported by Salviati et al. (2005), Quinzii et al. (2006) identified a homozygous 890A-G transition in the COQ2 gene, changing a highly conserved tyrosine to cysteine at amino acid 297 (Y297C) within a predicted transmembrane domain of the protein. He had a deficiency of CoQ10 in muscle and fibroblasts (22% of controls), and fibroblasts showed about 36% residual COQ2 enzymatic activity. His younger sister, who had only proteinuria and coenzyme Q deficiency in fibroblasts, carried the same homozygous mutation.
Lopez-Martin et al. (2007) showed that the Y297C-mutant protein could not functionally complement Coq2-defective yeast. An equivalent mutation introduced into the wildtype yeast Coq2 gene decreased CoQ10 levels and impaired growth in respiratory-chain dependent medium, consistent with a loss of function. Growth was restored by CoQ10 supplementation. The CoQ10 deficiency was also found to impair de novo pyrimidine synthesis, which may contribute to the pathogenesis of the disease.
Quinzii et al. (2010) studied fibroblasts carrying a homozygous Y297C mutation. CoQ10 levels were decreased to 42.7% of normal, and the cells showed decreased ATP synthesis and increased oxidative stress-induced death. The results suggested that partial CoQ10 deficiency can cause oxidative stress that is toxic to the cells.
Mollet et al. (2007) reported a French family with coenzyme Q10 deficiency-1 (607426) in which a son and daughter died shortly after birth due to anemia, liver failure, and renal insufficiency. The healthy parents were from the same region and shared a patronymic but no known ancestry. In 1 of the affected children, Mollet et al. (2007) identified a homozygous 1-bp deletion (T) at nucleotide 1198 in exon 7 of the COQ2 gene, resulting in a premature stop codon. The parents were heterozygous for the mutation, which was absent in controls.
In a patient with coenzyme Q10 deficiency (607426) who presented with steroid-resistant nephrotic syndrome at age 18 months, Diomedi-Camassei et al. (2007) identified compound heterozygosity for 2 mutations in the COQ2 gene: a 590G-A transition resulting in an arg197-to-his (R197H) substitution on the maternal allele, and a 683A-G transition resulting in an asn228-to-ser (N228S; 609825.0004) substitution on the paternal allele. Neither mutation was found in 500 control chromosomes.
Quinzii et al. (2010) studied fibroblasts carrying the compound heterozygous R197H/N228S mutations. CoQ10 levels were decreased to 36% of normal, and the cells showed impaired respiratory-dependent growth after 48 hours, decreased ATP levels, increased oxidative stress markers, and increased cell death. The results suggested that partial CoQ10 deficiency can cause both impaired bioenergetics and oxidative stress that is toxic to the cells.
For discussion of the asn228-to-ser (N228S) mutation in the COQ2 gene that was found in compound heterozygous state in a patient with coenzyme Q10 deficiency (607426) by Diomedi-Camassei et al. (2007), see 609825.0003.
In an Italian child with coenzyme Q10 deficiency-1 (607426), Diomedi-Camassei et al. (2007) identified homozygosity for a 437G-A transition in the COQ2 gene, resulting in a ser146-to-asn (S146N) substitution. Both parents were shown to be carriers and the mutation was not identified in 500 control chromosomes. The child presented with severe renal disease in the newborn period characterized as severe crescentic glomerulonephritis on biopsy at 10 days of age, developed intractable seizures and end-stage renal disease, and died at 6 months of age.
Jeon et al. (2014) noted that this mutation is a c.382A-G transition in the COQ2 gene, resulting in a met128-to-val (M128V) substitution, based on the NCBI reference sequence (NM_015697.7) and not a met78-to-val substitution as originally published by The Multiple-System Atrophy Research Collaboration (2013).
In 2 Japanese sibs, born of consanguineous parents, with multiple system atrophy-1 (MSA1; 146500), originally reported by Hara et al. (2007), The Multiple-System Atrophy Research Collaboration (2013) identified a homozygous met128-to-val substitution in the COQ2 gene. The mutation, which was found by linkage analysis combined with whole-genome sequencing, was not found in a large control database or in 360 control Japanese alleles. Each sib also carried a homozygous val393-to-ala (V393A; 609825.0007) substitution that was found in heterozygous state in 5 of 360 control Japanese alleles. An unaffected sib did not carry either variant, and family history indicated that the parents, each of whom was an obligate carrier of both variants, showed no signs of the disorder. In vitro functional expression assays in yeast Coq2-null strains demonstrated that the M128V variant showed severely decreased growth similar to the null strain. Patient cerebellar tissue from a homozygous carrier showed severely decreased intracellular levels of COQ2.
Jeon et al. (2014) noted that this mutation is a c.1178T-C transition in the COQ2 gene, resulting in a val393-to-ala (V393A) substitution, based on the NCBI reference sequence (NM_015697.7) and not a val343-to-ala substitution as originally published by The Multiple-System Atrophy Research Collaboration (2013).
The Multiple-System Atrophy Research Collaboration (2013) found that a val393-to-ala variant in the COQ2 gene was associated with multiple system atrophy-1 (146500) in Japanese patients. V393A was present in homozygous state with another pathogenic homozygous mutation (M128V; 609825.0006) in 2 Japanese sibs with the disorder. It was also found in compound heterozygosity with R387X (609825.0008) in 2 additional Japanese sibs from another family with the disorder. Among 363 Japanese patients with sporadic MSA1, homozygous V393A was found in 2 patients and none of 520 controls, and heterozygous V393A was found in 31 patients and 17 controls; 2 heterozygous carriers were compound heterozygous with another potentially pathogenic COQ2 variant. The allele frequency was 4.8% in Japanese patients and 1.6% in Japanese controls (odds ratio (OR) for MSA1 of 3.05, p = 1.5 x 10(-4)). Genotyping in a second series of 2,383 Japanese controls showed that the V393A variant had an allele frequency of 2.2%, yielding an OR of 2.23 (p = 6.0 x 10(-5)). Two patients with Alzheimer disease (AD; 104300) who were found to carry a homozygous V393A mutation did not show any signs of parkinsonism, cerebellar ataxia, or autonomic dysfunction. Otherwise, the V393A variant appeared to be specific for MSA. V393A was not found in 395 patients or 609 controls from European/North American cohorts. In vitro functional expression assays in yeast Coq2-null strains showed that the V393A variant could restore growth similar to wildtype, but showed somewhat decreased COQ2 activities in cell lines derived from patients with MSA.
Jeon et al. (2014) did not find an association between the V393A variant and multiple system atrophy among 299 Korean patients with the disorder and 365 controls (minor allele frequency 2.7% of cases versus 2.6% of controls).
Sharma et al. (2014) did not find the V393A variant in a large cohort of 788 European patients with MSA or 600 European controls.
Schottlaender and Houlden (2014) did not find the V393A variant in more than 300 European patients with MSA or 262 European controls.
Based on the NCBI reference sequence (NM_015697.7), this mutation is an arg387-to-ter (R387X) substitution and not an arg337-to-ter substitution as originally reported by The Multiple-System Atrophy Research Collaboration (2013).
In 2 Japanese sibs with multiple system atrophy-1 (MSA1; 146500), The Multiple-System Atrophy Research Collaboration (2013) identified compound heterozygosity for 2 variants in the COQ2 gene: an arg387-to-ter substitution, and V393A (609825.0007). V393A was present in 5 of 360 control Japanese alleles, but R387X was not found in controls. Their unaffected mother was heterozygous for V393A and another unaffected sib was heterozygous for R387X. In vitro functional expression assays in yeast Coq2-null strains showed that the R387X variant resulted in severely impaired growth similar to the null strain, and COQ2 activity levels in patient cells was decreased compared to wildtype.
Based on the NCBI reference sequence (NM_015697.7), this mutation is an arg387-to-gln (R387Q) substitution and not an arg337-to-gln substitution as originally reported by The Multiple-System Atrophy Research Collaboration (2013).
In a Japanese patient with sporadic multiple system atrophy-1 (MSA1; 146500), The Multiple-System Atrophy Research Collaboration (2013) identified compound heterozygosity for 2 variants in the COQ2 gene: arg387-to-gln (R387Q) and V393A (609825.0007). In vitro functional expression assays in yeast Coq2-null strains showed that the R387Q variant resulted in severely impaired growth similar to the null strain, and COQ2 activity levels in patient cells was decreased compared to wildtype.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Diomedi-Camassei, F., Di Giandomenico, S., Santorelli, F. M., Caridi, G., Piemonte, F., Montini, G., Ghiggeri, G. M., Murer, L., Barisoni, L., Pastore, A., Muda, A. O., Valente, M. L., Bertini, E., Emma, F. COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J. Am. Soc. Nephrol. 18: 2773-2780, 2007. [PubMed: 17855635] [Full Text: https://doi.org/10.1681/ASN.2006080833]
Forsgren, M., Attersand, A., Lake, S., Grunler, J., Swiezewska, E., Dallner, G., Climent, I. Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ. Biochem. J. 382: 519-526, 2004. [PubMed: 15153069] [Full Text: https://doi.org/10.1042/BJ20040261]
Hara, K., Momose, Y., Tokiguchi, S., Shimohata, M., Terajima, K., Onodera, O., Kakita, A., Yamada, M., Takahashi, H., Hirasawa, M., Mizuno, Y., Ogata, K., Goto, J., Kanazawa, I., Nishizawa, M., Tsuji, S. Multiplex families with multiple system atrophy. Arch. Neurol. 64: 545-551, 2007. [PubMed: 17420317] [Full Text: https://doi.org/10.1001/archneur.64.4.545]
Jeon, B. S., Farrer, M. J., Bortnick, S. F. Mutant COQ2 in multiple-system atrophy. (Letter) New Eng. J. Med. 371: 80 only, 2014. [PubMed: 24988567] [Full Text: https://doi.org/10.1056/NEJMc1311763]
Kurata, K., Hosono, K., Takayama, M., Katsuno, M., Saitsu, H., Ogata, T., Hotta, Y. Retinitis pigmentosa with optic neuropathy and COQ2 mutations: a case report. Am. J. Ophthal. Case Rep. 25: 101298, 2022. [PubMed: 35112026] [Full Text: https://doi.org/10.1016/j.ajoc.2022.101298]
Lopez-Martin, J. M., Salviati, L., Trevisson, E., Montini, G., DiMauro, S., Quinzii, C., Hirano, M., Rodriguez-Hernandez, A., Cordero, M. D., Sanchez-Alcazar, J. A., Santos-Ocana, C., Navas, P. Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum. Molec. Genet. 16: 1091-1097, 2007. [PubMed: 17374725] [Full Text: https://doi.org/10.1093/hmg/ddm058]
Mollet, J., Giurgea, I., Schlemmer, D., Dallner, G., Chretien, D., Delahodde, A., Bacq, D., de Lonlay, P., Munnich, A., Rotig, A. Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. J. Clin. Invest. 117: 765-772, 2007. [PubMed: 17332895] [Full Text: https://doi.org/10.1172/JCI29089]
Quinzii, C. M., Lopez, L. C., Gilkerson, R. W., Dorado, B., Coku, J., Naini, A. B., Lagier-Tourenne, C., Schuelke, M., Salviati, L., Carrozzo, R., Santorelli, F., Rahman, S., Tazir, M., Koenig, M., DiMauro, S., Hirano, M. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 24: 3733-3743, 2010. [PubMed: 20495179] [Full Text: https://doi.org/10.1096/fj.09-152728]
Quinzii, C., Naini, A., Salviati, L., Trevisson, E., Navas, P., DiMauro, S., Hirano, M. A mutation in Para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am. J. Hum. Genet. 78: 345-349, 2006. [PubMed: 16400613] [Full Text: https://doi.org/10.1086/500092]
Salviati, L., Sacconi, S., Murer, L., Zacchello, G., Franceschini, L., Laverda, A. M., Basso, G., Quinzii, C., Angelini, C., Hirano, M., Naini, A. B., Navas, P., DiMauro, S., Montini, G. Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 65: 606-608, 2005. [PubMed: 16116126] [Full Text: https://doi.org/10.1212/01.wnl.0000172859.55579.a7]
Schottlaender, L. V., Houlden, H. Mutant COQ2 in multiple-system atrophy. (Letter) New Eng. J. Med. 371: 81 only, 2014. [PubMed: 24988569] [Full Text: https://doi.org/10.1056/NEJMc1311763]
Sharma, M., Wenning, G., Kruger, R. Mutant COQ2 in multiple-system atrophy. (Letter) New Eng. J. Med. 371: 80-81, 2014. [PubMed: 24988568] [Full Text: https://doi.org/10.1056/NEJMc1311763]
The Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. New Eng. J. Med. 369: 233-244, 2013. Note: Erratum: New Eng. J. Med. 371: 94 only, 2014. [PubMed: 23758206] [Full Text: https://doi.org/10.1056/NEJMoa1212115]
Wullner, U., Schmitt, I., Kammal, M., Kretzschmar, H. A., Neumann, M. Definite multiple system atrophy in a German family. J. Neurol. Neurosurg. Psychiat. 80: 449-450, 2009. [PubMed: 19289484] [Full Text: https://doi.org/10.1136/jnnp.2008.158949]