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Leonardo Salviati - One of the best experts on this subject based on the ideXlab platform.
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genetic bases and clinical manifestations of coenzyme q10 coq10 deficiency
Journal of Inherited Metabolic Disease, 2015Co-Authors: Maria Andrea Desbats, Mara Doimo, Eva Trevisso, Giada Lunardi, Leonardo SalviatiAbstract:Coenzyme Q10 is a remarkable lipid involved in many cellular processes such as energy production through the mitochondrial respiratory chain (RC), beta-oxidation of fatty acids, and pyrimidine biosynthesis, but it is also one of the main cellular antioxidants. Its biosynthesis is still incompletely characterized and requires at least 15 genes. Mutations in eight of them (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) cause primary CoQ10 deficiency, a heterogeneous group of disorders with variable age of onset (from birth to the seventh decade) and associated clinical phenotypes, ranging from a fatal multisystem disease to isolated steroid resistant nephrotic syndrome (SRNS) or isolated central nervous system disease. The pathogenesis is complex and related to the different functions of CoQ10. It involves defective ATP production and oxidative stress, but also an impairment of pyrimidine biosynthesis and increased apoptosis. CoQ10 deficiency can also be observed in patients with defects unrelated to CoQ10 biosynthesis, such as RC defects, multiple acyl-CoA dehydrogenase deficiency, and ataxia and oculomotor apraxia.
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genetics of coenzyme q10 deficiency
Molecular Syndromology, 2014Co-Authors: Mara Doimo, Maria Andrea Desbats, Cristina Cerqua, Matteo Cassina, Eva Trevisso, Leonardo SalviatiAbstract:Coenzyme Q10 (CoQ10) is an essential component of eukaryotic cells and is involved in crucial biochemical reactions such as the production of ATP in the mitochondrial respiratory chain, the biosynthesis of pyrimidines, and the modulation of apoptosis. CoQ10 requires at least 13 genes for its biosynthesis. Mutations in these genes cause primary CoQ10 deficiency, a clinically and genetically heterogeneous disorder. To date mutations in 8 genes (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) have been associated with CoQ10 deficiency presenting with a wide variety of clinical manifestations. Onset can be at virtually any age, although pediatric forms are more common. Symptoms include those typical of respiratory chain disorders (encephalomyopathy, ataxia, lactic acidosis, deafness, retinitis pigmentosa, hypertrophic cardiomyopathy), but some (such as steroid-resistant nephrotic syndrome) are peculiar to this condition. The molecular bases of the clinical diversity of this condition are still unknown. It is of critical importance that physicians promptly recognize these disorders because most patients respond to oral administration of CoQ10.
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treatment of coq10 deficient fibroblasts with ubiquinone coq analogs and vitamin c time and compound dependent effects
PLOS ONE, 2010Co-Authors: Luis C. Lopez, Ali Naini, Leonardo Salviati, Catarina M Quinzii, Shamima Rahman, Salvatore Dimauro, Estela Area, Markus Schuelke, Michio HiranoAbstract:Background: Coenzyme Q10 (CoQ10) and its analogs are used therapeutically by virtue of their functions as electron carriers, antioxidant compounds, or both. However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress. Methodology/Principal Findings: To test these concepts, we have evaluated the effects of CoQ10, coenzyme Q2 (COQ2), idebenone, and vitamin C on bioenergetics and oxidative stress in human skin fibroblasts with primary CoQ10 deficiency. A final concentration of 5 mM of each compound was chosen to approximate the plasma concentration of CoQ10 of patients treated with oral ubiquinone. CoQ10 supplementation for one week but not for 24 hours doubled ATP levels and ATP/ADP ratio in CoQ10 deficient fibroblasts therein normalizing the bioenergetics status of the cells. Other compounds did not affect cellular bioenergetics. In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements. Conclusions/Significance: These results indicate that: 1) pharmacokinetics of CoQ10 in reaching the mitochondrial respiratory chain is delayed; 2) short-tail ubiquinone analogs cannot replace CoQ10 in the mitochondrial respiratory chain under conditions of CoQ10 deficiency; and 3) oxidative stress and cell death can be counteracted by administration of lipophilic or hydrophilic antioxidants. The results of our in vitro experiments suggest that primary CoQ10 deficiencies should be treated with CoQ10 supplementation but not with short-tail ubiquinone analogs, such as idebenone or COQ2. Complementary administration of antioxidants with high bioavailability should be considered if oxidative stress is present.
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missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis
Human Molecular Genetics, 2007Co-Authors: Jose M Lopezmartin, Eva Trevisson, Leonardo Salviati, Michio Hirano, Catarina M Quinzii, Giovanni Montini, Salvatore Dimauro, Angeles Rodriguezhernandez, Mario D Cordero, Jose Antonio SanchezalcazarAbstract:Coenzyme Q10 (CoQ10) deficiency has been associated with an increasing number of clinical phenotypes that respond to CoQ10 supplementation. In two siblings with encephalomyopathy, nephropathy and severe CoQ10 deficiency, a homozygous mutation was identified in the CoQ10 biosynthesis gene COQ2, encoding polyprenyl-pHB transferase. To confirm the pathogenicity of this mutation, we have demonstrated that human wild-type, but not mutant COQ2, functionally complements COQ2 defective yeast. In addition, an equivalent mutation introduced in the yeast COQ2 gene also decreases both CoQ6 concentration and growth in respiratory-chain dependent medium. Polyprenyl-pHB transferase activity was 33–45% of controls in COQ2 mutant fibroblasts. CoQ-dependent mitochondrial complexes activities were restored in deficient fibroblasts by CoQ10 supplementation, and growth rate was restored in these cells by either CoQ10 or uridine supplementation. This work is the first direct demonstration of the pathogenicity of a COQ2 mutation involved in human disease, and establishes yeast as a useful model to study human CoQ10 deficiency. Moreover, we demonstrate that CoQ10 deficiency in addition to the bioenergetics defect also impairs de novo pyrimidine synthesis, which may contribute to the pathogenesis of the disease.
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a mutation in para hydroxybenzoate polyprenyl transferase COQ2 causes primary coenzyme q10 deficiency
American Journal of Human Genetics, 2006Co-Authors: Catarina M Quinzii, Eva Trevisson, Plácido Navas, Ali Naini, Leonardo Salviati, Michio HiranoAbstract:Ubiquinone (coenzyme Q10 or CoQ10) is a lipid-soluble component of virtually all cell membranes, where it functions as a mobile electron and proton carrier. CoQ10 deficiency is inherited as an autosomal recessive trait and has been associated with three main clinical phenotypes: a predominantly myopathic form with central nervous system involvement, an infantile encephalomyopathy with renal dysfunction, and an ataxic form with cerebellar atrophy. In two siblings of consanguineous parents with the infantile form of CoQ10 deficiency, we identified a homozygous missense mutation in the COQ2 gene, which encodes para-hydroxybenzoate-polyprenyl transferase. The A→G transition at nucleotide 890 changes a highly conserved tyrosine to cysteine at amino acid 297 within a predicted transmembrane domain. Radioisotope assays confirmed a severe defect of CoQ10 biosynthesis in the fibroblasts of one patient. This mutation in COQ2 is the first molecular cause of primary CoQ10 deficiency.
Michio Hirano - One of the best experts on this subject based on the ideXlab platform.
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the COQ2 genotype predicts the severity of coenzyme q10 deficiency
Human Molecular Genetics, 2016Co-Authors: Maria Andrea Desbats, Michio Hirano, Mara Doimo, Matteo Cassina, Valeria Morbidoni, Micol Silicbenussi, Vincenzo Ciminale, Sabrina Sacconi, Giuseppe Asso, Fabie PierrelAbstract:COQ2 (p-hydroxybenzoate polyprenyl transferase) encodes the enzyme required for the second step of the final reaction sequence of Coenzyme Q10 (CoQ) biosynthesis. Its mutations represent a frequent cause of primary CoQ deficiency and have been associated with the widest clinical spectrum, ranging from fatal neonatal multisystemic disease to late-onset encephalopathy. However, the reasons of this variability are still unknown.We have characterized the structure of human COQ2, defined its subcellular localization and developed a yeast model to validate all the mutant alleles reported so far.Our findings show that the main functional transcript of COQ2 is shorter than what was previously reported and that its protein product localizes to mitochondria with the C-terminus facing the intermembrane space. Complementation experiments in yeast showed that the residual activity of the mutant proteins correlates with the clinical phenotypes observed in patients.We defined the structure of COQ2 with relevant implications for mutation screening in patients and demonstrated that, contrary to other COQ gene defects such as ADCK3, there is a correlation between COQ2 genotype and patient's phenotype.
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treatment of coq10 deficient fibroblasts with ubiquinone coq analogs and vitamin c time and compound dependent effects
PLOS ONE, 2010Co-Authors: Luis C. Lopez, Ali Naini, Leonardo Salviati, Catarina M Quinzii, Shamima Rahman, Salvatore Dimauro, Estela Area, Markus Schuelke, Michio HiranoAbstract:Background: Coenzyme Q10 (CoQ10) and its analogs are used therapeutically by virtue of their functions as electron carriers, antioxidant compounds, or both. However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress. Methodology/Principal Findings: To test these concepts, we have evaluated the effects of CoQ10, coenzyme Q2 (COQ2), idebenone, and vitamin C on bioenergetics and oxidative stress in human skin fibroblasts with primary CoQ10 deficiency. A final concentration of 5 mM of each compound was chosen to approximate the plasma concentration of CoQ10 of patients treated with oral ubiquinone. CoQ10 supplementation for one week but not for 24 hours doubled ATP levels and ATP/ADP ratio in CoQ10 deficient fibroblasts therein normalizing the bioenergetics status of the cells. Other compounds did not affect cellular bioenergetics. In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements. Conclusions/Significance: These results indicate that: 1) pharmacokinetics of CoQ10 in reaching the mitochondrial respiratory chain is delayed; 2) short-tail ubiquinone analogs cannot replace CoQ10 in the mitochondrial respiratory chain under conditions of CoQ10 deficiency; and 3) oxidative stress and cell death can be counteracted by administration of lipophilic or hydrophilic antioxidants. The results of our in vitro experiments suggest that primary CoQ10 deficiencies should be treated with CoQ10 supplementation but not with short-tail ubiquinone analogs, such as idebenone or COQ2. Complementary administration of antioxidants with high bioavailability should be considered if oxidative stress is present.
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missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis
Human Molecular Genetics, 2007Co-Authors: Jose M Lopezmartin, Eva Trevisson, Leonardo Salviati, Michio Hirano, Catarina M Quinzii, Giovanni Montini, Salvatore Dimauro, Angeles Rodriguezhernandez, Mario D Cordero, Jose Antonio SanchezalcazarAbstract:Coenzyme Q10 (CoQ10) deficiency has been associated with an increasing number of clinical phenotypes that respond to CoQ10 supplementation. In two siblings with encephalomyopathy, nephropathy and severe CoQ10 deficiency, a homozygous mutation was identified in the CoQ10 biosynthesis gene COQ2, encoding polyprenyl-pHB transferase. To confirm the pathogenicity of this mutation, we have demonstrated that human wild-type, but not mutant COQ2, functionally complements COQ2 defective yeast. In addition, an equivalent mutation introduced in the yeast COQ2 gene also decreases both CoQ6 concentration and growth in respiratory-chain dependent medium. Polyprenyl-pHB transferase activity was 33–45% of controls in COQ2 mutant fibroblasts. CoQ-dependent mitochondrial complexes activities were restored in deficient fibroblasts by CoQ10 supplementation, and growth rate was restored in these cells by either CoQ10 or uridine supplementation. This work is the first direct demonstration of the pathogenicity of a COQ2 mutation involved in human disease, and establishes yeast as a useful model to study human CoQ10 deficiency. Moreover, we demonstrate that CoQ10 deficiency in addition to the bioenergetics defect also impairs de novo pyrimidine synthesis, which may contribute to the pathogenesis of the disease.
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a mutation in para hydroxybenzoate polyprenyl transferase COQ2 causes primary coenzyme q10 deficiency
American Journal of Human Genetics, 2006Co-Authors: Catarina M Quinzii, Eva Trevisson, Plácido Navas, Ali Naini, Leonardo Salviati, Michio HiranoAbstract:Ubiquinone (coenzyme Q10 or CoQ10) is a lipid-soluble component of virtually all cell membranes, where it functions as a mobile electron and proton carrier. CoQ10 deficiency is inherited as an autosomal recessive trait and has been associated with three main clinical phenotypes: a predominantly myopathic form with central nervous system involvement, an infantile encephalomyopathy with renal dysfunction, and an ataxic form with cerebellar atrophy. In two siblings of consanguineous parents with the infantile form of CoQ10 deficiency, we identified a homozygous missense mutation in the COQ2 gene, which encodes para-hydroxybenzoate-polyprenyl transferase. The A→G transition at nucleotide 890 changes a highly conserved tyrosine to cysteine at amino acid 297 within a predicted transmembrane domain. Radioisotope assays confirmed a severe defect of CoQ10 biosynthesis in the fibroblasts of one patient. This mutation in COQ2 is the first molecular cause of primary CoQ10 deficiency.
Shoji Tsuji - One of the best experts on this subject based on the ideXlab platform.
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COQ2 v393a confers high risk susceptibility for multiple system atrophy in east asian population
Journal of the Neurological Sciences, 2021Co-Authors: Kristine Joyce Porto, Hiroyuki Ishiura, Takashi Matsukawa, Shoji Tsuji, Jun Mitsui, Makito Hirano, Ayaka Chikada, Tatsushi Toda, Susumu KusunokiAbstract:Abstract Multiple system atrophy (MSA) is a rare, late-onset, and devastating neurodegenerative disease characterized by autonomic failure, alongside with various combination of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Since we first identified biallelic mutations in the COQ2 gene in two multiplex MSA families and further reported that heterozygous COQ2 V393A variant confers a susceptibility to sporadic MSA, the results of nearly a decade of investigating this association globally were quite remarkable. COQ2 V393A was virtually absent in the American and European populations but was shown to have varying associations with sporadic MSA in the East Asian populations. In our attempt to clarify the latter and provide a coherent regional conclusion, we conducted two independent case-control series which showed clear association of the V393A variant with sporadic MSA in the Japanese population. We then pooled the results with other studies from the East Asian population and conducted a meta-analysis which broadened and established the association regionally (pooled OR 2.12, 95% CI: 1.35–3.31, PI: 0.63–7.15, p = 0.0047). The subgroup analysis identified a strong association of V393A with MSA-C (pooled OR 2.57, 95% CI: 1.98–3.35; p = 2.56 × 10−12) but not with MSA-P (pooled OR 1.41, 95% CI: 0.88–2.26; p = 0.16). Our results highlighted the importance of investigating region-specific and pan-regional genetic variants that may potentially underlie the pathomechanisms of neurodegenerative diseases. COQ2 V393A variant remains a susceptibility variant rather than causative for MSA particularly, MSA-C subtype, in the East Asian population.
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plasma coenzyme q10 levels in patients with multiple system atrophy
JAMA Neurology, 2016Co-Authors: Ju Mitsui, Hiroyuki Ishiura, Takashi Matsukawa, Tsutomu Yasuda, Shoji TsujiAbstract:Importance Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2 , which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA. Objective To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype–matched controls. Design, Setting, and Participants We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level. Main Outcomes and Measures Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype. Results Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] µg/mL; P = .01) (difference between medians: −0.14; 95% CI, –0.25 to –0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) µg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) ( P = .02). Conclusions and Relevance Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.
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Mutant COQ2 in multiple-system atrophy.
New England Journal of Medicine, 2014Co-Authors: Jun Mitsui, Shoji TsujiAbstract:To the Editor: Tsuji and colleagues (July 18 issue)1 report that variants in the gene encoding coenzyme Q2 (COQ2) increase the risk of multiple-system atrophy. They observed homozygous COQ2 variants encoding the substitutions M78V and V343A in a consanguineous Japanese family with multiple-system atrophy subtype P and noted an association between V343A and sporadic multiple-system atrophy (minor-allele frequency [MAF], 4.8% of cases vs. 1.6% of controls; odds ratio, 3.05; 95% confidence interval, 1.65 to 5.85). However, the authors erroneously labeled human COQ2 variability from the fourth ATG start codon in exon 1, which encodes the smallest protein isoform and does not functionally complement the yeast COQ2-null mutant.2 On the basis of the National Center for Biotechnology Information (NCBI) Reference Sequence (NM_015697.7), M78V should be labeled COQ2 c.382A→G (p.M128V) and V343A should be labeled c.1178T→C (p.V393A). We sequenced COQ2 in 299 Korean persons with multiple-system atrophy and 365 unaffected Korean persons and observed heterozygous COQ2 c.320G→C (encoding p.S107T) and c.382A→T (encoding p.M128R) in 2 patients with sporadic multiple-system atrophy; COQ2 c.1178T→C (p.V393A) was not associated with multiple-system atrophy (MAF, 2.7% of cases vs. 2.6% of controls). It is a challenge to reconcile recessive linkage of homozygous COQ2 mutations in familial multiple-system atrophy with a heterozygous, presumably dominant-negative association in sporadic multiple-system atrophy. Respectfully, we suggest that Tsuji and colleagues reconsider whether variations in COQ2 represent a risk factor for multiple-system atrophy. Genomic multiplications of the SNCA 6.4-Mb locus telomeric to COQ2 have previously been implicated in parkinsonism and multiple-system atrophy3; copy number analysis of linked loci, or genomewide analysis, should be considered.
Agnes Rotig - One of the best experts on this subject based on the ideXlab platform.
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prenyldiphosphate synthase subunit 1 pdss1 and oh benzoate polyprenyltransferase COQ2 mutations in ubiquinone deficiency and oxidative phosphorylation disorders
Journal of Clinical Investigation, 2007Co-Authors: Julie Mollet, Irina Giurgea, Dimitri Schlemmer, Gustav Dallner, Dominique Chretien, Agnes Delahodde, Delphine Bacq, Pascale De Lonlay, Arnold Munnich, Agnes RotigAbstract:Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Δcoq1 and ΔCOQ2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.
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prenyldiphosphate synthase subunit 1 pdss1 and oh benzoate polyprenyltransferase COQ2 mutations in ubiquinone deficiency and oxidative phosphorylation disorders
Journal of Clinical Investigation, 2007Co-Authors: Julie Mollet, Irina Giurgea, Dimitri Schlemmer, Gustav Dallner, Dominique Chretien, Agnes Delahodde, Delphine Bacq, Pascale De Lonlay, Arnold Munnich, Agnes RotigAbstract:Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Deltacoq1 and DeltaCOQ2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.
Gustav Dallner - One of the best experts on this subject based on the ideXlab platform.
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prenyldiphosphate synthase subunit 1 pdss1 and oh benzoate polyprenyltransferase COQ2 mutations in ubiquinone deficiency and oxidative phosphorylation disorders
Journal of Clinical Investigation, 2007Co-Authors: Julie Mollet, Irina Giurgea, Dimitri Schlemmer, Gustav Dallner, Dominique Chretien, Agnes Delahodde, Delphine Bacq, Pascale De Lonlay, Arnold Munnich, Agnes RotigAbstract:Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Δcoq1 and ΔCOQ2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.
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prenyldiphosphate synthase subunit 1 pdss1 and oh benzoate polyprenyltransferase COQ2 mutations in ubiquinone deficiency and oxidative phosphorylation disorders
Journal of Clinical Investigation, 2007Co-Authors: Julie Mollet, Irina Giurgea, Dimitri Schlemmer, Gustav Dallner, Dominique Chretien, Agnes Delahodde, Delphine Bacq, Pascale De Lonlay, Arnold Munnich, Agnes RotigAbstract:Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Deltacoq1 and DeltaCOQ2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.
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Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ.
The Biochemical journal, 2004Co-Authors: Margareta Forsgren, Gustav Dallner, Anneli Attersand, Staffan Lake, Jacob Grünler, Ewa Swiezewska, Isabel ClimentAbstract:The COQ2 gene in Saccharomyces cerevisiae encodes a COQ2 (p-hydroxybenzoate:polyprenyl transferase), which is required in the biosynthetic pathway of CoQ (ubiquinone). This enzyme catalyses the prenylation of p-hydroxybenzoate with an all-trans polyprenyl group. We have isolated cDNA which we believe encodes the human homologue of COQ2 from a human muscle and liver cDNA library. The clone contained an open reading frame of length 1263 bp, which encodes a polypeptide that has sequence homology with the COQ2 homologues in yeast, bacteria and mammals. The human COQ2 gene, when expressed in yeast COQ2 null mutant cells, rescued the growth of this yeast strain in the absence of a non-fermentable carbon source and restored CoQ biosynthesis. However, the rate of CoQ biosynthesis in the rescued cells was lower when compared with that in cells rescued with the yeast COQ2 gene. CoQ formed when cells were incubated with labelled decaprenyl pyrophosphate and nonaprenyl pyrophosphate, showing that the human enzyme is active and that it participates in the biosynthesis of CoQ.