Dataset Information

Phenotypic, molecular, and functional characterization of COQ7-related primary CoQ₁₀ deficiency: Hypomorphic variants and two distinct disease entities.

ABSTRACT: Primary coenzyme Q10 (CoQ₁₀) deficiency is a group of inborn errors of metabolism caused by defects in CoQ₁₀ biosynthesis. Biallelic pathogenic variants in COQ7, encoding mitochondrial 5-demethoxyubiquinone hydroxylase, have been reported in nine patients from seven families. We identified five new patients with COQ7-related primary CoQ₁₀ deficiency, performed clinical assessment of the patients, and studied the functional effects of current and previously reported COQ7 variants and potential treatment options. The main clinical features included a neonatal-onset presentation with severe neuromuscular, cardiorespiratory and renal involvement and a late-onset disease presenting with progressive neuropathy, lower extremity weakness, abnormal gait, and variable developmental delay. Baker's yeast orthologue of COQ7, CAT5, is required for growth on oxidative carbon sources and cat5Δ strain demonstrates oxidative growth defect. Expression of wild-type CAT5 could completely rescue the defect; however, yeast CAT5 harboring equivalent human pathogenic variants could not. Interestingly, cat5Δ yeast harboring p.Arg57Gln (equivalent to human p.Arg54Gln), p.Arg112Trp (equivalent to p.Arg107Trp), p.Ile69Asn (equivalent to p.Ile66Asn) and combination of p.Lys108Met and p.Leu116Pro (equivalent to the complex allele p.[Thr103Met;Leu111Pro]) partially rescued the growth defects, indicating these variants are hypomorphic alleles. Supplementation with 2,4 dihydroxybenzoic acid (2,4-diHB) rescued the growth defect of both the leaky and severe mutants. Overexpression of COQ8 and 2,4-diHB supplementation synergistically restored oxidative growth and respiratory defect. Overall, we define two distinct disease presentations of COQ7-related disorder with emerging genotype-phenotype correlation and validate the use of the yeast model for functional studies of COQ7 variants.

SUBMITTER: Wongkittichote P

PROVIDER: S-EPMC10995746 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phenotypic, molecular, and functional characterization of COQ7-related primary CoQ10 deficiency: Hypomorphic variants and two distinct disease entities.

Wongkittichote Parith P Duque Lasio Maria Laura ML Magistrati Martina M Pathak Sheel S Sample Brooke B Carvalho Daniel Rocha DR Ortega Adriana Banzzatto AB Castro Matheus Augusto Araújo MAA de Gusmao Claudio M CM Toler Tomi L TL Bellacchio Emanuele E Dallabona Cristina C Shinawi Marwan M

Molecular genetics and metabolism 20230622 4

Primary coenzyme Q10 (CoQ10) deficiency is a group of inborn errors of metabolism caused by defects in CoQ10 biosynthesis. Biallelic pathogenic variants in COQ7, encoding mitochondrial 5-demethoxyubiquinone hydroxylase, have been reported in nine patients from seven families. We identified five new patients with COQ7-related primary CoQ10 deficiency, performed clinical assessment of the patients, and studied the functional effects of current and previously report ...[more]

PMID: 37392700

Similar Datasets

Project description:BackgroundOxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis.Study designPlacebo-controlled, 3-arm, double-blind, randomized, clinical trial.Setting & participants65 patients undergoing thrice-weekly maintenance hemodialysis.InterventionPatients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10; 600 or 1,200mg) or matching placebo for 4 months.OutcomesThe primary outcome was plasma oxidative stress, defined as plasma concentration of F2-isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability.MeasurementsF2-isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro-brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months.ResultsOf 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200mg, but not 600mg, of CoQ10 significantly reduced plasma F2-isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of -10.7 [95% CI, -7.1 to -14.3] pg/mL [P<0.001] and -8.3 [95% CI, -5.5 to -11.0] pg/mL [P=0.1], respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures.LimitationsStudy not powered to detect small treatment effects; difference in baseline characteristics among randomized groups.ConclusionsIn patients undergoing maintenance hemodialysis, daily supplementation with 1,200mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2-isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.

Dataset Information

Phenotypic, molecular, and functional characterization of COQ7-related primary CoQ₁₀ deficiency: Hypomorphic variants and two distinct disease entities.

Publications

Phenotypic, molecular, and functional characterization of COQ7-related primary CoQ<sub>10</sub> deficiency: Hypomorphic variants and two distinct disease entities.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets