title: Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.
abstract: Human COQ6 encodes a monooxygenase which is responsible for the C5-hydroxylation of the quinone ring of coenzyme Q (CoQ). Mutations in COQ6 cause primary CoQ deficiency, a condition responsive to oral CoQ10 supplementation. Treatment is however still problematic given the poor bioavailability of CoQ10. We employed S. cerevisiae lacking the orthologous gene to characterize the two different human COQ6 isoforms and the mutations found in patients. COQ6 isoform a can partially complement the defective yeast, while isoform b, which lacks part of the FAD-binding domain, is inactive but partially stable, and could have a regulatory/inhibitory function in CoQ10 biosynthesis. Most mutations identified in patients, including the frameshift Q461fs478X mutation, retain residual enzymatic activity, and all patients carry at least one hypomorphic allele, confirming that the complete block of CoQ biosynthesis is lethal. These mutants are also partially stable and allow the assembly of the CoQ biosynthetic complex. In fact treatment with two hydroxylated analogues of 4-hydroxybenzoic acid, namely, vanillic acid or 3-4-hydroxybenzoic acid, restored the respiratory growth of yeast Δcoq6 cells expressing the mutant huCOQ6-isoa proteins. These compounds, and particularly vanillic acid, could therefore represent an interesting therapeutic option for COQ6 patients.
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy; IRP Città della Speranza, Padova, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Doimo
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.forename: Marc
authors.initials: M
authors.lastname: Bergdoll
authors.forename: Carlos
authors.initials: C
authors.lastname: Santos-Ocaña
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Placido
authors.initials: P
authors.lastname: Navas
authors.forename: Fabien
authors.initials: F
authors.lastname: Pierrel
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
mesh_terms: D000595:Amino Acid Sequence; D062365:Aminobenzoates / Q000494:pharmacology*; D001259:Ataxia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018908:Muscle Weakness / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014641:Vanillic Acid / Q000494:pharmacology*
chemical_list: D062365:Aminobenzoates; D062385:Hydroxybenzoates; D029701:Saccharomyces cerevisiae Proteins; C032165:ubiquinone 6; D014451:Ubiquinone; C110924:3-amino-4-hydroxybenzoic acid; C024989:coenzyme Q10; D014641:Vanillic Acid
keywords: 3,4 diHB; 3,4 dihydroxybenzoic acid; 4-hydroxybenzoate; 4HB; COQ6; COQ8-ADCK3; CYC1; CoQ; CoQ(10); Coenzyme Q; FAD; SRNS; Steroid-resistant nephrotic syndrome; VA; Vanillic acid; aarF domain containing kinase 3; coenzyme Q; coenzyme Q(10); cytochrome c1; flavin adenine dinucleotide; flavin-dependent monooxygenase; pHBH; para-hydroxybenzoate hydroxylase; steroid resistant nephrotic syndrome; vanillic acid