Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Qw deficiency

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Article

Doimo, Mara^1,2  Trevisson, Eva^1,2  Airik, Rannar³  Bergdoll, Marc⁴  Santos-Ocana, Carlos^5,6  Hildebrandt, Friedhelm³  Navas, Placido^5,6  Pierrel, Fabien⁷  Salviati, Leonardo^1,2 

[1] Univ Padua, Dept Woman & Child Hlth, Clin Genet Unit, Padua, Italy

[2] IRP Citta Speranza, Padua, Italy

[3] Boston Childrens Hosp, Howard Hughes Med Inst, Div Nephrol, Boston, MA USA

[4] CNRS UDS UPR2357, Inst Biol Mol Plantes, Strasbourg, France

[5] Univ Pablo Olavide, CSIC, CABD, Seville, Spain

[6] Inst Salud Carlos III, CIBERER, Seville, Spain

[7] UMR5249 CEA CNRS UJF, Lab Chim & Biol Met, Grenoble, France

关键词: Coenzyme Q;    Vanillic acid;    COQ6;    Steroid-resistant nephrotic syndrome;   

DOI  :  10.1016/j.bbadis.2013.10.007

来源: Elsevier

【 摘 要 】

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 CoQw supplementation. Treatment is however still problematic given the poor bioavailability of C0Q10. 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 CoQm 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 Acoq6 cells expressing the mutant huC0Q6-isoa proteins. These compounds, and particularly vanillic acid, could therefore represent an interesting therapeutic option for COQ6 patients. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.

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