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Haploinsufficiency of COQ4 causes coenzyme Q 10 deficiency

2012; BMJ; Volume: 49; Issue: 3 Linguagem: Inglês

10.1136/jmedgenet-2011-100394

1468-6244

Leonardo Salviati, Eva Trevisson, María Hernández, Alberto Casarin, Vanessa Pertegato, Mara Doimo, Matteo Cassina, Caterina Agosto, María Andrea Desbats, Geppo Sartori, Sabrina Sacconi, Luigi Memo, Orsetta Zuffardi, Rafael Artuch, Catarina M. Quinzii, Salvatore DiMauro, Michio Hirano, Carlos Santos–Ocaña, Plácido Navas,

Advanced battery technologies research

Background COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q 10 (CoQ 10 ). A 3.9 Mb deletion of chromosome 9q34.13 was identified in a 3-year-old boy with mental retardation, encephalomyopathy and dysmorphic features. Because the deletion encompassed COQ4, the patient was screened for CoQ 10 deficiency. Methods A complete molecular and biochemical characterisation of the patient9s fibroblasts and of a yeast model were performed. Results The study found reduced COQ4 expression (48% of controls), CoQ 10 content and biosynthetic rate (44% and 43% of controls), and activities of respiratory chain complex II+III. Cells displayed a growth defect that was corrected by the addition of CoQ 10 to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ 10. Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ 10 biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4 . Oral CoQ 10 supplementation resulted in a significant improvement of neuromuscular symptoms, which reappeared after supplementation was temporarily discontinued. Conclusion Mutations of COQ4 should be searched for in patients with CoQ 10 deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ 10 deficiency, as they could benefit from supplementation.