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Haploinsufficiency of COQ4 causes coenzyme Q10 deficiency
  1. Leonardo Salviati1,
  2. Eva Trevisson1,
  3. Maria Angeles Rodriguez Hernandez2,
  4. Alberto Casarin1,
  5. Vanessa Pertegato1,
  6. Mara Doimo1,
  7. Matteo Cassina1,
  8. Caterina Agosto3,
  9. Maria Andrea Desbats1,
  10. Geppo Sartori4,
  11. Sabrina Sacconi5,
  12. Luigi Memo6,
  13. Orsetta Zuffardi7,
  14. Rafael Artuch8,
  15. Catarina Quinzii9,
  16. Salvatore DiMauro9,
  17. Michio Hirano9,
  18. Carlos Santos-Ocaña2,
  19. Plácido Navas2
  1. 1Clinical Genetics Unit, Department of Pediatrics, University of Padova, Padova, Italy
  2. 2Centro Andaluz de Biología del Desarrollo, and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC, Sevilla, Spain
  3. 3Department of Pediatrics, University of Padova, Padova, Italy
  4. 4Department of Biochemistry, University of Padova, Padova, Italy
  5. 5Centre de référence des maladies Neuromusculaires, Nice Hospital and UMR CNRS6543, Nice University, Nice, France
  6. 6Pediatrics and Neonatology Unit, San Martino Hospital, Belluno, Italy
  7. 7Department of Biology and Medical Genetics, University of Pavia, and Fondazione IRCCS C. Mondino, Pavia, Italy
  8. 8Department of Clinical Biochemistry, Hospital Sant Joan de Déu and Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III. Barcelona, Spain
  9. 9Department of Neurology, Columbia University Medical Center, New York, New York, USA
  1. Correspondence to Leonardo Salviati, Clinical Genetics Unit, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy; leonardo.salviati{at}unipd.it

Abstract

Background COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q10 (CoQ10). 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 CoQ10 deficiency.

Methods A complete molecular and biochemical characterisation of the patient's fibroblasts and of a yeast model were performed.

Results The study found reduced COQ4 expression (48% of controls), CoQ10 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 CoQ10 to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ10. Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ10 biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4. Oral CoQ10 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 CoQ10 deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ10 deficiency, as they could benefit from supplementation.

  • Academic medicine
  • molecular genetics
  • muscle disease
  • neuromuscular disease
  • neurosciences

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Footnotes

  • Funding This work was supported by Telethon Italy grant no GGP09207, CARIPARO foundation, the Spanish Ministerio de Sanidad (FIS) grant no PI 08/0500, University of Padova grant no 2010-CPDA102953, Italian Ministry of Health grant no GR-2009-1578914, National Institute of Health grant nos 1R01HD057543-01 and HD 32062, and Cariplo Foundation grant no 2007.5197.

  • Competing interests None.

  • Patient consent All analyses were performed with the informed consent of the parents of the patients. All analyses on patient fibroblasts were part of the standard set of investigations carried out to diagnose coenzyme Q deficiency.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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