title: Haploinsufficiency of COQ4 causes coenzyme Q10 deficiency.
abstract: 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 patient's 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Genetics Unit, Department of Pediatrics, University of Padova, Padova, Italy. leonardo.salviati@unipd.it
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Rodriguez Hernandez
authors.forename: Alberto
authors.initials: A
authors.lastname: Casarin
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pertegato
authors.forename: Mara
authors.initials: M
authors.lastname: Doimo
authors.forename: Matteo
authors.initials: M
authors.lastname: Cassina
authors.forename: Caterina
authors.initials: C
authors.lastname: Agosto
authors.forename: Maria Andrea
authors.initials: MA
authors.lastname: Desbats
authors.forename: Geppo
authors.initials: G
authors.lastname: Sartori
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.forename: Luigi
authors.initials: L
authors.lastname: Memo
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.forename: Catarina
authors.initials: C
authors.lastname: Quinzii
authors.forename: Salvatore
authors.initials: S
authors.lastname: Dimauro
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Carlos
authors.initials: C
authors.lastname: Santos-Ocaña
authors.forename: Plácido
authors.initials: P
authors.lastname: Navas
mesh_terms: D000015:Abnormalities, Multiple / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D057895:Haploinsufficiency; D006367:HeLa Cells; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D014158:Transcription, Genetic; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000172:deficiency / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C529610:COQ4 protein, human; D045222:Electron Transport Chain Complex Proteins; D024101:Mitochondrial Proteins; D014451:Ubiquinone; C024989:coenzyme Q10