title: Functional characterization of human COQ4, a gene required for Coenzyme Q10 biosynthesis.
abstract: Defects in genes involved in coenzyme Q (CoQ) biosynthesis cause primary CoQ deficiency, a severe multisystem disorders presenting as progressive encephalomyopathy and nephropathy. The COQ4 gene encodes an essential factor for biosynthesis in Saccharomyces cerevisiae. We have identified and cloned its human ortholog, COQ4, which is located on chromosome 9q34.13, and is transcribed into a 795 base-pair open reading frame, encoding a 265 amino acid (aa) protein (Isoform 1) with a predicted N-terminal mitochondrial targeting sequence. It shares 39% identity and 55% similarity with the yeast protein. Coq4 protein has no known enzymatic function, but may be a core component of multisubunit complex required for CoQ biosynthesis. The human transcript is detected in Northern blots as a approximately 1.4 kb single band and is expressed ubiquitously, but at high levels in liver, lung, and pancreas. Transcription initiates at multiple sites, located 333-23 nucleotides upstream of the ATG. A second group of transcripts originating inside intron 1 of the gene encodes a 241 aa protein, which lacks the mitochondrial targeting sequence (isoform 2). Expression of GFP-fusion proteins in HeLa cells confirmed that only isoform 1 is targeted to mitochondria. The functional significance of the second isoform is unknown. Human COQ4 isoform 1, expressed from a multicopy plasmid, efficiently restores both growth in glycerol, and CoQ content in COQ4(null) yeast strains. Human COQ4 is an interesting candidate gene for patients with isolated CoQ(10) deficiency.
authors.affiliation: Clinical Genetics Unit, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Casarin
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Jimenez-Ortega
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pertegato
authors.forename: Mara
authors.initials: M
authors.lastname: Doimo
authors.forename: Maria Lara
authors.initials: ML
authors.lastname: Ferrero-Gomez
authors.forename: Sara
authors.initials: S
authors.lastname: Abbadi
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.forename: Catarina
authors.initials: C
authors.lastname: Quinzii
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Carlos Santos
authors.initials: CS
authors.lastname: Ocaña
authors.forename: Placido
authors.initials: P
authors.lastname: Navas
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
mesh_terms: D000595:Amino Acid Sequence; D015152:Blotting, Northern; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003001:Cloning, Molecular; D005816:Genetic Complementation Test; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics
chemical_list: C433869:COQ4 protein, S cerevisiae; C529610:COQ4 protein, human; D007527:Isoenzymes; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D014451:Ubiquinone; D049452:Green Fluorescent Proteins; C024989:coenzyme Q10