title: Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency.
abstract: All molybdoenzymes other than nitrogenase require molybdopterin as a metal-binding cofactor. Several genes necessary for the synthesis of the molybdenum cofactor (MoCo) have been characterized in bacteria and plants. The proteins encoded by the Escherichia coli genes moaA and moaC catalyse the first steps in MoCo synthesis. The human homologues of these genes are therefore candidate genes for molybdenum cofactor deficiency, a rare and fatal disease. Using oligonucleotides complementary to a conserved region in the moaA gene, we have isolated a human cDNA derived from liver mRNA. This transcript contains an open reading frame (ORF) encoding the human moaA homologue and a second ORF encoding a human moaC homologue. Mutations can be found in the majority of MoCo-deficient patients that confirm the functional role of both ORFs in the corresponding gene MOCS1 (for 'molybdenum cofactor synthesis-step 1'). Northern-blot analysis detected only full-length transcripts containing both consecutive ORFs in various human tissues. The mRNA structure suggests a translation reinitiation mechanism for the second ORF. These data indicate the existence of a eukaryotic mRNA, which as a single and uniform transcript guides the synthesis of two different enzymatic polypeptides with disease-causing potential.
authors.affiliation: Institut für Humangenetik, Göttingen, Germany. jreiss@gwdg.de
authors.forename: J
authors.initials: J
authors.lastname: Reiss
authors.forename: N
authors.initials: N
authors.lastname: Cohen
authors.forename: C
authors.initials: C
authors.lastname: Dorche
authors.forename: H
authors.initials: H
authors.lastname: Mandel
authors.forename: R R
authors.initials: RR
authors.lastname: Mendel
authors.forename: B
authors.initials: B
authors.lastname: Stallmeyer
authors.forename: M T
authors.initials: MT
authors.lastname: Zabot
authors.forename: T
authors.initials: T
authors.lastname: Dierks
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D019755:Carbon-Carbon Lyases; D003067:Coenzymes; D017124:Conserved Sequence; D005260:Female; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008667:Metalloproteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D000090006:Molybdenum Cofactors; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D016366:Open Reading Frames; D010375:Pedigree; D011621:Pteridines / Q000378:metabolism*; D012333:RNA, Messenger; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D019755:Carbon-Carbon Lyases; D003067:Coenzymes; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D009687:Nuclear Proteins; D011621:Pteridines; D012333:RNA, Messenger; C022261:molybdopterin; C114840:MOCS1 protein, human