title: Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase.
abstract: Molybdenum cofactor deficiency (MIM#252150) is a severe autosomal-recessive disorder with a devastating outcome. The cofactor is the product of a complex biosynthetic pathway involving four different genes (MOCS1, MOCS2, MOCS3 and GEPH). This disorder is caused almost exclusively by mutations in the MOCS1 or MOCS2 genes. Mutations affecting this biosynthetic pathway result in a lethal phenotype manifested by progressive neurological damage via the inactivation of the molybdenum cofactor-dependent enzyme, sulphite oxidase. Here we describe a total of ten novel disease-causing mutations in the MOCS1 and MOCS2 genes. Nine out of these ten mutations were classified as pathogenic in nature, since they create a stop codon, affect constitutive splice site positions, or change strictly conserved motifs. The tenth mutation abolishes the stop codon of the MOCS2B gene, thus elongating the corresponding protein. The mutation was expressed in vitro and was found to abolish the binding affinities of the large subunit of molybdopterin synthase (MOCS2B) for both precursor Z and the small subunit of molybdopterin synthase (MOCS2A).
authors: Institut für Biochemie und Biologie, Universität Potsdam, 14476 Potsdam, Germany.
authors: Silke
authors: S
authors: Leimkühler
authors: Mathilde
authors: M
authors: Charcosset
authors: Philippe
authors: P
authors: Latour
authors: Claude
authors: C
authors: Dorche
authors: Soledad
authors: S
authors: Kleppe
authors: Fernando
authors: F
authors: Scaglia
authors: Irmina
authors: I
authors: Szymczak
authors: Petra
authors: P
authors: Schupp
authors: Rita
authors: R
authors: Hahnewald
authors: Jochen
authors: J
authors: Reiss
mesh_terms: D019755:Carbon-Carbon Lyases; D003067:Coenzymes / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008667:Metalloproteins / Q000172:deficiency / Q000235:genetics*; D000090006:Molybdenum Cofactors; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011621:Pteridines; D013466:Sulfurtransferases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019755:Carbon-Carbon Lyases; D003067:Coenzymes; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D009687:Nuclear Proteins; D011621:Pteridines; D013466:Sulfurtransferases; C022261:molybdopterin; C085585:molybdopterin synthase; C114840:MOCS1 protein, human