Human Genetics

, Volume 117, Issue 6, pp 565–570

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

  • Silke Leimkühler
  • Mathilde Charcosset
  • Philippe Latour
  • Claude Dorche
  • Soledad Kleppe
  • Fernando Scaglia
  • Irmina Szymczak
  • Petra Schupp
  • Rita Hahnewald
  • Jochen Reiss
Original Investigation

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).

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Silke Leimkühler
    • 1
  • Mathilde Charcosset
    • 2
  • Philippe Latour
    • 2
  • Claude Dorche
    • 2
  • Soledad Kleppe
    • 3
  • Fernando Scaglia
    • 3
  • Irmina Szymczak
    • 4
  • Petra Schupp
    • 4
  • Rita Hahnewald
    • 4
  • Jochen Reiss
    • 4
  1. 1.Institut für Biochemie und BiologieUniversität PotsdamPotsdamGermany
  2. 2.Hopital DebrousseLyonFrance
  3. 3.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  4. 4.Institut für Humangenetik der Universität GöttingenGöttingenGermany

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