Identification and characterization of the first mutation (Arg776Cys) in the C-terminal domain of the Human Molybdenum Cofactor Sulfurase (HMCS) associated with type II classical xanthinuria

Hava Peretz, Meirav Shtauber Naamati, David Levartovsky, Ayala Lagziel, Esther Shani, Ivona Horn, Hanna Shalev, Daniel Landau

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    49 Scopus citations

    Abstract

    Classical xanthinuria type II is an autosomal recessive disorder characterized by deficiency of xanthine dehydrogenase and aldehyde oxidase activities due to lack of a common sulfido-olybdenum cofactor (MoCo). Two mutations, both in the N-terminal domain of the Human Molybdenum Cofactor Sulfurase (HMCS), were reported in patients with type II xanthinuria. Whereas the N-terminal domain of HMCS was demonstrated to have cysteine desulfurase activity, the C-terminal domain hypothetically transfers the sulfur to the MoCo. We describe the first mutation in the C-terminal domain of HMCS identified in a Bedouin-Arab child presenting with urolithiasis and in an asymptomatic Jewish female. Patients were diagnosed with type II xanthinuria by homozygosity mapping and/or allopurinol loading test. The Bedouin-Arab child was homozygous for a c.2326C > T (p.Arg776Cys) mutation, while the female patient was compound heterozygous for this and a novel c.1034insA (p.Gln347fsStop379) mutation in the N-terminal domain of HMCS. Cosegregation of the homozygous mutant genotype with hypouricemia and hypouricosuria was demonstrated in the Bedouin family. Haplotype analysis indicated that p.Arg776Cys is a recurrent mutation. Arg776 together with six surrounding amino acid residues were found fully conserved and predicted to be buried in homologous eukaryotic MoCo sulfurases. Moreover, Arg776 is conserved in a diversity of eukaryotic and prokaryotic proteins that posses a domain homologous to the C-terminal domain of HMCS. Our findings suggest that Arg776 is essential for a core structure of the C-terminal domain of the HMCS and identification of a mutation at this site may contribute clarifying the mechanism of MoCo sulfuration.

    Original languageEnglish
    Pages (from-to)23-29
    Number of pages7
    JournalMolecular Genetics and Metabolism
    Volume91
    Issue number1
    DOIs
    StatePublished - 1 May 2007

    Keywords

    • Allopurinol loading test
    • Bedouin-Arab patient
    • C-terminal domain of HMCS
    • Classical xanthinuria type II
    • Homozygosity mapping
    • Jewish patient
    • Muscle pain
    • XDH and AO deficiency

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Biochemistry
    • Molecular Biology
    • Genetics
    • Endocrinology

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