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
| Autor: | Meirav Shtauber Naamati, Hava Peretz, Hanna Shalev, Daniel Landau, Ivona Horn, Ayala Lagziel, Esther Shani, David Levartovsky |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Xanthine Dehydrogenase Endocrinology Diabetes and Metabolism Allopurinol Coenzymes Biology Compound heterozygosity medicine.disease_cause Arginine Biochemistry Endocrinology Metalloproteins Genetics medicine Humans Xanthinuria Amino Acid Sequence Cysteine Molecular Biology Phylogeny Mutation Base Sequence Molybdenum cofactor sulfurase Pteridines Haplotype Homozygote Infant Newborn Disease gene identification medicine.disease Molecular biology Pedigree Protein Structure Tertiary Aldehyde Oxidase Xanthine dehydrogenase Amino Acid Substitution Cysteine desulfurase activity Sulfurtransferases Xanthines Female Molybdenum Cofactors Sequence Alignment |
| Zdroj: | Molecular genetics and metabolism. 91(1) |
| ISSN: | 1096-7192 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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