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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.
- Source :
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Molecular genetics and metabolism [Mol Genet Metab] 2007 May; Vol. 91 (1), pp. 23-9. Date of Electronic Publication: 2007 Mar 23. - Publication Year :
- 2007
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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.
- Subjects :
- Aldehyde Oxidase genetics
Aldehyde Oxidase metabolism
Allopurinol metabolism
Amino Acid Sequence
Arginine genetics
Base Sequence
Coenzymes metabolism
Cysteine genetics
Female
Homozygote
Humans
Infant, Newborn
Male
Metalloproteins metabolism
Molybdenum Cofactors
Mutation
Pedigree
Phylogeny
Protein Structure, Tertiary
Pteridines metabolism
Sequence Alignment
Sulfurtransferases chemistry
Sulfurtransferases metabolism
Xanthine Dehydrogenase genetics
Xanthine Dehydrogenase metabolism
Xanthines blood
Aldehyde Oxidase deficiency
Amino Acid Substitution
Sulfurtransferases genetics
Xanthine Dehydrogenase deficiency
Xanthines urine
Subjects
Details
- Language :
- English
- ISSN :
- 1096-7192
- Volume :
- 91
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular genetics and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 17368066
- Full Text :
- https://doi.org/10.1016/j.ymgme.2007.02.005