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

Mol Genet Metab. 2007 May;91(1):23-9. doi: 10.1016/j.ymgme.2007.02.005. Epub 2007 Mar 23.


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.

MeSH terms

  • Aldehyde Oxidase / deficiency*
  • Aldehyde Oxidase / genetics
  • Aldehyde Oxidase / metabolism
  • Allopurinol / metabolism
  • Amino Acid Sequence
  • Amino Acid Substitution*
  • 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 / genetics*
  • Sulfurtransferases / metabolism
  • Xanthine Dehydrogenase / deficiency*
  • Xanthine Dehydrogenase / genetics
  • Xanthine Dehydrogenase / metabolism
  • Xanthines / blood
  • Xanthines / urine*


  • Coenzymes
  • Metalloproteins
  • Molybdenum Cofactors
  • Pteridines
  • Xanthines
  • Allopurinol
  • Arginine
  • molybdenum cofactor
  • Xanthine Dehydrogenase
  • Aldehyde Oxidase
  • MOCOS protein, human
  • Sulfurtransferases
  • Cysteine