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.

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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 .2326 C >T (p .Arg 776 C ys ) mutation , while the female patient was compound heterozygous for this and a novel c .1034 insA (p .Gln 347 fsStop 379 ) 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 .A rg 776 C ys is a recurrent mutation . Arg 776 together with six surrounding amino acid residues were found fully conserved and predicted to be buried in homologous eukaryotic MoCo sulfurases . Moreover , Arg 776 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 Arg 776 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 .