title: 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.
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.
authors: Clinical Biochemistry Laboratory, Sourasky Medical Center, Tel Aviv, Israel. hperetz@tasmc.health.gov.il
authors: Hava
authors: H
authors: Peretz
authors: Meirav Shtauber
authors: MS
authors: Naamati
authors: David
authors: D
authors: Levartovsky
authors: Ayala
authors: A
authors: Lagziel
authors: Esther
authors: E
authors: Shani
authors: Ivona
authors: I
authors: Horn
authors: Hanna
authors: H
authors: Shalev
authors: Daniel
authors: D
authors: Landau
mesh_terms: D042931:Aldehyde Oxidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000493:Allopurinol / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D003067:Coenzymes / Q000378:metabolism; D003545:Cysteine / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008667:Metalloproteins / Q000378:metabolism; D000090006:Molybdenum Cofactors; D009154:Mutation; D010375:Pedigree; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D011621:Pteridines / Q000378:metabolism; D016415:Sequence Alignment; D013466:Sulfurtransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014970:Xanthines / Q000097:blood / Q000652:urine*
chemical_list: D042931:Aldehyde Oxidase; D000493:Allopurinol; D001120:Arginine; D003067:Coenzymes; D003545:Cysteine; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D011621:Pteridines; D013466:Sulfurtransferases; D014968:Xanthine Dehydrogenase; D014970:Xanthines; C022261:molybdopterin; C425823:MOCOS protein, human