Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0451641 (urolithiasis)
 3,973 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 1736 66

Classical xanthinuria is a rare autosomal recessive metabolic disorder characterized by lack of xanthine dehydrogenase activity that often manifests as xanthine urolithiasis and risk of drug toxicity. Variants in the XDH or HMCS gene underlie classical xanthinuria type I and type II, respectively. Here we present two Israeli Arab families affected by type I xanthinuria in whom a c.2164A>T (Lys722Ter) variant in the XDH gene, previously reported in a Turkish family of Turkmen origin, was identified. Analysis of polymorphic markers surrounding the variant site revealed common haplotypes spanning 0.6 Mbp shared by all three, and 1.7 Mbp shared by two of the studied families. By applying Bayesian methods to a simple model of crossover events through generations in the chromosomes carrying the variant, the most recent common ancestor of these families was found to be 179 (95% credible limit 70) generations old. The estimated antiquity of the variant, the historical genealogy of the affected families and the history and present day dispersion of their people strongly suggest prevalence of this variant in the Afro-Asian stone-forming belt. As far as we are aware, this is a first report of an ancient variant causing xanthinuria with potential wide geographical dispersion.
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PMID:An ancestral variant causing type I xanthinuria in Turkmen and Arab families is predicted to prevail in the Afro-Asian stone-forming belt. 3207 38