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A 60-year-old Japanese man was diagnosed as having hypouricemia at an annual health check-up. The routine laboratory data was not remarkable except that the patient's hypouricemia and plasma levels of xanthine and hypoxanthine were much higher than those of normal subjects. Furthermore, the patient's daily urinary excretion of xanthine and hypoxanthine was markedly increased compared with reference values. The xanthine dehyrogenase activity of the duodenal mucosa was below the limits of detection. Nevertheless, allopurinol was metabolized to oxypurinol in vivo. Based on these findings, a subtype of classical xanthinuria (type I) was diagnosed. The xanthine dehyrogenase protein was detected by Western blotting analysis. Sequencing of the cDNA of the xanthine dehyrogenase obtained from the duodenal mucosa revealed that a point mutation of C to T had occurred in nucleotide 445. This changed codon 149 from CGC (Arg) to TGC (Cys), a finding that has not been previously reported in patients with classical xanthinuria type I.

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Abstract. Aims. A missense mutation in the low density lipoprotein receptor-related protein 6 gene (LRP6) was recently shown to be responsible for a disorder characterized by early-onset coronary artery disease as well as diabetes mellitus (DM), hyperlipidemia, hypertension, and osteoporosis. Mice deficient in LRP5, a closely related paralog of LRP6, manifest a marked impairment in glucose tolerance. The aim of the present study was to examine whether common variants of LRP5 and LRP6 are associated with Type 2 DM or dyslipidemia in Japanese individuals. Methods. Thirteen single nucleotide polymorphisms (SNPs) of LRP6 and nine SNPs of LRP5 were genotyped in a total of 608 Type 2 DM patients and 366 nondiabetic control subjects (initial study). An association analysis was then performed for each SNP and for haplotypes. For some of the SNPs, we provided another sample panel of 576 cases and 576 controls for the replication study. The relation to clinical characteristics was also examined in diabetic subjects. Results. In the initial study, three SNPs of LRP6 were found to be associated with susceptibility to Type 2 DM. However, this association was not detected in the replication panel. None of SNPs in LRP5 were associated with Type 2 DM in the initial panel. Neither LRP6 nor LRP5 was associated with body mass index, HOMA-β, HOMA-IR or serum lipid concentrations. Conclusions. We found no evidence for a substantial effect of LRP5 or LRP6 SNPs on susceptibility to type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population.

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