Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion

Abstract

Background: Renal hypouricemia (RHUC) is a hereditary disorder where mutations in SLC22A12 gene and SLC2A9 gene cause RHUC type 1 (RHUC1) and RHUC type 2 (RHUC2), respectively. These genes regulate renal tubular reabsorption of urates while there exist other genes counterbalancing the net excretion of urates including ABCG2 and SLC17A1. Urate metabolism is tightly interconnected with glucose metabolism, and SLC2A9 gene may be involved in insulin secretion from pancreatic β-cells. On the other hand, a myriad of genes are responsible for the impaired insulin secretion independently of urate metabolism. Case presentation: We describe a 67 year-old Japanese man who manifested severe hypouricemia (0.7 mg/dl (3.8-7.0 mg/dl), 41.6 μmol/l (226-416 μmol/l)) and diabetes with impaired insulin secretion. His high urinary fractional excretion of urate (65.5%) and low urinary C-peptide excretion (25.7 μg/day) were compatible with the diagnosis of RHUC and impaired insulin secretion, respectively. Considering the fact that metabolic pathways regulating urates and glucose are closely interconnected, we attempted to delineate the genetic basis of the hypouricemia and the insulin secretion defect observed in this patient using whole exome sequencing. Intriguingly, we found homozygous Trp258* mutations in SLC22A12 gene causing RHUC1 while concurrent mutations reported to be associated with hyperuricemia were also discovered including ABCG2 (Gln141Lys) and SLC17A1 (Thr269Ile). SLC2A9, that also facilitates glucose transport, has been implicated to enhance insulin secretion, however, the nonsynonymous mutations found in SLC2A9 gene of this patient were not dysfunctional variants. Therefore, we embarked on a search for causal mutations for his impaired insulin secretion, resulting in identification of multiple mutations in HNF1A gene (MODY3) as well as other genes that play roles in pancreatic β-cells. Among them, the Leu80fs in the homeobox gene NKX6.1 was an unreported mutation.

Modulation of Urate Transport by Drugs

“…It appears that URAT1 plays a key role in urate reabsorption and in the maintenance of serum urate levels. A recent study demonstrated hypouricemia in a patient homozygous for the Trp258* (rs121907892) mutation in URAT1 despite being heterozygous for a variant of BCRP (ABCG2 Gln141Lys (rs2231142)) as well as homozygous for a mutation in NPT1 (SLC17A1 Thr269Ile (rs1165196)), both known to cause hyperuricemia [ 154 ]. In addition, four of six uricosuric agents ( Table 3 ) but only two of five hyperuricemic drugs ( Table 5 ) with available BCRP inhibition data showed clinically significant inhibition of gut BCRP, suggesting a less prominent role for gut-localized BCRP than results with Abcg2 knockout mice would suggest [ 3 ].…”

Purine metabolites and complex diseases: role of genes and nutrients

“…Genetic polymorphisms in genes purine nucleoside phosphorylase ( PNP ), adenosine deaminase, xanthine dehydrogenase/oxidase, AMPD , and 5′-nucleotidase have been also linked to altered purine biosynthesis and catabolism and immunodeficiency syndromes [3 ▪▪ ,27,28]. Many of these SNPs have also been associated with hypertension, diabetes, obesity, CVD, and neurodegenerative diseases [29,30].…”