肾高尿酸血症(RHUC)是一种遗传性疾病,其中SLC22A12基因和SLC2A9基因突变导致RHUC1型(RHUC1)和RHUC2型(RHUC2),分别。这些基因调节尿酸盐的肾小管重吸收,而存在其他平衡尿酸盐净排泄的基因,包括ABCG2和SLC17A1。尿酸盐代谢与葡萄糖代谢密切相关,和SLC2A9基因可能参与胰腺β细胞的胰岛素分泌。另一方面,无数基因独立于尿酸盐代谢而导致胰岛素分泌受损。
我们描述了一名67岁的日本男子,他表现出严重的低尿酸血症(0.7mg/dl(3.8-7.0mg/dl),41.6μmol/l(226-416μmol/l))和胰岛素分泌受损的糖尿病。他的高尿尿酸排泄分数(65.5%)和低尿C肽排泄(25.7μg/天)与RHUC和胰岛素分泌受损的诊断相符,分别。考虑到调节尿酸盐和葡萄糖的代谢途径密切相关,我们试图使用全外显子组测序来描述该患者中观察到的低尿酸血症和胰岛素分泌缺陷的遗传基础.有趣的是,我们在SLC22A12基因中发现了导致RHUC1的Trp258*纯合突变,同时还发现了与高尿酸血症相关的并发突变,包括ABCG2(Gln141Lys)和SLC17A1(Thr269Ile).SLC2A9,也促进葡萄糖转运,被牵涉到增强胰岛素分泌,然而,在该患者的SLC2A9基因中发现的非同义突变不是功能异常变异.因此,我们开始寻找他胰岛素分泌受损的因果突变,从而鉴定出HNF1A基因(MODY3)以及在胰腺β细胞中起作用的其他基因中的多个突变。其中,同源异型盒基因NKX6.1中的Leu80fs是未报道的突变.
我们发现一例携带SLC22A12基因突变的RHUC1,伴有与高尿酸血症相关的代偿性突变,代表第一份报告显示突变共存,具有相反的调节尿酸浓度的潜力。另一方面,独立的基因突变可能是他胰岛素分泌受损的原因,其中包含胰腺β细胞功能关键基因的新突变,值得进一步研究。
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.
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 non-synonymous 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.
We found a
case of RHUC1 carrying mutations in SLC22A12 gene accompanied with compensatory mutations associated with hyperuricemia, representing the first report showing coexistence of the mutations with opposed potential to regulate urate concentrations. On the other hand, independent gene mutations may be responsible for his impaired insulin secretion, which contains novel mutations in key genes in the pancreatic β-cell functions that deserve further scrutiny.