肾性高尿酸血症(RHUC)是一种病理状况,其特征是血清尿酸极低和肾脏中尿酸盐过度排泄;这种遗传性疾病根据编码生理重要尿酸盐转运蛋白的致病基因分为1型和2型,分别为URAT1和GLUT9;然而,对RHUC2型的研究仍落后于1型。我们在此描述了一个斯洛伐克家庭中发现的RHUC2型典型家族性病例,该家庭患有严重的低尿酸血症和高尿酸尿症。通过临床遗传学分析,包括全外显子组测序和体外功能测定,我们确定了一个内含子GLUT9变体,c.1419+1G>A,作为可能导致p.Gly431GlufsTer28表达的因果突变,p.Gly431GlufsTer28是一种由外显子11跳跃产生的功能无效变体。在另一个患有轻度低尿酸血症的无关马其顿家庭中也证实了因果关系。因此,在低尿酸血症的基因诊断过程中,还应牢记非编码区.我们的发现为RHUC和GLUT9的病理生理重要性提供了更好的致病性理解。
Renal hypouricemia (
RHUC) is a pathological condition characterized by extremely low serum urate and overexcretion of urate in the kidney; this inheritable disorder is classified into type 1 and type 2 based on causative genes encoding physiologically-important urate transporters, URAT1 and GLUT9, respectively; however, research on
RHUC type 2 is still behind type 1. We herein describe a typical familial case of
RHUC type 2 found in a Slovak family with severe hypouricemia and hyperuricosuria. Via clinico-genetic analyses including whole exome sequencing and in vitro functional assays, we identified an intronic GLUT9 variant, c.1419+1G>A, as the causal mutation that could lead the expression of p.Gly431GlufsTer28, a functionally-null variant resulting from exon 11 skipping. The causal relationship was also confirmed in another unrelated Macedonian family with mild hypouricemia. Accordingly, non-coding regions should be also kept in mind during genetic diagnosis for hypouricemia. Our findings provide a better pathogenic understanding of
RHUC and pathophysiological importance of GLUT9.