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Kidney Week

Abstract: SA-PO420

Contribution of SLC22A12 on Hypouricemia and Its Clinical Significance for Screening Purposes

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Cho, Sungkweon, NCI, Frederick, United States
  • Winkler, Cheryl Ann, NCI, NIH, Frederick National Laboratory, Frederick, Maryland, United States

Renal hypouricemia (RHUC) is a rare inherited disorder strongly associated with genetic mutations of renal transporters genes. Despite its adverse complications (e.g. acute kidney failure and nephrolithiasis), differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to identify genetic variants in hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis in primary screening.


We selected all cases (N=31) with extreme hypouricemia (<1.3 mg/dl) from Korean urban cohort of 179,381 subjects; selection criteria included 1) abstinence from alcohol or smoking and 2) an absence of underlying conditions (i.e., hypertension, diabetes and taking anti-hypertensive medication). WES and corresponding downstream analyses were performed for the discovery of coding variants causal for hypouricemia. Two known causal variants within SLC22A12 (p.Trp258*, pArg90His) were identified, we then directly genotyped the 2 SLC22A12 variants in independent 50 hypouricemia subjects to assess the diagnostic utility of these two causal variants.


For the discovery cohort who had undergone WES, 27 of 31 (87.1%) individuals harbored missense or nonsense variants in either the homozygous or compound heterozygous state in SLC22A12. 24 of 31 (77.4%) subjects were shown to have at least 1 copy of the truncating p.Trp258* and/or p.Arg90His. Four novel variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys were discovered and were predicted to cause uric acid transport defects by molecular dynamics. Individuals (n=50) from an independent cohort were directly genotyped for the p.Trp258* and p.Arg90His variants, 47 of 50 cases (94%) were explained by only these two variants.


This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.


  • Government Support - Non-U.S.