Introduction and Aims: Idiopathic renal hypouricemia is a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule. Patients present low serum levels of UA associated with excessive urinary wasting of UA, and some have severe complications like exercise-induced acute renal failure or nephrolithiasis. Mutations in the SLC22A12 gene, encoding the renal tubular uric acid transporter 1 (URAT1), are the major cause of this disorder. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. Here, we report clinical and molecular data of five Spanish patients diagnosed with idiopathic renal hypouricemia. Methods: Blood and urinary samples were collected for measurement of UA and creatinine levels and for genetic analysis. Patients were evaluated for renal stones or other renal diseases. Genomic DNA was isolated using a commercial kit. SLC22A12 exons were amplified by PCR and the products were sequenced. URAT1 allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. Results: The patients had persistently low serum UA levels ranging from 0.8 to 1.3 mg/ ml and elevated fractional excretion of UA (27%-60%). One of the patients had nephrolithiasis and was also diagnosed with polycystic kidney disease. The other patients were asymptomatic. Sequence analysis revealed mutations in each patient. A new missense mutation, p.A476D, affecting transmembrane domain 11 of URAT1 was identified. Functional studies showed that this mutation considerably diminished UA transport. Oocytes expressing p.A476D showed a discontinuous URAT1 signal on the plasma membrane and intracytoplasmic staining was lower than in the normal control. Two previously reported mutations, p.T467M and p.L415_G417del, associated with renal hypouricemia in families from the Czech Republic were also found. Conclusions: Our study describes the clinical and molecular characteristics of the first Spanish patients diagnosed with renal hypouricemia. A new pathogenic SLC22A12 mutation causing loss of function was identified. Although this disorder has been described predominantly in Asian patients it should be considered in European countries as well.
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