Hereditary Renal Hypouricemia: Identification of the Gene Defect in Hereditary Renal Hypouricemia

INTRODUCTION

A major breakthrough in our understanding of the etiology of hereditary renal hypouricemia (HRH) occurred recently owing to identification of the renal urate transporter hURAT1 and demonstration that loss-of-function mutational alterations in the gene SLC22A12 coding for this transporter are associated with HRH.¹ These findings have major implications for our understanding of renal urate handling in humans and of the etiology of HRH.²

CURRENT CONCEPTS CONCERNING THE RENAL HANDLING OF URATE

The validity of the dominant historical model of the renal handling of urate in humans, as depicted in Fig. 241-1, has been questioned recently.³ Recent studies suggest that in contrast to the historical model, the secreted urate probably contributes only minimally to urate excretion, implying that the excreted urate represents mainly the filtered urate that escapes reabsorption.^4,5 Several transporters are involved in the bidirectional transport of urate in the proximal tubule cells.^1,3,5-8 Urate reabsorption is controlled mainly by the urate-anion exchanger hURAT1. The presence of additional urate-reabsorbing transporters is presently a matter of speculation. The anions exchanged for urate uptake (such as lactate and nicotinate) enter the cells from the lumen presumably through the Na⁺/anions cotransporter SLC5A8. Urate secretion to the lumen is carried out by UAT, a urate transporter/channel that allows efflux of urate from the cells into the lumen and probably also into the peritubular space. Urate also may be secreted to the lumen through the ATP-driven human organic anion transporter MRP4. The urate/organic anion exchangers OAT1 and OAT3 participate in urate transport between the tubule cells and the peritubular space.

MOLECULAR ALTERATIONS OF HURAT1 IN HRH

The urate transporter hURAT1 is coded by the gene SLC22A12, mapped to chromosome 11q13.¹ It belongs to the family of organic anion transporters (OATs) It is a member of the major facilitator superfamily coded by SLC22A. The hURAT1 protein contains 555 amino acids and is hypothesized to contain 12 transmembrane domains with a cytoplasmic C terminus. It is expressed only in the kidney and is located at the luminal membrane of the epithelium of the proximal tubules.⁹ The hURAT1 transporter absorbs urate from the lumen to the cytosol of the proximal tubules in exchange for monovalent organic anions such as lactate and nicotinate.

Mutational analyses established a correlation between the clinical and genetic features of HRH patients and the significance of hURAT1 in the regulation of serum urate level.^10-15 Mutations in the SLC22A12 gene were detected in most HRH patients studied: in 30 of 32 patients ...