Elsevier

Molecular Genetics and Metabolism

Volume 89, Issues 1–2, September–October 2006, Pages 14-18
Molecular Genetics and Metabolism

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Hereditary renal hypouricemia

https://doi.org/10.1016/j.ymgme.2006.03.015Get rights and content

Abstract

Hereditary renal hypouricemia (HRH) is an inborn error of renal membrane transport specific for uric acid, resulting in increased renal urate clearance associated with hypouricemia. Apparently in most HRH patients, the disorder is caused by loss of function mutations in the gene SLC22A12 coding for human urate transporter 1 (hURAT1), shown to control urate reabsorption in the proximal tubules. The small group of HRH patients with normal SLC22A12 may be affected with mutations in other not yet identified urate transporters. Patients affected with SLC22A12 mutations exhibit attenuated response of urinary urate excretion to pyrazinamide (PZA) and to probenecid (PBD) loading, attributed previously to reflect defective tubular presecretory urate reabsorption. HRH is inherited in an autosomal recessive mode. Most HRH patients are asymptomatic, but some may form renal tract stones and or be predisposed to exercise-induced acute renal failure.

Introduction

Hereditary renal hypouricemia (HRH) (Mendelian inheritance in man 220150) is a rare hereditary renal transport disorder specific for uric acid. The defective urate reabsorption in the proximal tubules results in increased renal urate clearance associated with hypouricemia. It is distinguished from other hereditary conditions associated with renal hypouricemia, such as the Fanconi [1] and Hartnup [2] syndromes, in which the urate transport defect is only one component in a generalized disturbance of membrane transport. The first HRH case was reported by Greene et al. in 1972 [3], but the identification of the defective gene responsible for the disorder in probably most HRH patients was established only recently [4], 30 years following the report of the first HRH case. The defective urate transporter identified appears to be human urate transporter 1 (hURAT1) [4], coded by the gene SLC22A12 mapped to chromosome 11q13 [5], [6], [7], [8], [9], [10]. This recent development is of major importance concerning our understanding of the etiology of this disorder, as well as of our understanding of the handling of urate in the human kidney, justifying reevaluation of the previous concepts concerning these topics.

Section snippets

Renal handling of urate in humans

The nature of the renal handling of urate in humans has not been clarified conclusively, in part due to the lack of an animal model in which the renal handling of urate is identical to that in humans. Experiments in humans were limited to the study of the effects of urate loading and of various drugs on uric acid excretion [11], [12], [13], [14], [15], [16]. As with many other inborn errors, study of HRH patients furnished important information concerning the normal renal urate handling in

Urate transport in the proximal tubule cells

Several urate transport proteins carry out the bi-directional transport of urate in the proximal tubule cells [20], [21], [23], [24] (Fig. 1). The uptake of filtered urate (reabsorption) is carried out by the urate-anion exchanger hURAT1. 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

The hURAT1 transporter

The urate transporter hURAT1 belongs to the family of organic anion transporters (OAT), a member of the major facilitator superfamily coded by SLC22A. hURAT1 protein is coded by the gene SLC22A12, mapped to chromosome 11q13 [4]. It was cloned from a human kidney [4]. hURAT1 contains 555 amino acids and modeled to contain 12 transmembrane domains with cytoplasmic amino acid carboxy termini. It is expressed only in the kidney, located at the luminal membrane of the epithelium of the proximal

Molecular characterization of hURAT1 abnormalities in HRH

Enomoto et al. [4] were the first to identify the urate transporter hURAT1 and to demonstrate that mutational alterations in the gene SLC22A12 coding for hURAT1 are associated with HRH. Mutational analyses in larger populations that followed this finding [5], [6], [7], [8], [9], [10] established a correlation between the clinical and genetic features of HRH patients and the significance of hURAT1 in the regulation of serum urate level. Mutations in the SLC22A12 gene were detected in most HRH

Is HRH a homogeneous or heterogeneous disorder?

Until recently, in the pre hURAT1 era, HRH was considered to be a heterogeneous disorder consisting of several subtypes of transport defects [29]. In absence of identified defective urate transporters, the postulated defects were site-specific (genetic control not established), rather than transporter-specific. This former classification was based on the effects of administration of PBD and PZA on urate excretion in the HRH patients. In normal humans PBD and PZA are known to exert profound

Clinical significance

A representative characterization of the HRH disorder was obtained by review of the data reported on the first twenty eight affected propositi (1972–1990) [29]. Twenty of the propositi were males and eight were females; their ages at diagnosis ranged from 3 to 74 years. Serum urate levels were significantly decreased, ranging from 12 to 119 μM, renal urate clearance was markedly elevated, ranging from 39.5 to 173 ml/min, and urinary urate excretion was normal or excessive. FCUR values ranged from

Genetics

The gene SLC22A12 coding for the transporter hURAT1 was mapped to an autosomal chromosome (11q13). Review of the pedigree of many affected HRH families indicates clearly the autosomal recessive mode of inheritance of the trait [29]. A dominant mode was suggested in some families, in whom a direct transfer of the defect from parents to offspring, without consanguinity, was suspected [31], [41], but the data presented for these families could comply with the possibility that the seemingly

Acknowledgment

The author is the incumbent of the Dr. Boris (Dov) Quartin Chair in Chemical Pathology of the Sackler Faculty of Medicine of Tel Aviv University.

References (42)

  • K. Ichida et al.

    Clinical and molecular analysis of patients with renal hypouricemia in Japan: influence of HURAT1 gene on urinary urate excretion

    J. Am. Soc. Nephrol.

    (2004)
  • N. Wakida et al.

    Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia

    J. Clin. Endocrinol. Metab.

    (2005)
  • T. Takahashi et al.

    Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese

    Pediatr. Nephrol.

    (2005)
  • F. Komoda et al.

    The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia

    Pediatr. Nephrol.

    (2004)
  • H.I. Cheong et al.

    Mutational analysis of idiopathic renal hypouricemia in Korea

    Pediatr. Nephrol.

    (2005)
  • P.G. Dayton et al.

    The physiological disposition of probenecid, including renal clearance, in man, studied by an improved method for its estimation in biological material

    J. Pharmacol. Exp. Ther.

    (1963)
  • R.W. Berliner et al.

    The renal mechanism for urate excretion in man

    J. Clin. Invest.

    (1950)
  • A.B. Gutman et al.

    Tubular secretion of urate in man

    J. Clin. Invest.

    (1959)
  • T.F. Yu et al.

    Effect of pyrazinamide and pyrazinoic acid on urate clearance and other discrete renal functions

    Proc. Soc. Exp. Biol. Med.

    (1957)
  • T.F. Yu et al.

    Suppression of tubular secretion of urate by pyrazinamide in the dog

    Proc. Soc. Exp. Biol. Med.

    (1961)
  • E. Praetorius et al.

    Hypouricemia with evidence for tubular elimination of uric acid

    J. Lab. Clin. Med.

    (1950)
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