Hypouricemia, Renal, 1

A number sign (#) is used with this entry because of evidence that renal hypouricemia-1 (RHUC1) is caused by homozygous or compound heterozygous mutation in the SLC22A12 gene (607096) on chromosome 11q13.

Description

Renal hypouricemia is characterized by impaired uric acid reabsorption at the apical membrane of proximal renal tubule cells. The syndrome is not lethal and may be asymptomatic. However, it is accompanied by nephrolithiasis and exercise-induced acute renal failure in about 10% of patients (Ichida et al., 2008).

Genetic Heterogeneity of Renal Hypouricemia

See also RHUC2 (612076), which is caused by mutation in the SLC2A9 gene (606142).

Clinical Features

Greene et al. (1972) reported brother and sister with low serum urate concentration due to an isolated defect in renotubular reabsorption of urate such as occurs in the Dalmatian coachhound (see 242050). Akaoka et al. (1975) described a family with at least 4 persons with a nearly complete defect in reabsorptive transport of urate. Both males and females were affected. All affected persons were from consanguineous marriages. In a retrospective survey of urate concentrations in blood from 47,420 patients, followed by further selective studies, Harkness et al. (1983) detected 2 women with persistent marked hypouricemia and high urinary urate concentrations. No instance of xanthine oxidase deficiency (278300), another cause of hypouricemia, turned up. Uric acid urolithiasis occurs in some cases (Frank et al., 1979; Hedley and Phillips, 1980). Hydration and alkalinization of urine may help prevent this complication.

Takeda et al. (1985) found that the urate/creatinine clearance ratio of parents was intermediate between the normal and that of patients. Takeda et al. (1985) found no change in the increased uric acid clearance in 3 of their 4 patients when given pyrazinamide (PZA). They concluded that abnormal tubular secretion was not the basis of hypouricemia, because PZA response has been thought to be a measure of tubular secretion which PZA selectively and completely blocks. Benzbromarone, which like probenecid inhibits postsecretory tubular reabsorption of urate, had no effect in any of the 4. A 4-component system for handling of urate by the human kidney has been proposed; the components are glomerular filtration, early proximal tubular reabsorption, tubular secretion, and postsecretory tubular reabsorption. Defects in this condition have been classified into 3 groups: defect in proximal reabsorption, defect in postsecretory reabsorption, and a combination of the 2. A fourth form, increased secretion of uric acid by the renal tubules, was reported by Shichiri et al. (1982). Gafter et al. (1989) used the combined pyrazinamide-probenecid test to define the lesion as presecretory, postsecretory or combined impairment, or hypersecretion with intact reabsorption.

Tanaka et al. (2003) reported 2 brothers with hereditary renal hypouricemia and exercise-induced acute renal failure. The proband was a 45-year-old man who presented with abdominal pain, vomiting, backache, and oliguria after strenuous running. He and his younger brother reported histories of similar episodes occurring once or twice per year since their twenties. Laboratory examination showed that both brothers had hypouricemia, 0.8 mg/dl and 1.0 mg/dl, respectively, and an elevated fractional excretion of uric acid, 46% and 65.7%, respectively. Radiologic examination showed bilateral urolithiasis in both sibs, presumably caused by high urinary urate excretion.

Molecular Genetics

In a 48-year-old Japanese male with a blood urate level of 4.3 +/- 0.9 microgram/milliliter (normal range, 58 to 70 microgram/milliliter), Enomoto et al. (2002) identified a homozygous trp258-to-ter mutation in the SLC22A12 gene (W258X; 607096.0001). The patient had a fractional excretion of urate of 95% +/- 10 (normal, less than 10%), and the patient showed only mild responses in pyrazinamide- and benzbromarone-loading tests, indicating that he had a selective defect in the urate reabsorption mechanism of his kidneys.

In 2 brothers with hypouricemia and exercise-induced acute renal failure, Tanaka et al. (2003) identified homozygosity for the W258X mutation. The parents of the sibs and all of the sibs' 5 children were heterozygous for the mutation.

Population Genetics

Gafter et al. (1989) emphasized the high frequency of this disorder in Iraqi Jews. Of 11 families with a presecretory defect, 8 were of Sephardic Jewish origin and 6 of these were Iraqi. An American patient reported by Greene et al. (1972) was also Iraqi.

Ichida et al. (2008) identified SLC22A12 mutations in 66 of 71 Japanese patients with hypouricemia. The W258X mutation (607096.0001) was by far the most common mutation, occurring in 93 alleles, including 31 homozygotes and 23 compound heterozygotes. A total of 13 mutations, including 3 novel mutations, were identified (see, e.g., 607096.0005; 607096.0006). Acute renal failure and urolithiasis occurred in 21.1% and 8.5% of patients, respectively. Three patients had chronic renal failure. By haplotype analysis, Ichida et al. (2008) found that W258X was a founder mutation with an estimated age of 6,820 years. This mutation dates back from between the time when the Jomon people predominated in Japan and the time when the Yayoi people started to migrate to Japan from the Korean peninsula.