Hypoxanthine‐guanine phosphoribosyltransferase deficiency in three brothers with gout: Characterization of a variant, HPRT Edinburgh , having altered isoelectric point, increased thermal lability and normal levels of messenger RNA (original) (raw)
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Arthritis & Rheumatism, 2009
A deficiency in hypoxanthine guanine phosphoribosyltransferase (HPRT) activity leads to overproduction of uric acid. According to the degree of enzymatic deficiency, a large spectrum of neurologic features can also be observed, ranging from mild or no neurologic involvement to complete Lesch-Nyhan disease. Herein, we describe a patient with hyperuricemia, juvenile-onset gouty arthritis, nephrolithiasis, and mild neurologic symptoms, attributed to a newly identified variant of the hprt gene, c.596T>G, resulting in the amino acid change p.F199C. Residual HPRT activity (8%) protected against severe neurologic involvement in this patient. Modeling of the mutated protein was used to predict the mechanisms that led to partial enzymatic activity. Careful neurologic examination is warranted in juvenile and middle-aged patients with gout, in order to detect mild symptoms that may lead to a diagnosis of HPRT deficiency.
The Journal of rheumatology, 2007
The frequency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency within the gout-affected population in Taiwan was unclear. We evaluated its frequency and sought to identify a new genetic variation in a case with HPRT deficiency. From 2004 to 2005, a total of 983 patients with gout were followed among outpatients attending the Department of Rheumatology. Among these, 12 cases were suspected to have HPRT deficiency, and HPRT activity was examined by HPLC. In the index case found to have HPRT deficiency, genetic variation was analyzed by RT-PCR, direct sequencing, and SSCP. Only a single case proved to have partial HPRT deficiency among 12 suspicious cases. Both cDNA and genomic DNA analysis identified a new mutation on exon 2 with T to G transition at cDNA base 93, resulting in a change from aspartic acid to glutamic acid at position 31. It was designated as HPRTChia-Yi, from our case's residence at Chia-Yi Hsein, Taiwan. According to this hospital-based survey, ...
Acta Medica Scandinavica, 1979
A family is reported where four males have developed hyperuricemia, renal damage and, except for the youngest person affected, gout at an early age. The disease appears to be inherited as an X-linked recessive metabolic error. Clinically the patients have developed classical, tophaceous gout before the age of 25 and have suffered repeated attacks of renal colic. Renal tubular damage with decreased ability to concentrate and acidify urine was seen in a family member of only 16 years of age. Progressive renal failure seems to develop slowly. None in the family has shown neurologic symptoms, and two of the four affected men are apparently of at least average intelligence, two slightly below average. One female carrier has repeatedly passed uric acid stones. Studies of the red blood cell lysate have shown a normal activity of enzyme hypoxanthine phosphoribosyltransferase, and an increased level of adenine phosphoribosyltransferase. Skin fibroblasts from affected family members grew normally in the presence of 8-azaguanine. Administration of azathioprine to the patients did not decrease their serum uric acid levels. This is the first family described with this type of disorder of the purine metabolism.
Renal excretion of hypoxanthine and xanthine in primary gout
The American Journal of Medicine, 1988
The renal excretion of uric acid is usually diminished in primary gout with respect to increased serum urate levels. To determine whether the renal excretion of uric acid precursors, hypoxanthine and xanthine, is also abnormal in primary gout, the concentrations of these purines were measured in plasma and 24-hour urine samples in normal subjects, in patients with primary gout and uric acid underexcretion, and in patients with enzyme deficiencies that are known to result in overproduction of uric acid. SUBJECTSANDMEI'HODS: Threegroupsofsubjects were studied: Group I consisted of 10 ambulatory healthy normal men; Group II consisted of 15 patients in whom primary gout was diagnosed; and Group III consisted of 10 patients with various enzyme defects lmown to produce an excessive synthesis of uric acid. In each subject, plasma and 24hour urinary uric acid, hypoxanthine, xanthine, and creatinine concentrations were measured and the mean of three consecutive determinations was used. The fractional excretion of puke compounds was calculated from a formula. Hypoxanthine phosphoribosyltransferase, adenine phosphoribosyltransferase, and hemoglobin were also measured in each subject. RESULTS: Plasma hypoxanthine and xanthine were increased in the two groups of patients compared with the control subjects. Urinary hypoxanthine and xanthine levels were reduced in gouty patients compared with control subjects, whereas levels were increased in patients with uric acid overproduction. A positive correlation was found between the renal clearances of uric acid, hypoxanthine, and xanthine. CONCLUSION: The results indicate that the renal excretion of hypoxanthine and xanthine is severely impaired in most patients with primary gout. From the Departments of Internal Medi ci ne and Clinical Biochemistiy. Metabol i c Unit, "
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2000
A male child, who presented at the age of 3.5 years with acute renal failure, was diagnosed as having partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8). The underlying HPRT mutation was unique in that the specific activity of HPRT in erythrocyte and in fibroblast lysates was normal, but the rate of uptake of hypoxanthine into nucleotides of intact cultured fibroblasts was markedly reduced (23% of normal). The low functioning of HPRT in the intact fibroblasts was associated with decreased utilization of endogenously generated hypoxanthine and with decreased utilization of the cosubstrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The non-utilized hypoxanthine was excreted into the incubation medium. The accumulation of PRPP was indicated by the 2.3-fold increase in the rate of uptake of adenine into intact cell nucleotides and by the 7.5-fold enhancement of the rate of de novo purine synthesis. Kinetic studies of HPRT activity in fibroblast lysates revealed reduced affinity of the enzyme for PRPP (apparent K m 500 WM in comparison to 25 WM in control lysates), manifested in low activity at low (physiological), but not at high PRPP concentrations. The apparent K m for hypoxanthine was normal (23 WM in comparison to 14.2 WM in control lysates). With allopurinol treatment, our patient has had no problems since presentation, and is developing normally at 5 years of age.