Biochemistry of the X-Linked Uric Aciduria—Enzyme Defect and Its Genetic Variants

Kelley, William N.

doi:10.1001/archinte.1972.03650020029006

Cited by 5 publications

(1 citation statement)

References 58 publications

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“…In cell extracts of cultured lymphoblasts, the HPRT activity was 20% of control values and the APRT activity was normal. The PRPP concentration and the rate of de novo purine synthesis in cultured lymphoblasts were both intermediate between controls and lymphoblasts from patients with the Lesch-Nyhan syndrome.Mutations of hypoxanthine-guanine-phosphoribosyltransferase (HPRT; EC 2.4.2.8) present with either the severe deficiency syndrome (McKusick 30800; Lesch and Nyhan, 1964) or a milder form manifesting only with urate overproduction and gout (Kelley, 1972;Emmerson et al, 1976). Such deficiencies have almost invariably been associated with an increased activity of adenine phosphoribosyltransferase (APRT; EC 2.4.2.7) in erythrocytes, which has been most commonly attributed to the increased concentration of 5-phosphoribosyl-l-pyrophosphate (PRPP) in these cells (Kelley et al, 1969).…”

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HPRT‐Deficiency associated with normal PRPP concentration and APRT activity

Gordon

Keough

Emmerson

1986

J of Inher Metab Disea

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Deficiencies of HPRT are usually associated with increased concentrations of PRPP and increased levels of APRT activity in erythrocytes. We report the case of a male with a partial deficiency of HPRT in whom these two parameters were normal. The clinical features of this patient were those associated with severe hyperuricaemia and gout. Studies of intact erythrocytes showed rates of incorporation of [14C]hypoxanthine and of [14C]adenine into purine nucleotides which were almost indistinguishable from normal. However, HPRT activity in erythrocyte lysates was only 9% of normal. In cell extracts of cultured lymphoblasts, the HPRT activity was 20% of control values and the APRT activity was normal. The PRPP concentration and the rate of de novo purine synthesis in cultured lymphoblasts were both intermediate between controls and lymphoblasts from patients with the Lesch-Nyhan syndrome.

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confidence: 99%

HPRT‐Deficiency associated with normal PRPP concentration and APRT activity

Gordon

Keough

Emmerson

1986

J of Inher Metab Disea

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Further Studies of the Enzyme Composition of Mutant Cells in X-Linked Uric Aciduria

Sweetman

Nyhan

1972

Arch Intern Med

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Assay procedures have been developed for the determination of hypoxanthine guanine phosphoribosyltransferase (HGPRT) and adenine phosphoribosyltransferase (APRT) activity in erythrocytes and for HGPRT and inosinic acid dehydrogenase activity in fibroblasts. In normal erythrocytes the mean activity for HGPRT using hypoxanthine as substrate was 39.09 m\g=m\mols/hr/\g=m\lof cells. The mean value for patients with the Lesch-Nyhan syndrome was 0.003 m\g=m\mols/hr/\g=m\l. Nearly all of the obligate heterozygotes studied had normal levels of HGPRT activity in both erythrocytes and fibroblasts. The normal erythrocyte mean level of APRT activity was 23.56 m\g=m\mols/hr/\g=m\l.All subjects with complete or partial deficiency of HGPRT and heterozygotes had elevated APRT activity.There were no differences among the inosinic acid dehydrogenase (IMPDH) activities of fibroblasts from subjects who were normal, HGPRT-deficient, or hyperuricemic without HGPRT deficiency.The syndrome described by Lesch and Nyhan' consists clinically of mental retardation, athetoid cerebral palsy, and aggressive, compulsive be¬ havior most dramatically character¬ ized by self-mutilation.2 This is an in¬ herited metabolic disease. The locus for the mutant gene is on the X chro¬ mosome.3 It was shown by Seegmiller et al4 that the primary expression of the mutant gene is to determine the activity of the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT). Summaries of experience in their laboratory with the enzyme and its defects in the erythrocyte and in the fibroblasts have been presented by Kelley.5·6 It is the purpose of this report to describe our experience with the activity of HGPRT and other en¬ zymes of purine metabolism in con¬ trol individuals and in patients with disorders of purine metabolism.The methods employed for the as¬ say of HGPRT were different from those previously described. Levels of activity of HGPRT have been deter¬ mined using both hypoxanthine and guanine as substrates. Adenine phosphoribosyltransferase (APRT) activity has also been determined using similar methodology. Assess¬ ment of these activities has been car¬ ried out in erythrocytes of control in¬ dividuals and in patients with the Lesch-Nyhan syndrome, in whom the erythrocyte activity of HGPRT is vir¬ tually absent. Erythrocytes have also been studied in patients with partial deficiency of HGPRT in whom quite a different clinical syndrome has been observed.7 8 Patients described by Kogut and colleagues7 had 5% of normal activity of HGPRT and suffered from urinary tract stone disease in child¬ hood. There were no central nervous system abnormalities. We have also studied women who were obligate hétérozygotes and patients with hy¬ peruricemia of unknown cause. The activity of HGPRT has also been de¬ termined using hypoxanthine as sub¬ strate in fibroblasts in cell culture from the same populations of sub¬ jects. The activity of inosinic acid dehydrogenase (IMPDH) has also been assayed in fibroblasts cultured from some of these subjects. MethodsThe assays emp...

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Supplement: 21st rheumatism review

1974

Arthritis & Rheumatism

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Biochemistry of the X-Linked Uric Aciduria—Enzyme Defect and Its Genetic Variants

Cited by 5 publications

References 58 publications

HPRT‐Deficiency associated with normal PRPP concentration and APRT activity

HPRT‐Deficiency associated with normal PRPP concentration and APRT activity

Further Studies of the Enzyme Composition of Mutant Cells in X-Linked Uric Aciduria

Supplement: 21st rheumatism review

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