Hypoxanthine-guanine phosphoribosyl transferase deficiency

B. T. Emmerson, L. Thompson. The spectrum of hypoxanthine-guanine phosphoribosyl transferase deficiency. Quart.J.Med.,... 

J. Dancis, L. C. Yip, R. P. Cox, S, Piomelli, M. E. Balls. Disparate enzyme activity in erythrocytes and leucocytes a variant of hypoxanthine-guanine phosphoribosyl transferase deficiency with an unstable enzyme. J.Clin.Invest., 52 206 (1973). 

C. H. M. M. de Bruyn. An atypical case of hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome) I. Clinical Studies. Clin.Genet., 40 348 (1973). 

M. R. Watson. Clinical and biochemical observations on three cases of hypoxanthine-guanine phosphoribosyl transferase deficiency. Ann.Rheum.Pis., 34 249 (1975). 

B. B. Migeon, X-linked hypoxanthine-guanine phosphoribosyl transferase deficiency Detection of heterozygotes by selective medium, Biochem. Genet, 4 377 (1970). 

STABILIZATION BY PRPP OF CELLULAR PURINE PHOSPHORIBOSYL-TRANSFERASES AGAINST INACTIVATION BY FREEZING AND THA ING. STUDY OF NORMAL AND HYPOXANTHINE-GUANINE PHOSPHORIBOSYL-TRANSFERASE DEFICIENT HUMAN FIBROBLASTS... 

PROPERTIES OF ERYTHROCYTE PURINE PHOSPHORIBOSYLTRANS-FERASES IN PARTIAL HYPOXANTHINE-GUANINE PHOSPHORIBOSYL-TRANSFERASE DEFICIENCY... 

Hypoxanthine - Guanine phosphoribosyl transferase deficiency in gout ... 

As yet there is no firm evidence to suppose the hyperproduction of uric acid in the propositus is the result of deficiency of APRT and a raised feed back. Although this may be the mechanism in the case of gout associated with a hypoxanthine guanine phosphoribosyl transferase deficiency. 

Rare hereditary deficiency Avoid in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), such as Lesch-Nyhan and Kelley-Seegmiller syndromes. 

Inherited deficiency in hypoxanthine-guanine phosphoribosyl-transferase... 

Cultivate a suitable malignant myeloma cells deficient in HPGRT (hypoxanthine guanine phosphoribosyl transferase), which is a genetic marker for the selection of the hybrid cells after fusion. 

One system uses mouse lymphoma cells and detects mutations that cause deficiency of thymidine kinase (TK). Another uses Chinese hamster cells and detects mutations in the gene that produces hypoxanthine-guanine phosphoribosyl transferase (HGPRT). Both tests cure efficient, are widely applied, and can be completed in a few weeks. Although not as simple, rapid, and efficient as the Salmonella tests, they have the advantage of being done in a eukaryote. Mammalian-cell cultures cure also used to test for chromosomal mutation. 

Xanthine nephropathy has been reported in tumor lysis syndrome (TLS) in patients with hypoxanthine-guanine phosphoribosyl transferase (HGPRT) enzyme deficiency [180b], however, this patients cultured fibroblasts yielded normal levels of HGPRT enzyme. Allopurinol pretreatment allows the build up of both xanthine and hypoxanthine which, in the absence of HGPRT, cannot be recycled and thus xanthine supersaturation in the urine resulting in xanthine stones with subsequent obstructive renal failure. 

Two enzyme abnormalities resulting in an overproduction of uric acid have been well described (Fig. 91-1). The first is an increase in the activity of phosphoribosyl pyrophosphate (PRPP) synthetase, which leads to an increased concentration of PRPP. PRPP is a key determinant of purine synthesis and thus uric acid production. The second is a deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT). 

S.J. (1999) Characterization of the mutational profile of (+)-7R,8S-dihydroxy-9 S,10R-epoxy-7,8,9,l 0-tetrahydrobenzo[a]pyrene at the hypoxanthine (guanine) phosphoribosyl-transferase gene in repair-deficient Chinese hamster V-Hl cells. Carcinogenesis, 20, 2279-2286. 

EXAMPLE 14.13 In some diseases, excessive amounts of purines are produced in the body, leading to accumulation of urate. Patients with Lesch-Nyhan syndrome lack the enzyme hypoxanthine-guanine phosphoribosyl-transferase (HG-PRTase). Children born with this disorder are mentally retarded and prone to self-mutilation. They produce excessive amounts of purines due to accumulation of P-Rib-PP which stimulates the first enzyme of the purine synthesis pathway, amido PRTase (Fig. 14-18). Patients with Lesch-Nyhan syndrome may also suffer from gout, which is due to an accumulation of urate in the body with deposition of crystals of sodium urate in the joints and kidneys, or due to accumulation of P-Rib-PP for reasons other than a deficiency of HG-PRTase. 

Once the fusion has taken place, it is necessary to eliminate any unfused myeloma cells and to select only hybrid cells secreting antibody. This is primarily achieved by the use of hypoxanthine aminopterin thymidine (HAT) media and cells that are deficient in the enzyme responsible for incorporation of hypoxanthine into DNA. Figure 3 illustrates this process. The unfused splenocytes are not immortal and naturally die off in culture. The elimination of the unfused myeloma cells is carried out by the initial use of mutant myeloma cells selected for a deficiency in the enzymes hypoxanthine guanine phosphoribosyl transferase (HGPRT) and thymidine kinase (TK), rendering them unable to use the salvage pathway for nucleic acid synthesis. The myelomas will die off... 

The quantitative importance of the salvage pathway in purine metabolism is difficult to estimate [156]. Comparison between uric acid production in normal children and in children affected with a deficiency in hypoxanthine guanine phosphoribosyl transferase has, however, permitted researchers to approximate how much the salvage pathway contributes to purine metabolism. Thus, whereas in normal children uric acid excretion in the urine (per 24 hours and per kilogram of body weight) is of the order of 10 mg, in children affected with the Lesch-Nyhan syndrome, uric acid excretion is around 47 mg. The difference between enzyme-deficient and normal children is believed to reflect the amount of uric acid normally used in the salvage pathway. 

HYPOXANTHINE-GUANINE PHOSPHORIBOSYL TRANSFERASE (HGPRT) DEFICIENCY IN A GIRL... 

An almost complete deficiency of the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT) is known to be the cause of the Lesch-Nyhan syndrome (1,2) The gene for HPRT is located on the X-chromosome, so that heterozygous females show two populations of cells, one HPRT and one HPRT ", as predicted by the hypothesis of Lyon (3,4). Such mosaicism has been demonstrated in populations of cultured fibroblasts and in hair root follicles of heterozygotes (4,5). 

Fig. 1. Effects of varying concentrations of orotic acid on the synthesis of FGAR and intracellular PP-ribose-P concentration. PP-ribose-P content is indicated on the panel to the left and FGAR synthesis on the panel to the right.o — mean ( S.D.) in six different strains with normal hypoxanthine-guanine phosphoribosyl-transferase o—omean in two different cell strains deficient in hypoxanthine-guanine phosphoribosyltransferase o—onormal cell strain preincubated with 1 mM azoorotate.

Possession of a genetic marker, such as the lack of an enzyme, to allow cell selection. For example, myelomas deficient in HGPRT (hypoxanthine guanine phosphoribosyl transferase) are commonly used. This allows selection of hybridomas in HAT medium (see selectable gene markers ). 

A. A. van Zeeland, Y. C. E. M. de Ruijfer, and J. W. I. M. Simons, The role of 8-azagua-nine in the selection from human diploid cells of mutants deficient in hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT), Mutat. Res. 23, 55 (1974). 

The Lesch-Nyhan Syndrome (LNS) is a rare x-linked neurological disease of children characterized by choreoathetosis, spasticity, mental retardation and compulsive self mutilation accompanied by excessive purine production and hyperuricemia (l). The virtually complete deficiency of activity of a purine salvage enzyme, hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) (EC 2.4.2.8.) (2), due to structural gene mutation (3 4) has been shown to be the basic abnormality in this disease. In erythrocytes of LNS patients, HGPRT deficiency has been found to be associated with increased activity and relative thermal stability of adenine phosphoribosyltransferase (APRT) (EC 2.4.2.7 ) (5 6) an autosomally determined enzyme (7) ... 

Partial deficiency of hypoxanthine-guanine phosphoribosyl-transferase Intermediate enzyme deficiency in heterozygote red cells. Ann. Intern. Med. 76 285-287. 

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