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Hypoxanthine-guanine phosphoribosyl transferase deficiency

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Summary

In man congenital lack of an enzyme of the purine salvage system, hypoxanthineguanine phosphoribosyl transferase (HG-PRT E.C. 2.4.2.8), is mostly accompanied by a picture known as the Lesch-Nyhan syndrome. The degree of deficiency may vary from zero to a few percent of normal activity but a correlation between the severity of HG-PRT deficiency and the clinical picture has not been observed, no more than a correlation between HG-PRT deficiency and neurological dysfunction. But individuals with undetectable HG-PRT activity but without the Lesch-Nyhan syndrome have been described. Patients with partial HG-PRT deficiency have clinically distinctive findings. Sometimes mild neurological abnormalities are observed. Because of marked overproduction of uric acid severe gouty arthritis and renal dysfunction are often encountered in both complete and partial deficiency.

There is considerable molecular heterogeneity in HG-PRT deficiency in man. Mutant enzymes may exhibit different kinetic and electrophoretic properties, indicating that there might be a mutation on the structural gene coding for HG-PRT.

Lack of HG-PRT disturbs purine interconversions profoundly. In addition to an important function of HG-PRT in the uptake of the purine bases hypoxanthine and guanine into the cell, the effective uptake of inosine, guanosine and adenosine also seems to be dependent on HG-PRT. Uptake of purine bases into intact red blood cells occurs according to a two component mechanism, one component probably involving a phosphoribosyl transferase system.

The inheritance of HG-PRT deficiency is X-linked recessive and it is transmitted by asymptomatic carrier females. Several methods have been introduced for carrier detection. As a consequence of X chromosome inactivation, in these females a mosaicism of HG-PRT positive and HG-PRT negative fibroblasts can be demonstrated after cloning or after selection of HG-PRT negative cells in a selective medium. A more rapid method involves direct measurements of HG-PRT activities in single hair roots from the scalp. Because hair roots develop more or less clonally, in heterozygote females HG-PRT positive and negative hair roots are encountered. HG-PRT deficiency can be detected antenatally by demonstrating the presence or absence of enzyme activity in ammiotic fluid derived fibroblasts qualitatively by autoradiography and quantitatively by ultramicrochemical measurements of enzyme activities in single or small numbers of cells.

In studies with isolated cells the metabolic defect can be corrected in several ways. Metabolic cooperation between HG-PRT positive and HG-PRT negative cells leads to apparently normal phenotype of all cells, provided there is cell to cell contact. There is evidence that a missing enzyme product or a derivative might be transferred from the normal to the mutant cells. Apparent correction of the enzyme defect is also observed when HG-PRT deficient lymphocytes are stimulated with phytohaemagglutinin.

The first data suggestive of genetic complementation between two human HG-PRT deficient cell strains by which hybrid cells can synthesize a functionally active HG-PRT, are consistent with the view that HG-PRT deficiency in man is due to a structural gene mutation. Recent results show that other interesting findings might come from experiments in which HG-PRT deficient cells are treated with exogenous genetic material (isolated DNA or metaphase chromosomes) to reactivate or induce HG-PRT activity.

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  1. Department of Human Genetics, Faculty of Medicine, University of Nijmegen, Nijmegen, The Netherlands

    Chris H. M. M. de Bruyn

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Supported by grants from FUNGO (Foundation for Medical Scientific Research in the Netherlands) and the Medical Prevention Fund.

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de Bruyn, C.H.M.M. Hypoxanthine-guanine phosphoribosyl transferase deficiency. Hum Genet 31, 127–150 (1976). https://doi.org/10.1007/BF00296142

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