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Altered membrane NTPase activity in Lesch–Nyhan disease fibroblasts: comparison with HPRT knockout mice and HPRT‐deficient cell lines

Lesch–Nyhan disease (LND) is a rare disorder caused by a defect of an enzyme in the purine salvage pathway, hypoxanthine phosphoribosyl transferase (HPRT). It is still unknown how the metabolic defect translates into the complex neuropsychiatric phenotype characterized by self‐injurious behavior, dystonia and mental retardation. There are abnormalities in purine and pyrimidine nucleotide content in HPRT‐deficient cells. We hypothesized that altered nucleotide concentrations in HPRT deficiency change G‐protein‐mediated signal transduction. Therefore, our original study aim was to examine the high‐affinity GTPase activity of G‐proteins in membranes from primary human skin and immortalized mouse skin fibroblasts, rat B103 neuroblastoma cells and mouse Neuro‐2a neuroblastoma cells. Unexpectedly, in membranes from human fibroblasts, B103‐ and Neuro‐2a cells, Vmax of low‐affinity nucleoside 5′‐triphosphatase (NTPase) activities was decreased up to 7‐fold in HPRT deficiency. In contrast, in membranes from mouse fibroblasts, HPRT deficiency increased NTPase activity up to 4‐fold. The various systems analyzed differed from each other in terms of Km values for NTPs, absolute Vmax values and Ki values for nucleoside 5′‐[β,γ‐imido]triphosphates. Our data show that altered membrane NTPase activity is a biochemical hallmark of HPRT deficiency, but species and cell‐type differences have to be considered. Thus, future studies on biochemical changes in LND should be conducted in parallel in several HPRT‐deficient systems.