Lesch-Nyhan disease and its attenuated variants are caused by mutations in the 
HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine 
phosphoribosyltransferase. The mutations are heterogeneous, with more than 400 
different mutations already documented. Prior efforts to correlate variations in 
the clinical phenotype with different mutations have suggested that milder 
phenotypes typically are associated with mutants that permit some residual 
enzyme function, whereas the most severe phenotype is associated with null 
mutants. However, multiple exceptions to this concept have been reported. In the 
current studies 44 HPRT1 mutations associated with a wide spectrum of clinical 
phenotypes were reconstructed by site-directed mutagenesis, the mutant enzymes 
were expressed in vitro and purified, and their kinetic properties were examined 
toward their substrates hypoxanthine, guanine, and phosphoribosylpyrophosphate. 
The results provide strong evidence for a correlation between disease severity 
and residual catalytic activity of the enzyme (k(cat)) toward each of its 
substrates as well as several mechanisms that result in exceptions to this 
correlation. There was no correlation between disease severity and the affinity 
of the enzyme for its substrates (K(m)). These studies provide a valuable model 
for understanding general principles of genotype-phenotype correlations in human 
disease, as the mechanisms involved are applicable to many other disorders.