Mutations in the HPRT gene cause a spectrum of diseases that ranges from 
hyperuricemia alone to hyperuricemia with profound neurological and behavioral 
dysfunction. The extreme phenotype is termed Lesch-Nyhan syndrome. In 271 cases 
in which the germinal HPRT mutation has been characterized, 218 different 
mutations have been found. Of these, 34 (13%) are large- (macro-) deletions of 
one exon or greater and four (2%) are partial gene duplications. The deletion 
breakpoint junctions have been defined for only three of the 34 macro-deletions. 
The molecular basis of two of the four duplications has been defined. We report 
here the breakpoint junctions for three new deletion mutations, encompassing 
exons 4-8 (20033bp), exons 4 and 5 (13307bp) and exons 5 and 6 (9454bp), 
respectively. The deletion breakpoints were defined by a combination of long 
polymerase chain reaction (PCR) amplifications, and conventional PCR and DNA 
sequencing. All three deletions are the result of non-homologous recombinations. 
A fourth mutation, a duplication of exons 2 and 3, is the result of an 
Alu-mediated homologous recombination between identical 19bp sequences in 
introns 3 and 1. In toto, two of three germinal HPRT duplication mutations 
appear to have been caused by Alu-mediated homologous recombination, while only 
one of six deletion mutations appears to have resulted from this type of 
recombination mechanism. The other five deletion mutations resulted from 
non-homologous recombination. With this admittedly limited number of 
characterized macro-mutations, Alu-mediated unequal homologous recombinations 
account for at least 8% (3 of 38) of the macro-alterations and 1% (3 of 271) of 
the total HPRT germinal mutations.