Direct Evidence for a Hot Spot of Germline Mutation at HPRT Locus

Abstract

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is a well-studied purine metabolic enzyme which converts hypoxanthine or guanine into IMP or GMP in the presence of 5-phosphoribosyl-l-pyrophosphate. A genetic deficiency of this enzyme causes either Lesch-Nyhan syndrome characterized by neurological symptoms and self-mutilation behavior or severe overproduction-type gout, both of which show X-linked inheritance. The germline mutations causing this enzyme deficiency have been studied extensively at the molecular level (Sculley et al. 1992). Typically, germline mutations associated with HPRT deficiencies differ from family to family. These data imply that the defective mutant genes at this locus do not expand in human populations and that mutations in patients from different families are a reflection of different germline mutations. Although the mutations in a limited number of families with this disease have shown the same molecular alteration, conclusive evidence that these mutations reflected independent events has been lacking (Davidson et al.1991, Sculley et al.1991, Marcus et al. 1992, Peterson et al. 1993).