ClinVar

In 9 patients from 7 unrelated families with the neurologic variant of Lesch-Nyhan syndrome (see 300322), Sampat et al. (2011) identified a 143G-A transition in the HPRT gene, resulting in an arg48-to-his (R48H) substitution in an alpha-2 helix at the interface between dimerization of the protein. An additional patient with hyperuricemia and impulsive/oppositional behavior, whom the authors classified as having HPRT-related hyperuricemia (HRH; 300323), also carried the mutation. The mutation likely arose independently multiple times, because it occurred at a CpG motif. There was almost no detectable HPRT enzyme activity in patient erythrocytes, but there was some residual activity in patient fibroblasts. Kinetic studies in E. coli showed that the mutant enzyme had normal affinity for hypoxanthine and guanine, but V(max) was decreased by 33% and 37% for those substrates, respectively, compared to wildtype. However, additional studies showed that the mutant protein had poor thermal stability, with only 16% residual activity at 37 degrees C and undetectable activity at 55 degrees C, which may have explained the variable phenotypic consequences in mutation carriers.