Lesch-Nyhan Syndrome and HPRT Variants: Study of Heterogeneity at the Gene Level
The purine salvage enzyme hypoxanthine-guanine phospho-ribosyltransferase (HPRT: EC 220.127.116.11) catalyses the conversion hypoxanthine and guanine to their respective nucleotides, IMP and GMP. A partial deficiency of HPRT is associated with overproduction of uric acid which results in the development of severe form of Gout and nephrolithiasis.(Kelly et al. 1967). An almost complete deficiency of HPRT leads to an Xlinked disorder Lesch-Nyhan Syndrome, which in its classical form shows clinical symptoms of hyperuricemia, choreoathetosis, mental retardation and compulsive self mutilation. A large number of patients with different severity of these symptoms and levels of rest activity of HPRT have been reported and attempts have been made to classify them into various catagories on the basis of enzyme kinetics or behaviour of the cultured fibroblasts or lyphoblasts in various selection media (Page et al.1983., Singh et al., 1986). By sequence analysis of tryptic peptides, several HPRT variants have been chracterised to be due to single amino acid substitution(Wilson et al. 1983). Two of these have been recently shown to be due to point mutation of a single base by employing the strategy of cDNA cloning or genomic amplification of a specific region of the gene and followed by nucleotide sequencing (Fujimori et al., 1988; Cariello et al., 1988). Some of them have also been detected as gross rearrangements of the Gene (Yang et al., 1984.; Wilson et al. 1986). By employing the ribonuclease cleavage anlysis technique, also known as RNA mapping, Gibbs and Casky (1987) have been successful in localising a number of mutations of one to five nucleotides in five patients.
KeywordsUric Acid Single Amino Acid Substitution Partial Deficiency Rest Activity Complete Deficiency
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