title: Genetic basis of hypoxanthine guanine phosphoribosyltransferase deficiency in a patient with the Lesch-Nyhan syndrome (HPRTFlint).
abstract: The molecular basis for complete hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency has been determined in a patient with Lesch-Nyhan syndrome. A B-lymphoblastoid cell line derived from this patient expresses normal amounts of HPRT mRNA yet no detectable immunoreactive protein as determined by radioimmunoassay. These findings suggest either a decreased rate of translation or accelerated degradation due to enhanced proteolytic susceptibility. cDNAs synthesized from this patient's RNA have a single nucleotide (nt) substitution, a C----A transversion at nt 222. RNase A cleavage analysis confirms the presence of a mutation at this position within mRNA isolated from lymphoblasts from patient A.C. This transversion predicts a phenylalanine to leucine replacement at amino acid position 73 in the translated protein. We have designated this mutant HPRTFlint. The mutation in HPRTFlint disrupts a strongly conserved region among PRTases from Escherichia coli, rodents and man, suggesting an important role for this region for the normal function of HPRT. Since it is unlikely that this amino acid substitution alters the translational rate, we hypothesize that disruption of the secondary structure within this region renders HPRTFlint more susceptible to proteolysis.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109.
authors.forename: B L
authors.initials: BL
authors.lastname: Davidson
authors.forename: M
authors.initials: M
authors.lastname: Pashmforoush
authors.forename: W N
authors.initials: WN
authors.lastname: Kelley
authors.forename: T D
authors.initials: TD
authors.lastname: Palella
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D005796:Genes; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics; D007926:Lesch-Nyhan Syndrome / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase