title: The role of the HPRT gene in human disease.
abstract: Human HPRT deficiency leads to two major forms of human disease. Partial enzyme deficiency results in gouty arthritis, while an almost complete deficiency leads to the Lesch-Nyhan disease. The latter is characterized by severe neurological dysfunction in addition to gouty arthritis, including retardation, choreoathetosis and aggressive and compulsive self-mutilation. The biochemical basis for the neurological symptoms is not understood. The human and mouse cDNA (RNA copy) genes have been isolated and sequenced. In addition, the amino acid sequence of the human protein has been directly determined. The human and mouse proteins differ at 7 amino acids out of the total, (including the N terminal methionine, which is processed off during maturation) of 218. There are 42 out of 654 nucleotide differences between the human and mouse genes in the amino acid coding region. The mouse genomic structure has been determined. It has 9 exons and 8 introns with a total size of approximately 36 kb. The human gene is very similar with identical intron-exon junction points and approximately the same total gene size. Both mouse and human presumed promotor region at the 5' end, lack a recognizable promotor in the form of a "TATAA" box and are very G-C rich, though not the same. This may be a feature of most "housekeeping" genes. HPRT gene point mutations in three gouty arthritis and one Lesch-Nyhan patient have been identified by peptide sequencing. Six gross gene rearrangements have been identified in Lesch-Nyhan HPRT genes. However it is likely that most mutations are point mutations or small deletions. So far all gene mutations identified are different from all others. The gene has been engineered into retrovirus vehicles which allows its efficient introduction into a wide variety of cells, including mouse marrow stem cells. This may allow treatment of Lesch-Nyhan patients as a model of gene therapy.
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000503:physiopathology; D002874:Chromosome Mapping; D005786:Gene Expression Regulation; D005796:Genes; D005818:Genetic Engineering; D006073:Gout / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000235:genetics; D008745:Methylation; D051379:Mice; D018377:Neurotransmitter Agents / Q000502:physiology; D011687:Purines / Q000378:metabolism*; D014960:X Chromosome
chemical_list: D018377:Neurotransmitter Agents; D011687:Purines; D007041:Hypoxanthine Phosphoribosyltransferase