title: Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency.
abstract: The Lesch-Nyhan disease is caused by an almost complete lack of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Partial HPRT-deficiency, associated with less severe phenotype, has also been identified. We have characterized mutations occurring in HPRT cDNA isolated from patients with HPRT-deficiency with an emphasis on examining the more unusual partial variants of HPRT-deficiency. HPRT cDNA was amplified by PCR, cloned and analyzed by automated DNA sequence analysis. Twenty-two, unrelated individuals with HPRT deficiency were studied including eight classic Lesch-Nyhan patients and fourteen patients representing the different groups of partial HPRT deficiency. We found a diverse pattern of mutations with point mutations accounting for the majority of abnormal HPRT genes. Nonsense mutations and exon deletions were only found in HPRT cDNA isolated from classic Lesch-Nyhan patients. Mutations associated with partial HPRT-deficiency were frequently located in the amino terminal part of the molecule. A CpG mutational hot spot was identified at the position for Arg-51 in the HPRT protein. Two hyperuricemic patients exhibited unusual splice site mutations: in one this led to the creation of an additional exon in the HPRT gene and in the other part of exon 6 was missing in a subpopulation of the transcripts, producing the effect of a dominant, negative mutation.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla 92093.
authors.forename: K
authors.initials: K
authors.lastname: Sege-Peterson
authors.forename: J
authors.initials: J
authors.lastname: Chambers
authors.forename: T
authors.initials: T
authors.lastname: Page
authors.forename: O W
authors.initials: OW
authors.lastname: Jones
authors.forename: W L
authors.initials: WL
authors.lastname: Nyhan
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005091:Exons; D005347:Fibroblasts / Q000201:enzymology; D014644:Genetic Variation; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000201:enzymology / Q000235:genetics*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D012867:Skin / Q000201:enzymology / Q000473:pathology
chemical_list: D009838:Oligodeoxyribonucleotides; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase