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Record 1 of 14 in MEDLINE EXPRESS (R) 2000/11-2000/12
TITLE: Elevated UTP and CTP content in cultured neurons from HPRT-deficient transgenic mice.
AUTHOR(S): Brosh-S; Boer-P; Sperling-O; Zoref-Shani-E
ADDRESS OF AUTHOR: Felsenstein Medical Research Center, Rabin Medical Center, Petah-Tikva, Israel.
SOURCE (BIBLIOGRAPHIC CITATION): J-Mol-Neurosci. 2000 Feb-Apr; 14(1-2): 87-91
INTERNATIONAL STANDARD SERIAL NUMBER: 0895-8696
PUBLICATION YEAR: 2000
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8.; HPRT) catalyzes the salvage synthesis of inosine-5'-monophosphate (IMP) and guanosine-5'-monophosphate (GMP) from the purine bases hypoxanthine and guanine, respectively. Complete deficiency of HPRT activity is associated with the Lesch-Nyhan syndrome (LNS), characterized by excessive purine production and severe neurological manifestations. The etiology of the metabolic consequences of HPRT deficiency is clarified, but that of the neurological manifestations is not yet understood. HPRT-deficient mice represent an experimental animal model of LNS. In search for a possible metabolic abnormality in LNS brains, connecting the neurological deficit to HPRT deficiency, the purine and pyrimidine nucleotide content of cultured neurons, prepared from HPRT-deficient transgenic mice, was now determined. The HPRT-deficient neuronal cultures exhibited a significantly elevated content of the pyrimidine nucleotides UTP!
(1.33-fold the normal level, p = 0.0002) and CTP (1.28-fold the normal level, p = 0.02), but normal content of the purine nucleotides ATP and GTP. This abnormality in neuronal pyrimidine nucleotide content may be associated with the pathophysiology of the neurological deficit in LNS.
MINOR MESH HEADINGS: Brain-cytology; Cells,-Cultured; Embryo-; Hypoxanthine-Phosphoribosyltransferase-deficiency; Lesch-Nyhan-Syndrome-genetics; Mice-; Mice,-Inbred-C57BL; Mice,-Transgenic
MAJOR MeSH HEADINGS: *Cytidine-Triphosphate-metabolism; *Hypoxanthine-Phosphoribosyltransferase-genetics; *Neurons-metabolism; *Uridine-Triphosphate-metabolism
CHECKTAGS: Animal; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8; 63-39-8; 65-47-4
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase; Uridine-Triphosphate; Cytidine-Triphosphate
MEDLINE ACCESSION NUMBER: 20311087
UPDATE CODE: 200012
Record 2 of 14 in MEDLINE EXPRESS (R) 2000/11-2000/12
TITLE: Characterization of the dopamine defect in primary cultures of dopaminergic neurons from hypoxanthine phosphoribosyltransferase knockout mice.
AUTHOR(S): Smith-DW; Friedmann-T
ADDRESS OF AUTHOR: Center for Molecular Genetics, Room 122, Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0634, USA. dwsmith@ucsd.edu
SOURCE (BIBLIOGRAPHIC CITATION): Mol-Ther. 2000 May; 1(5 Pt 1): 486-91
INTERNATIONAL STANDARD SERIAL NUMBER: 1525-0016
PUBLICATION YEAR: 2000
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan disease (LND) is an X-linked metabolic disorder caused by lack of activity of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT) and characterized by hyperuricemia and debilitating neurological manifestations. The mechanisms underlying the neuropathology are not well understood and the principal neurochemical lesion characterized to date is a deficiency of the dopamine system in the basal ganglia. To facilitate the study of mechanism(s) by which HPRT deficiency causes the dopamine defect, we have compared the survival and dopamine phenotype of primary cultures of dopamine neurons derived from HPRT-deficient mice with the dopaminergic neurons from wild-type mice. The survival of dopaminergic neurons from both sources was promoted to an equal extent by glial cell line-derived neurotrophic factor (GDNF), a potent survival factor for dopamine neurons in vitro. Although the survival of the HPRT-deficient neurons was indistinguishable fr!
om that of cells derived from wild-type counterparts, the HPRT-deficient cells demonstrated a persistent deficiency of dopamine content and dopamine uptake with increasing neuritic differentiation, indicating that GDNF does not restore the normal phenotype in HPRT-deficient dopamine neurons despite its well-known protective and regenerative properties in several neurodegeneration models. Nevertheless, the demonstration that GDNF trophic support promotes the survival of these dopaminergic neurons will facilitate gaining a better understanding of the neuropathological mechanisms of LND by allowing a more extensive analysis of the cells central to the Lesch-Nyhan phenotype, the dopaminergic neurons of the basal ganglia.
MINOR MESH HEADINGS: Animal-; Basal-Ganglia-metabolism; Cells,-Cultured; Chromatography,-High-Pressure-Liquid; Female-; Immunohistochemistry-; Male-; Mesencephalon-physiology; Mice-; Mice,-Inbred-C57BL; Mice,-Knockout; Nerve-Tissue-Proteins-pharmacology; Neurites-physiology; Neurons-drug-effects; Phenotype-; Pregnancy-; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.; Survival-Rate
MAJOR MeSH HEADINGS: *Dopamine-metabolism; *Hypoxanthine-Phosphoribosyltransferase-deficiency; *Hypoxanthine-Phosphoribosyltransferase-genetics; *Neurons-enzymology
CHECKTAGS: Animal; Female; Male; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 51-61-6; EC 2.4.2.8
NAME OF SUBSTANCE: Nerve-Tissue-Proteins; glial-cell-line-derived-neurotrophic-factor; Dopamine; Hypoxanthine-Phosphoribosyltransferase
MEDLINE ACCESSION NUMBER: 20394336
UPDATE CODE: 200011
Record 3 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Adenoviruses encoding HPRT correct biochemical abnormalities of HPRT-deficient cells and allow their survival in negative selection medium.
AUTHOR(S): Southgate-TD; Bain-D; Fairbanks-LD; Morelli-AE; Larregina-AT; Simmonds-HA; Castro-MG; Lowenstein-PR
ADDRESS OF AUTHOR: Molecular Medicine and Gene Therapy Unit, School of Medicine, University of Manchester, England.
SOURCE (BIBLIOGRAPHIC CITATION): Metab-Brain-Dis. 1999 Dec; 14(4): 205-21
INTERNATIONAL STANDARD SERIAL NUMBER: 0885-7490
PUBLICATION YEAR: 1999
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: The Lesch-Nyhan syndrome is an X-linked disorder caused by a virtually complete absence of the key enzyme of purine recycling, hypoxanthine-guanine phosphoribosyltransferase (HPRT). It is characterized by uric acid overproduction and severe neurological dysfunction. No treatment is yet available for the latter symptoms. A possible long-term solution is gene therapy, and recombinant adenoviruses have been proposed as vectors for gene transfer into postmitotic neuronal cells. We have constructed an adenoviral vector expressing the human HPRT cDNA under the transcriptional control of a short human cytomegalovirus major immediate early promoter (RAd-HPRT). Here we show that infection of human 1306, HPRT-negative cells with RAd-HPRT, expressed high enough levels of HPRT enzyme activity, as to reverse their abnormal biochemical phenotype, thus enhancing hypoxanthine incorporation and restoring purine recycling, increasing GTP levels, decreasing adenine incorporation, an!
d allowing cell survival in HAT medium in which only cells expressing high levels of HPRT can survive. Infection of murine STO cells, increased hypoxanthine incorporation and restored purine recycling, thus allowing cell survival in HAT medium, and reduced de novo purine synthesis. Although both cells were able to survive in HAT medium post infection with RAd-HPRT, some of the biochemical consequences differed. In summary, even though adenoviral vectors do not integrate into the genome of target HPRT-deficient human or murine cells, RAd-HPRT mediated enzyme replacement corrects abnormal purine metabolism, increases intracellular GTP levels, and allows cells to survive in a negative selection medium.
MINOR MESH HEADINGS: Adenine-metabolism; Adenine-pharmacology; Carbon-Radioisotopes-diagnostic-use; Cells,-Cultured-drug-effects; Cells,-Cultured-enzymology; Cytomegalovirus-genetics; DNA,-Complementary-genetics; Fibroblasts-cytology; Fibroblasts-metabolism; Gene-Therapy; Genes,-Immediate-Early-genetics; Glycine-metabolism; Glycine-pharmacology; Hypoxanthine-metabolism; Hypoxanthine-pharmacology; Lesch-Nyhan-Syndrome-physiopathology; Lesch-Nyhan-Syndrome-therapy; Mice-; Promoter-Regions-Genetics; Ribonucleotides-metabolism; Time-Factors; Transcription,-Genetic-genetics
MAJOR MeSH HEADINGS: *Adenoviridae-genetics; *Cell-Survival-drug-effects; *Cell-Survival-physiology; *Culture-Media; *Genetic-Vectors-pharmacology; *Hypoxanthine-Phosphoribosyltransferase-deficiency; *Hypoxanthine-Phosphoribosyltransferase-genetics
CHECKTAGS: Animal; Human; Support,-Non-U.S.-Gov't
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8; 0; 0; 0; 0; 0; 56-40-6; 68-94-0; 73-24-5
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase; Carbon-Radioisotopes; Culture-Media; DNA,-Complementary; Genetic-Vectors; Ribonucleotides; Glycine; Hypoxanthine; Adenine
MEDLINE ACCESSION NUMBER: 20306721
UPDATE CODE: 200009
Record 4 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: [Gene therapy--hopes and fears]
ORIGINAL TITLE: Terapia genowa--nadzieje i obawy.
AUTHOR(S): Pietrzyk-JJ
ADDRESS OF AUTHOR: Uniwersytet Jagiellonski, Wydzial Lekarski, Zaklad Genetyki Medycznej, Krakow.
SOURCE (BIBLIOGRAPHIC CITATION): Folia-Med-Cracov. 1998; 39(3-4): 131-8
INTERNATIONAL STANDARD SERIAL NUMBER: 0015-5616
PUBLICATION YEAR: 1998
LANGUAGE OF ARTICLE: POLISH; NON-ENGLISH
COUNTRY OF PUBLICATION: POLAND
ABSTRACT: Gene therapy assumes the correction of a genetic defect by the delivery of a correct DNA sequence to the target cells. Depending on the target cells two types gene therapy have been defined: somatic and germinal. By July 1998, 351 protocols of somatic therapy were approved by the Recombinant DNA Advisory Committee. The majority of protocols focus on cancer therapy and monogenic diseases. By now, still there is more unfulfilled expectation than clinically sound achievements, since no effective prevention or successful treatment for genetic diseases or cancer have been developed. Germline genetic modification is considered as the treatment of choice for such a diseases like retinoblastoma. Tay-Sachs, Lesch-Nyhan and metachromatic leuko-dystrophy. This approach which is still illegal or prohibited by rules in many European countries, is gathering more and more advocates. Once we learn how to control gene expression the perspectives for clinical application of gene th!
erapy might be enormous. The safety of genetic modification of gametes or embryonal stem cells remains to be properly addressed and successfully solved. The ethical issues of germinal gene therapy are still the subject of controversial opinions among the scientists, lawyers and philosophers.
MINOR MESH HEADINGS: Clinical-Protocols-standards; Disease-Susceptibility-therapy; English-Abstract; European-Union; Gene-Therapy-legislation-and-jurisprudence; Neoplasms-therapy
MAJOR MeSH HEADINGS: *Ethics,-Medical; *Gene-Therapy
CHECKTAGS: English-Abstract; Human
PUBLICATION TYPE: JOURNAL-ARTICLE
MEDLINE ACCESSION NUMBER: 20276962
UPDATE CODE: 200009
Record 5 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Lesch-Nyhan disease and the basal ganglia.
AUTHOR(S): Visser-JE; Bar-PR; Jinnah-HA
ADDRESS OF AUTHOR: Laboratory of Experimental Neurology, Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht, Netherlands.
SOURCE (BIBLIOGRAPHIC CITATION): Brain-Res-Brain-Res-Rev. 2000 Apr; 32(2-3): 449-75
INTERNATIONAL STANDARD SERIAL NUMBER: 0165-0173
PUBLICATION YEAR: 2000
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: NETHERLANDS
ABSTRACT: The purpose of this review is to summarize emerging evidence that the neurobehavioral features of Lesch-Nyhan disease (LND), a developmental disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), may be attributable to dysfunction of the basal ganglia. Affected individuals have severe motor disability described by prominent extrapyramidal features that are characteristic of dysfunction of the motor circuits of the basal ganglia. They also display disturbances of ocular motility, cognition, and behavioral control that may reflect disruption of other circuits of the basal ganglia. Though neuropathologic studies of autopsy specimens have revealed no obvious neuroanatomical abnormalities in LND, neurochemical studies have demonstrated 60-90% reductions in the dopamine content of the basal ganglia. In addition, recent PET studies have documented significant reductions in dopamine transporters and [18!
F]fluorodopa uptake in the basal ganglia. These findings support the proposal that many of the neurobehavioral features of LND might be related to dysfunction of the basal ganglia.
MINOR MESH HEADINGS: Basal-Ganglia-Diseases-pathology; Basal-Ganglia-Diseases-psychology; Lesch-Nyhan-Syndrome-psychology
MAJOR MeSH HEADINGS: *Basal-Ganglia-pathology; *Lesch-Nyhan-Syndrome-pathology
CHECKTAGS: Animal; Human; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: JOURNAL-ARTICLE; REVIEW; REVIEW,-ACADEMIC
CONTRACT OR GRANT NUMBERS: K08198503
MEDLINE ACCESSION NUMBER: 20225534
UPDATE CODE: 200008
Record 6 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: A review of behavioral treatments used for Lesch-Nyhan syndrome.
AUTHOR(S): Olson-L; Houlihan-D
ADDRESS OF AUTHOR: University of South Carolina, USA.
SOURCE (BIBLIOGRAPHIC CITATION): Behav-Modif. 2000 Apr; 24(2): 202-22
INTERNATIONAL STANDARD SERIAL NUMBER: 0145-4455
PUBLICATION YEAR: 2000
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan syndrome is a genetic disorder resulting in hyperuricemia, choreoathetosis, mental retardation, and self-mutilation. The most salient feature of this disorder is the self-injurious behavior (SIB). Although the utility of behavioral interventions with SIB has been well documented, behavioral interventions with Lesch-Nyhan syndrome have been limited in number and long-term success. This article reviews the behavioral treatments that have been used in treating individuals with Lesch-Nyhan syndrome and discusses the strengths and weaknesses of these methods. Suggestions for future directions in the use of behavioral interventions for controlling SIB in Lesch-Nyhan syndrome are provided.
MINOR MESH HEADINGS: Child-; Extinction-Psychology; Models,-Psychological; Reinforcement-Psychology
MAJOR MeSH HEADINGS: *Behavior-Therapy-methods; *Lesch-Nyhan-Syndrome-psychology; *Lesch-Nyhan-Syndrome-therapy; *Restraint,-Physical-methods; *Self-Injurious-Behavior-prevention-and-control
CHECKTAGS: Case-Report; Human
PUBLICATION TYPE: JOURNAL-ARTICLE; REVIEW; REVIEW,-TUTORIAL
MEDLINE ACCESSION NUMBER: 20264801
UPDATE CODE: 200008
Record 7 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: An unexpected affected female patient in a classical Lesch-Nyhan family.
AUTHOR(S): De-Gregorio-L; Nyhan-WL; Serafin-E; Chamoles-NA
ADDRESS OF AUTHOR: Department of Pediatrics, University of California at San Diego, La Jolla, California 92093, USA.
SOURCE (BIBLIOGRAPHIC CITATION): Mol-Genet-Metab. 2000 Mar; 69(3): 263-8
INTERNATIONAL STANDARD SERIAL NUMBER: 1096-7192
PUBLICATION YEAR: 2000
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the!
HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient. Copyright 2000 Academic Press.
MINOR MESH HEADINGS: Adult-; Argentina-; Cells,-Cultured; Child-; Child,-Preschool; Dosage-Compensation-Genetics; DNA-genetics; DNA-Mutational-Analysis; DNA,-Complementary-chemistry; DNA,-Complementary-genetics; Family-Health; Fatal-Outcome; Hypoxanthine-Phosphoribosyltransferase-deficiency; Lesch-Nyhan-Syndrome-enzymology; Lesch-Nyhan-Syndrome-pathology; Mutation-; Pedigree-; Phenotype-; Point-Mutation; Polymorphism,-Restriction-Fragment-Length; Promoter-Regions-Genetics; Transcription-Factors-genetics; X-Chromosome-genetics
MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-genetics
CHECKTAGS: Case-Report; Female; Human; Male; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: JOURNAL-ARTICLE
CONTRACT OR GRANT NUMBERS: 2P30AI36214AINIAID
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8; 0; 0; 0; 9007-49-2
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase; DNA,-Complementary; Transcription-Factors; Xist-gene-product; DNA
MEDLINE ACCESSION NUMBER: 20232174
UPDATE CODE: 200008
Record 8 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Relationship of dopamine to serotonin in the neonatal 6-OHDA rat model of Lesch-Nyhan syndrome.
AUTHOR(S): Allen-SM; Davis-WM
ADDRESS OF AUTHOR: Department of Pharmacology, School of Pharmacy, University of Mississippi 38677, USA. sallen@olemiss.edu
SOURCE (BIBLIOGRAPHIC CITATION): Behav-Pharmacol. 1999 Sep; 10(5): 467-74
INTERNATIONAL STANDARD SERIAL NUMBER: 0955-8810
PUBLICATION YEAR: 1999
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: ENGLAND
ABSTRACT: Rats were treated as neonates with either 6-hydroxydopamine (6-OHDA) 100 micrograms or vehicle intracisternally. Upon maturation, animals receiving 6-OHDA were assigned to four groups, with two of the four groups receiving intraventricular 5,7-dihydroxytryptamine (5,7-DHT) 75 micrograms bilaterally. At 94 days of age, animals were injected with either SKF-38393 (3.0 mg/kg, intraperitoneally (i.p.)), a dopamine D1 agonist, or m-chlorophenylpiperazine (m-CPP) (3.0 mg/kg, i.p.), a 5-HT2C agonist, in an attempt to evoke behaviors such as stereotypical chewing, head-nodding, self-biting and self-mutilation. Both SKF-38393 and m-CPP induced the target behaviors in animals receiving 6-OHDA alone. Animals receiving additional 5,7-DHT treatment did not show any of the target behaviors in response to SKF-38393, but exhibited a much higher sensitivity to m-CPP. Pre-treatment with SCH-23390 in animals receiving 6-OHDA alone was effective in preventing SKF-38393-induced target!
behaviors, but not those induced by m-CPP. Pre-treatment with mianserin partially antagonized the effects of both SKF-38393 and m-CPP in these same animals. In groups receiving both neonatal 6-OHDA and adult 5,7-DHT, mianserin was effective in reducing m-CPP-induced behaviors, while SCH-23390 was largely ineffective. These data provide evidence of a serial relationship between the D1 and 5-HT2C receptor systems in the neostriatum of animals receiving neonatal 6-OHDA lesions.
MINOR MESH HEADINGS: Adrenergic-Agents; Animals,-Newborn; Brain-Mapping; Disease-Models,-Animal; Lesch-Nyhan-Syndrome-chemically-induced; Neostriatum-drug-effects; Oxidopamine-; Pregnancy-; Rats-; Rats,-Sprague-Dawley; Receptors,-Dopamine-D1-drug-effects; Receptors,-Dopamine-D1-physiology; Receptors,-Serotonin-drug-effects; Receptors,-Serotonin-physiology; Stereotyped-Behavior-drug-effects; Stereotyped-Behavior-physiology
MAJOR MeSH HEADINGS: *Dopamine-physiology; *Lesch-Nyhan-Syndrome-physiopathology; *Neostriatum-physiopathology; *Serotonin-physiology
CHECKTAGS: Animal; Female; Male
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: 0; 0; 0; 0; 1199-18-4; 50-67-9; 51-61-6
NAME OF SUBSTANCE: serotonin-2C-receptor; Adrenergic-Agents; Receptors,-Dopamine-D1; Receptors,-Serotonin; Oxidopamine; Serotonin; Dopamine
MEDLINE ACCESSION NUMBER: 20242525
UPDATE CODE: 200007
Record 9 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in thirteen Spanish families.
AUTHOR(S): Torres-RJ; Mateos-FA; Molano-J; Gathoff-BS; O'Neill-JP; Gundel-RM; Trombley-L; Puig-JG
ADDRESS OF AUTHOR: Division of Clinical Biochemistry, Hospital La Paz, Universidad Autonoma, Madrid, Spain.
SOURCE (BIBLIOGRAPHIC CITATION): Hum-Mutat-Online. 2000 Apr; 15(4): 383
INTERNATIONAL STANDARD SERIAL NUMBER: 1098-1004
PUBLICATION YEAR: 2000
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: We have determined the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT; HPRT1) deficiency in eight Lesch-Nyhan patients and in five partially HPRT deficient patients with mild to severe neurologic symptoms. Eight of these thirteen mutations have not been previously described. HPRT Zaragoza II (a GG insertion in exon 2), HPRT Murcia (an AG deletion in exon 4), HPRT Asturias (a A deletion in exon 4) and HPRT Cartagena (a A insertion in exon 6) cause a frame-shift resulting in a premature stop codon. HPRT Sevilla is a splice-site mutation resulting in exon 8 skipping in the HPRT mRNA. HPRT Huelva, Madrid II and Zaragoza I are point mutations that result in single amino-acid changes in the mutated HPRT protein (118G-->A, G40R; 143G-->A, R 48 H; 397G-->A, V133 M, respectively). Three mutations have been previously described in unrelated families, and two mutations have been already published. All mutations that resulted in truncated proteins cor!
responded to patients with the Lesch-Nyhan phenotype. Characterization of the HPRT mutation allowed us to make carrier detection in 33 women and prenatal diagnosis in two fetuses. Hum Mutat 15:383, 2000. Copyright 2000 Wiley-Liss, Inc.
MINOR MESH HEADINGS: Alternative-Splicing-genetics; Exons-genetics; Frameshift-Mutation-genetics; Heterozygote-Detection; Lesch-Nyhan-Syndrome-enzymology; Lesch-Nyhan-Syndrome-genetics; Mutagenesis,-Insertional-genetics; Point-Mutation-genetics; Pregnancy-; Prenatal-Diagnosis; Sequence-Deletion-genetics; Spain-
MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-deficiency; *Hypoxanthine-Phosphoribosyltransferase-genetics
CHECKTAGS: Female; Human; Support,-Non-U.S.-Gov't; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: JOURNAL-ARTICLE
CONTRACT OR GRANT NUMBERS: CO6HL39475CONCI
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase
MEDLINE ACCESSION NUMBER: 20202839
UPDATE CODE: 200007
Record 10 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Identification of a new Lesch-Nyhan syndrome mutation (HPRTBrasil) and analysis of potentially heterozygous females.
AUTHOR(S): O'Neill-P; Trombley-L; Gundel-M; Hunter-T; Nicklas-JA; Ferreira-ML; Bugallo-MJ; Farias-AC; Lohr-A; Diamantopoulos-M; Raskin-S
ADDRESS OF AUTHOR: Genetics Laboratory, University of Vermont, Burlington, USA.
SOURCE (BIBLIOGRAPHIC CITATION): Arq-Neuropsiquiatr. 1999 Dec; 57(4): 907-11
INTERNATIONAL STANDARD SERIAL NUMBER: 0004-282X
PUBLICATION YEAR: 1999
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: BRAZIL
ABSTRACT: The mutation in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene has been determined in two brothers affected with Lesch-Nyhan syndrome. Female members of the family who are at risk for being heterozygous carriers of the HPRT mutation were also studied to determine whether they carry the mutation. DNA sequencing revealed that the boys' mother is heterozygous for the mutation in her somatic cells, but that three maternal aunts are not heterozygous. Such carrier information is important for the future pregnancy plans of at-risk females. The mutation, an A-->T transversion at cDNA base 590 (590A-->T), results in an amino acid change of glutamic acid to valine at codon 197, and has not been reported previously in a Lesch-Nyhan syndrome male. This mutation is designated HPRTBrasil.
MINOR MESH HEADINGS: Adolescence-; Adult-; Brazil-; Child-; DNA,-Complementary-analysis; Heterozygote-; Lesch-Nyhan-Syndrome-diagnosis; Pedigree-; Sex-Factors
MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-genetics; *Lesch-Nyhan-Syndrome-genetics; *Point-Mutation
CHECKTAGS: Female; Human; Male
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8; 0
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase; DNA,-Complementary
MEDLINE ACCESSION NUMBER: 20147301
UPDATE CODE: 200006
Record 11 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Adrenergic and noradrenergic plasma levels in Lesch-Nyhan disease.
AUTHOR(S): Ernst-M; Zametkin-AJ; Pascualvaca-D; Matochik-JA; Eisenhofer-G; Murphy-DL; Cohen-RM
ADDRESS OF AUTHOR: Laboratory of Cerebral Metabolism, NIMH, Bethesda, MD, USA.
SOURCE (BIBLIOGRAPHIC CITATION): Neuropsychopharmacology. 2000 Mar; 22(3): 320-6
INTERNATIONAL STANDARD SERIAL NUMBER: 0893-133X
PUBLICATION YEAR: 2000
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic, and MAO function in children and young adults with LN disease (n = 11), and healthy subjects (n = 9). Blood samples, collected in identical conditions prior to a positron emission tomography (PET) study, were assayed for concentrations of epinephrine (EPI), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (DHPG) (which results from the degradation of NE by monoamine oxidase type A [MAO-A]). The LN subjects had significantly higher EPI levels by 245% (p < .00) and lower DHPG levels by 42% (p < .00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with EPI in the LN group (r = 0.77, p = .009), but not in the control group. The abnorm!
ally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the HPRT enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT) enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function.
MINOR MESH HEADINGS: Adolescence-; Adult-; Age-Factors; Blood-Pressure; Child-; Lesch-Nyhan-Syndrome-physiopathology; Methoxyhydroxyphenylglycol-blood; Multivariate-Analysis; Pulse-; Reference-Values
MAJOR MeSH HEADINGS: *Epinephrine-blood; *Lesch-Nyhan-Syndrome-blood; *Methoxyhydroxyphenylglycol-analogs-and-derivatives; *Norepinephrine-blood
CHECKTAGS: Human
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: 3343-19-9; 51-41-2; 51-43-4; 534-82-7
NAME OF SUBSTANCE: dihydroxyphenylethylene-glycol; Norepinephrine; Epinephrine; Methoxyhydroxyphenylglycol
MEDLINE ACCESSION NUMBER: 20157549
UPDATE CODE: 200005
Record 12 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Successful preimplantation genetic diagnosis for sex Link Lesch--Nyhan Syndrome using specific diagnosis.
AUTHOR(S): Ray-PF; Harper-JC; Ao-A; Taylor-DM; Winston-RM; Hughes-M; Handyside-AH
ADDRESS OF AUTHOR: Centre Genetique, U393 Instutut Necker, Hopital des Enfants Malades,Paris, France.ray@necker.fr
SOURCE (BIBLIOGRAPHIC CITATION): Prenat-Diagn. 1999 Dec; 19(13): 1237-41
INTERNATIONAL STANDARD SERIAL NUMBER: 0197-3851
PUBLICATION YEAR: 1999
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: ENGLAND
ABSTRACT: Lesch-Nyhan syndrome (LN) is a severe X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine phosphoribosyl transferase (HRT). Clinical features displayed by affected boys are particularly severe and disturbing and include hyperuricaemia, Characteristic neurological features including self-mutilation, choreothetosis, spasticity and mental retardation. A couple with a boy diagnosed with LN and a history of pregnancy termination was referred to the Hammersmith Hospital. Their affected son was born in 1982 after an uncomplicated pregnancy and vaginal delivery. Eight subsequent pregnancies had been unsuccessful. There were five therapeutic terminations and three spontaneous abortions, one at least directly caused by the sampling procedure during amniocentesis. From 1989 to 1991 two unsuccessful preimplantation genetic diagnosis (PGD) cycles by sexing were performed by DNA amplification. The mutation was characterized and a nested PCR protocol wa!
s designed which allowed the efficient amplification of the affected loci followed by the detection of the mutant allele by restriction digestion. Three PGD cycles were performed using this specific diagnostic test before a successful pregnancy was achieved resulting in the birth of a healthy unaffected baby girl.
MINOR MESH HEADINGS: Embryo-Transfer; Fertilization-in-Vitro; Hypoxanthine-Phosphoribosyltransferase-deficiency; Hypoxanthine-Phosphoribosyltransferase-genetics; Polymerase-Chain-Reaction; Pregnancy-; Pregnancy-Outcome
MAJOR MeSH HEADINGS: *Lesch-Nyhan-Syndrome-diagnosis; *Lesch-Nyhan-Syndrome-genetics; *Linkage-Genetics; *Preimplantation-Diagnosis; *Preimplantation-Phase; *X-Chromosome
CHECKTAGS: Case-Report; Female; Human; Male
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase
MEDLINE ACCESSION NUMBER: 20157996
UPDATE CODE: 200005
Record 13 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Eighteen novel mutations in patients with Lesch-Nyhan syndrome or partial hypoxanthine phosphoribosyltransferase deficiency.
AUTHOR(S): Willers-I; Bolz-H; Wehnert-M; Gal-A
ADDRESS OF AUTHOR: Institut fur Humangenetik, Universitats-Klinikum Eppendorf, Hamburg, Germany.
SOURCE (BIBLIOGRAPHIC CITATION): J-Inherit-Metab-Dis. 1999 Oct; 22(7): 845-6
INTERNATIONAL STANDARD SERIAL NUMBER: 0141-8955
PUBLICATION YEAR: 1999
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: NETHERLANDS
MINOR MESH HEADINGS: Lesch-Nyhan-Syndrome-enzymology
MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-deficiency; *Lesch-Nyhan-Syndrome-genetics; *Mutation-
CHECKTAGS: Human
PUBLICATION TYPE: JOURNAL-ARTICLE
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase
MEDLINE ACCESSION NUMBER: 99446557
UPDATE CODE: 200002
Record 14 of 14 in MEDLINE EXPRESS (R) 2000/01-2000/10
TITLE: Crystal structure of Toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase with XMP, pyrophosphate, and two Mg(2+) ions bound: insights into the catalytic mechanism.
AUTHOR(S): Heroux-A; White-EL; Ross-LJ; Davis-RL; Borhani-DW
ADDRESS OF AUTHOR: Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35205, USA.
SOURCE (BIBLIOGRAPHIC CITATION): Biochemistry. 1999 Nov 2; 38(44): 14495-506
INTERNATIONAL STANDARD SERIAL NUMBER: 0006-2960
PUBLICATION YEAR: 1999
LANGUAGE OF ARTICLE: ENGLISH
COUNTRY OF PUBLICATION: UNITED-STATES
ABSTRACT: The crystal structure of the Toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-xanthosine 5'-monophosphate (XMP)-pyrophosphate-Mg(2+) ternary complex has been determined at 1. 60 A resolution. This biproduct, post-transition state structure is of a T. gondii HGPRT mutant (Asp150Ala or D150A). The D150A mutant has reduced activity (k(cat) lower by 11-, 296-, and 8.6-fold for hypoxanthine, guanine, and xanthine, respectively) compared to wild-type T. gondii HGPRT. The Michaelis constants for purine bases are altered only slightly, whereas those for alpha-D-5-phosphoribosyl 1-pyrophosphate (PRPP) are lower by approximately 6.5-fold. The ternary complex crystallizes in space group C222(1) (a = 55.21 A, b = 112.25 A, and c = 144.28 A) with two subunits in the asymmetric unit; the HGPRT tetramer is completed by the application of 2-fold crystallographic symmetry. All active sites contain XMP {bound in a fashion similar to that of the guanosine 5'-!
monophosphate (GMP) and inosine 5'-monophosphate (IMP) complexes reported in the preceding article [Heroux, A., et al. (1999) Biochemistry 38, 14485-14494]}, pyrophosphate, and two Mg(2+) ions. Each Mg(2+) ion is octahedrally coordinated by two terminal pyrophosphate oxygen atoms and several ordered water molecules. This structure shows how HGPRT uses two Mg(2+) ions to orient and activate the pyrophosphate moiety of PRPP for attack by a purine base, and why mutation in humans of the residue corresponding to Asp206, the only HGPRT amino acid that directly contacts the Mg(2+) ions, causes Lesch-Nyhan syndrome (HGPRT(Kinston), D193N). The Leu78-Lys79 peptide bond in the active site adopts the cis configuration, which it must to bind PRPP or pyrophosphate. The contribution of cis-trans isomerization of this peptide bond to the energetics of substrate binding and product release is discussed. A comprehensive description of the HGPRT reaction mechanism is also proposed.
MINOR MESH HEADINGS: Base-Sequence; Catalysis-; Catalytic-Domain-genetics; Crystallography,-X-Ray; Diphosphates-chemistry; DNA-Primers-genetics; Hypoxanthine-Phosphoribosyltransferase-genetics; Hypoxanthine-Phosphoribosyltransferase-metabolism; Kinetics-; Magnesium-chemistry; Models,-Molecular; Molecular-Sequence-Data; Mutagenesis,-Site-Directed; Protein-Conformation; Ribonucleotides-chemistry; Toxoplasma-genetics
MAJOR MeSH HEADINGS: *Hypoxanthine-Phosphoribosyltransferase-chemistry; *Toxoplasma-enzymology
CHECKTAGS: Animal; Comparative-Study; Human; Support,-U.S.-Gov't,-P.H.S.
PUBLICATION TYPE: JOURNAL-ARTICLE
CONTRACT OR GRANT NUMBERS: AI39952AINIAID
CAS REGISTRY NUMBER OR EC NUMBER: EC 2.4.2.8; 0; 0; 0; 523-98-8; 7439-95-4
NAME OF SUBSTANCE: Hypoxanthine-Phosphoribosyltransferase; Diphosphates; DNA-Primers; Ribonucleotides; xanthosine-monophosphate; Magnesium
MEDLINE ACCESSION NUMBER: 20014542
UPDATE CODE: 200002
SECONDARY SOURCE IDENTIFIER: PDB/1QK5; PDB/R1QK5SF; PDB/1QK3; PDB/R1QK3SF; PDB/1QK4; PDB/R1QK4SF