Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal and in vitro studies have implicated decreased protein synthesis in the pathogenesis of tissue damage in phenylketonuria (PKU) and of growth failure in Lesch-Nyhan syndrome. Protein turnover was measured in vivo in ten young adult subjects with classical PKU, two subjects with hyperphenylalaninemia, and three children with Lesch-Nyhan syndrome using techniques based on continuous infusions of [13C]leucine and, in Lesch-Nyhan subjects, [2H5]phenylalanine. The PKU subjects had various degrees of dietary phenylalanine restriction and plasma phenylalanine levels at the time of study ranged from 450-1540 mumol/L (mean 1106). Plasma phenylalanine in the two hyperphenylalaninemic subjects was 533 and 402 mumol/L. Rates of protein synthesis in all PKU subjects (mean 3.71 g/kg/24 h, range 2.68-5.10, [13C]leucine as tracer) were in a range similar to or above control values (mean 2.97, range 2.78-3.22, n = 6), as were rates of protein catabolism (PKU mean 4.23 g/kg/24 h, range 3.15-5.45; controls 3.64, 3.50-3.91). Protein turnover values in hyperphenylalaninemia were also similar to those in controls. With [13C]leucine as tracer, both mean protein synthesis and catabolism values in Lesch-Nyhan subjects (mean 4.80 and 5.64 g/kg/24 h, respectively) were higher than values in control children matched for protein intake (synthesis 4.32 +/- 0.74 (SD) and catabolism 4.85 +/- 0.57 (g/kg/24 h, n = 5). Similar results were obtained in Lesch-Nyhan subjects using [2H5]phenylalanine as tracer. These results suggest that protein turnover is not decreased in either PKU or Lesch-Nyhan syndrome. This conclusion is inconsistent with the hypothesis that tissue damage in PKU results from impaired protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein metabolism in phenylketonuria and Lesch-Nyhan syndrome. 223 21

Disorders primarily affecting the nervous system comprise approximately one third of all established Mendelian genetic diseases in man. Recombinant DNA technology provides new approaches to the diagnosis and elucidation of the molecular pathology of these disorders. For a small but increasing number of disorders the DNA sequence coding for the involved protein has been used to define the precise molecular defect. An example is the Lesch-Nyhan syndrome. In many other situations, DNA fragments located near to the mutant gene can be used in family linkage studies to determine who is likely to have inherited the abnormal allele(s). Examples include Duchenne muscular dystrophy, Huntington's disease, and phenylketonuria. This technology offers unique opportunities to investigate the function of the nervous system in health and disease and will have a major impact on the neurosciences and the practice of clinical neurology.
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PMID:Molecular genetic approaches to the study of the nervous system. 608 60

Recombinant DNA techniques provide new approaches to the diagnosis and analysis of inherited human diseases associated with mental retardation. Examples of such diseases include the Lesch-Nyhan syndrome, phenylketonuria, the Fragile X syndrome, Down syndrome, and those associated with deletions or duplications of subchromosomal regions, e.g., the proximal short arm of human chromosome #15. For a limited but increasing number of diseases, the DNA sequences responsible for the phenotype (e.g., sequences coding for abnormal proteins) can be isolated directly. In many other cases, DNA segments mapping near genes responsible for diseases of interest can be isolated, e.g., from recombinant phage libraries enriched for specific regions of the genome by metaphase chromosome flow-sorting and then used in molecular linkage studies to "track" the abnormal gene in a pedigree. Both the necessary technology and the methods for its application continue to improve, and the impact of recombinant DNA studies in the field of mental retardation should increase markedly in the very near future.
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PMID:Molecular genetic approaches to human diseases involving mental retardation. 673 92

Phenylketonuria is a defect in phenylalanine metabolism resulting in the excretion of phenylketones and severe intellectual disability. The principle of eliminating the offending amino acid from the diet as a successful treatment strategy was demonstrated. The development of a low methionine diet to treat homocystinuria was established after identifying the transsulfuration pathway resulting in cysteine synthesis. Both conditions are examples of disorders of amino acid metabolism. Lesch-Nyhan syndrome, a rare disorder of purine metabolism resulting in intellectual disability and self-injurious behavior, is a classical inborn error of metabolism. Disorders of creatine biosynthesis are relatively newly described and less known diseases.
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PMID:Inborn Errors of Metabolism with Cognitive Impairment: Metabolism Defects of Phenylalanine, Homocysteine and Methionine, Purine and Pyrimidine, and Creatine. 2950 13

Genetic model systems allow researchers to probe and decipher aspects of human disease, and animal models of disease are frequently specifically engineered and have been identified serendipitously as well. Animal models are useful for probing the etiology and pathophysiology of disease and are critical for effective discovery and development of novel therapeutics for rare diseases. Here we review the impact of animal model organism research in three examples of congenital metabolic disorders to highlight distinct advantages of model system research. First, we discuss phenylketonuria research where a wide variety of research fields and models came together to make impressive progress and where a nearly ideal mouse model has been central to therapeutic advancements. Second, we review advancements in Lesch-Nyhan syndrome research to illustrate the role of models that do not perfectly recapitulate human disease as well as the need for multiple models of the same disease to fully investigate human disease aspects. Finally, we highlight research on the GM2 gangliosidoses Tay-Sachs and Sandhoff disease to illustrate the important role of both engineered traditional laboratory animal models and serendipitously identified atypical models in congenital metabolic disorder research. We close with perspectives for the future for animal model research in congenital metabolic disorders.
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PMID:Animal Model Contributions to Congenital Metabolic Disease. 3230 75