Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013080 (Down syndrome)
 14,180 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A method for determining coordinate genetic regulation is proposed for mammalian cells. The method involves (i) isolation of a set of mutants defective in the relevant pathway; (ii) complementation analysis of these mutants to determine dominance and to categorize the mutants into various different complementation groups; (iii) determination of the biochemical blocks in the mutants; (iv) identification of individual mutants that fail to complement the members of at least two distinct complementation groups that complement each other, such mutants being said to show coordinate regulation of the affected functions; (v) biochemical and reversion analysis of the relevant cell types to confirm the basis for the observed coordinate regulation; (vi) assignment of the individual genes to particular human chromosomes; (vii) mapping of the genes to determine contiguity on the genome; and (viii) examination of the structure of the relevant gene products. This method has allowed the demonstration of coordinate regulation between the gene coding for phosphoribosylglycineamide synthetase [5-phosphoribosylamine:glycine ligase (ADP-forming), EC 6.3.4.13], defective in our Ade-C mutants, and the gene coding for phoshoribosylaminoimidazole synthetase [5'-phosphoribosylformylglycinamidine cyclo-ligase (ADP-forming), EC 6.3.3.1], defective in our Ade-G mutants. Moreover, both genes can be assigned to human chromosome 21. Because at least two genes for purine biosynthesis have now been assigned to chromosome 21, and because patients with trisomy 21 (Down syndrome) show increased levels of serum purines, it may be that cells of these patients overproduce purines and that this overproduction may be relevant to the pathology of the syndrome.
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PMID:Demonstration, by somatic cell genetics, of coordinate regulation of genes for two enzymes of purine synthesis assigned to human chromosome 21. 694 Dec 56

Mutations in several steps of de novo purine synthesis lead to human inborn errors of metabolism often characterized by mental retardation, hypotonia, sensorineural hearing loss, optic atrophy, and other features. In animals, the phosphoribosylglycinamide transformylase (GART) gene encodes a trifunctional protein carrying out 3 steps of de novo purine synthesis, phosphoribosylglycinamide synthase (GARS), phosphoribosylglycinamide transformylase (also abbreviated as GART), and phosphoribosylaminoimidazole synthetase (AIRS) and a smaller protein that contains only the GARS domain of GART as a functional protein. The GART gene is located on human chromosome 21 and is aberrantly regulated and overexpressed in individuals with Down syndrome (DS), and may be involved in the phenotype of DS. The GART activity of GART requires 10-formyltetrahydrofolate and has been a target for anti-cancer drugs. Thus, a considerable amount of information is available about GART, while less is known about the GARS and AIRS domains. Here we demonstrate that the amino acid residue glu75 is essential for the activity of the GARS enzyme and that the gly684 residue is essential for the activity of the AIRS enzyme by analysis of mutations in the Chinese hamster ovary (CHO-K1) cell that require purines for growth. We report the effects of these mutations on mRNA and protein content for GART and GARS. Further, we discuss the likely mechanisms by which mutations inactivating the GART protein might arise in CHO-K1 cells.
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PMID:Mutations in the Chinese hamster ovary cell GART gene of de novo purine synthesis. 1900 68