human model for Lesch-Nyhan disease
Mutations in the gene encoding the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, a neurodevelopmental disorder characterized by cognitive, neurological, and behavioral abnormalities. Despite detailed knowledge of the enzyme's function, t...
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Veröffentlicht in: | Journal of neurochemistry 2007, Vol.101 (3), p.841-853 |
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creator | Shirley, Thomas L Lewers, J. Chris Egami, Kiyoshi Majumdar, Alokes Kelly, Mairead Ceballos-Picot, Irene Seidman, Michael M Jinnah, H.A |
description | Mutations in the gene encoding the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, a neurodevelopmental disorder characterized by cognitive, neurological, and behavioral abnormalities. Despite detailed knowledge of the enzyme's function, the key pathophysiological changes that accompany loss of purine recycling are unclear. To facilitate delineating the consequences of HPRT deficiency, four independent HPRT-deficient sublines of the human dopaminergic neuroblastoma, SK-N-BE(2) M17, were isolated by targeted mutagenesis with triple helix-forming oligonucleotides. As a group, these HPRT-deficient cells showed several significant abnormalities: (i) impaired purine recycling with accumulation of hypoxanthine, guanine, and xanthine, (ii) reduced guanylate energy charge and GTP : GDP ratio, but normal adenylate energy charge and no changes in any adenine nucleotide ratios, (iii) increased levels of UTP and NADP⁺, (iv) reduced DOPA decarboxylase, but normal monoamines, and (v) reduction in cell soma size. These cells combine the analytical power of multiple lines and a human, neuronal origin to provide an important tool to investigate the pathophysiology of HPRT deficiency. |
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Chris ; Egami, Kiyoshi ; Majumdar, Alokes ; Kelly, Mairead ; Ceballos-Picot, Irene ; Seidman, Michael M ; Jinnah, H.A</creator><creatorcontrib>Shirley, Thomas L ; Lewers, J. Chris ; Egami, Kiyoshi ; Majumdar, Alokes ; Kelly, Mairead ; Ceballos-Picot, Irene ; Seidman, Michael M ; Jinnah, H.A</creatorcontrib><description>Mutations in the gene encoding the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, a neurodevelopmental disorder characterized by cognitive, neurological, and behavioral abnormalities. Despite detailed knowledge of the enzyme's function, the key pathophysiological changes that accompany loss of purine recycling are unclear. To facilitate delineating the consequences of HPRT deficiency, four independent HPRT-deficient sublines of the human dopaminergic neuroblastoma, SK-N-BE(2) M17, were isolated by targeted mutagenesis with triple helix-forming oligonucleotides. As a group, these HPRT-deficient cells showed several significant abnormalities: (i) impaired purine recycling with accumulation of hypoxanthine, guanine, and xanthine, (ii) reduced guanylate energy charge and GTP : GDP ratio, but normal adenylate energy charge and no changes in any adenine nucleotide ratios, (iii) increased levels of UTP and NADP⁺, (iv) reduced DOPA decarboxylase, but normal monoamines, and (v) reduction in cell soma size. These cells combine the analytical power of multiple lines and a human, neuronal origin to provide an important tool to investigate the pathophysiology of HPRT deficiency.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><language>eng</language><publisher>Oxford, UK : Blackwell Publishing Ltd</publisher><subject>high performance liquid chromatography ; hypoxanthine-guanine phosphoribosyltransferase ; Lesch-Nyhan disease ; monoamines ; purines ; triple helix-forming oligonucleotides</subject><ispartof>Journal of neurochemistry, 2007, Vol.101 (3), p.841-853</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024</link.rule.ids></links><search><creatorcontrib>Shirley, Thomas L</creatorcontrib><creatorcontrib>Lewers, J. Chris</creatorcontrib><creatorcontrib>Egami, Kiyoshi</creatorcontrib><creatorcontrib>Majumdar, Alokes</creatorcontrib><creatorcontrib>Kelly, Mairead</creatorcontrib><creatorcontrib>Ceballos-Picot, Irene</creatorcontrib><creatorcontrib>Seidman, Michael M</creatorcontrib><creatorcontrib>Jinnah, H.A</creatorcontrib><title>human model for Lesch-Nyhan disease</title><title>Journal of neurochemistry</title><description>Mutations in the gene encoding the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, a neurodevelopmental disorder characterized by cognitive, neurological, and behavioral abnormalities. Despite detailed knowledge of the enzyme's function, the key pathophysiological changes that accompany loss of purine recycling are unclear. To facilitate delineating the consequences of HPRT deficiency, four independent HPRT-deficient sublines of the human dopaminergic neuroblastoma, SK-N-BE(2) M17, were isolated by targeted mutagenesis with triple helix-forming oligonucleotides. As a group, these HPRT-deficient cells showed several significant abnormalities: (i) impaired purine recycling with accumulation of hypoxanthine, guanine, and xanthine, (ii) reduced guanylate energy charge and GTP : GDP ratio, but normal adenylate energy charge and no changes in any adenine nucleotide ratios, (iii) increased levels of UTP and NADP⁺, (iv) reduced DOPA decarboxylase, but normal monoamines, and (v) reduction in cell soma size. These cells combine the analytical power of multiple lines and a human, neuronal origin to provide an important tool to investigate the pathophysiology of HPRT deficiency.</description><subject>high performance liquid chromatography</subject><subject>hypoxanthine-guanine phosphoribosyltransferase</subject><subject>Lesch-Nyhan disease</subject><subject>monoamines</subject><subject>purines</subject><subject>triple helix-forming oligonucleotides</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNpjYuA0NDE31DUxNLVkYeA0MDAy0jU2MDHiYOAqLs4yMDA0MzEz5GRQzijNTcxTyM1PSc1RSMsvUvBJLU7O0PWrzACKpmQWpyYWp_IwsKYl5hSn8kJpbgZ5N9cQZw_dtMT8-MT0oszi-NBgIwNDYwMDc3MDI0NzY8IqAGCHKbo</recordid><startdate>2007</startdate><enddate>2007</enddate><creator>Shirley, Thomas L</creator><creator>Lewers, J. 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Chris</creatorcontrib><creatorcontrib>Egami, Kiyoshi</creatorcontrib><creatorcontrib>Majumdar, Alokes</creatorcontrib><creatorcontrib>Kelly, Mairead</creatorcontrib><creatorcontrib>Ceballos-Picot, Irene</creatorcontrib><creatorcontrib>Seidman, Michael M</creatorcontrib><creatorcontrib>Jinnah, H.A</creatorcontrib><collection>AGRIS</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shirley, Thomas L</au><au>Lewers, J. Chris</au><au>Egami, Kiyoshi</au><au>Majumdar, Alokes</au><au>Kelly, Mairead</au><au>Ceballos-Picot, Irene</au><au>Seidman, Michael M</au><au>Jinnah, H.A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>human model for Lesch-Nyhan disease</atitle><jtitle>Journal of neurochemistry</jtitle><date>2007</date><risdate>2007</risdate><volume>101</volume><issue>3</issue><spage>841</spage><epage>853</epage><pages>841-853</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><abstract>Mutations in the gene encoding the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, a neurodevelopmental disorder characterized by cognitive, neurological, and behavioral abnormalities. Despite detailed knowledge of the enzyme's function, the key pathophysiological changes that accompany loss of purine recycling are unclear. To facilitate delineating the consequences of HPRT deficiency, four independent HPRT-deficient sublines of the human dopaminergic neuroblastoma, SK-N-BE(2) M17, were isolated by targeted mutagenesis with triple helix-forming oligonucleotides. As a group, these HPRT-deficient cells showed several significant abnormalities: (i) impaired purine recycling with accumulation of hypoxanthine, guanine, and xanthine, (ii) reduced guanylate energy charge and GTP : GDP ratio, but normal adenylate energy charge and no changes in any adenine nucleotide ratios, (iii) increased levels of UTP and NADP⁺, (iv) reduced DOPA decarboxylase, but normal monoamines, and (v) reduction in cell soma size. These cells combine the analytical power of multiple lines and a human, neuronal origin to provide an important tool to investigate the pathophysiology of HPRT deficiency.</abstract><pub>Oxford, UK : Blackwell Publishing Ltd</pub></addata></record> |
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subjects | high performance liquid chromatography hypoxanthine-guanine phosphoribosyltransferase Lesch-Nyhan disease monoamines purines triple helix-forming oligonucleotides |
title | human model for Lesch-Nyhan disease |
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