A human neuronal tissue culture model for Lesch-Nyhan disease
- PMID: 17448149
- DOI: 10.1111/j.1471-4159.2007.04472.x
A human neuronal tissue culture model for Lesch-Nyhan disease
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.
Similar articles
-
Production of a model for Lesch-Nyhan syndrome in hypoxanthine phosphoribosyltransferase-deficient mice.Nat Genet. 1993 Mar;3(3):235-40. doi: 10.1038/ng0393-235. Nat Genet. 1993. PMID: 8485579
-
Altered membrane NTPase activity in Lesch-Nyhan disease fibroblasts: comparison with HPRT knockout mice and HPRT-deficient cell lines.J Neurochem. 2005 Jun;93(6):1579-86. doi: 10.1111/j.1471-4159.2005.03151.x. J Neurochem. 2005. PMID: 15935074
-
Human neural stem cells: a model system for the study of Lesch-Nyhan disease neurological aspects.Hum Mol Genet. 2010 May 15;19(10):1939-50. doi: 10.1093/hmg/ddq072. Epub 2010 Feb 16. Hum Mol Genet. 2010. PMID: 20159777
-
[Complete and partial deficiency of HPRT].Nihon Rinsho. 1996 Dec;54(12):3315-20. Nihon Rinsho. 1996. PMID: 8976112 Review. Japanese.
-
[Physiopathology of neurological signs of hypoxanthine-guanine phosphoribosyltransferase deficiency].Rev Neurol. 1998 Dec;27(160):1050-4. Rev Neurol. 1998. PMID: 9951034 Review. Spanish.
Cited by
-
Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling.J Neurochem. 2013 Dec;127(6):805-18. doi: 10.1111/jnc.12366. Epub 2013 Aug 18. J Neurochem. 2013. PMID: 23859490 Free PMC article.
-
Identification of small molecule compounds with higher binding affinity to guanine deaminase (cypin) than guanine.Bioorg Med Chem. 2010 Sep 15;18(18):6748-55. doi: 10.1016/j.bmc.2010.07.054. Epub 2010 Jul 27. Bioorg Med Chem. 2010. PMID: 20716488 Free PMC article.
-
Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways.Mol Genet Metab. 2015 Jan;114(1):55-61. doi: 10.1016/j.ymgme.2014.11.001. Epub 2014 Nov 8. Mol Genet Metab. 2015. PMID: 25481104 Free PMC article.
-
Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch-Nyhan disease: BODIPY-forskolin as pharmacological tool.Naunyn Schmiedebergs Arch Pharmacol. 2012 Jul;385(7):671-83. doi: 10.1007/s00210-012-0759-6. Epub 2012 May 3. Naunyn Schmiedebergs Arch Pharmacol. 2012. PMID: 22552731
-
Consequences of impaired purine recycling on the proteome in a cellular model of Lesch-Nyhan disease.Mol Genet Metab. 2015 Apr;114(4):570-579. doi: 10.1016/j.ymgme.2015.02.007. Epub 2015 Mar 5. Mol Genet Metab. 2015. PMID: 25769394 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous
