Transcriptomic Approach to Lesch-Nyhan Disease

• Type of Material: Conference Paper
• Authors: Luce Dauphinot, UPMC Hôpital de la Pitié-Salpêtrière; Lionel Mockel, Hôpital Necker-Enfants Malades; Julie Cahu, Hôpital Necker-Enfants Malades; Hyder A Jinnah, Emory University; Morgan Ledroit, Hôpital Necker-Enfants Malades; Marie-Claude Potier, UPMC Hôpital de la Pitié-Salpêtrière; Irene Ceballos-Picot, Hôpital Necker-Enfants Malades
• Language: English
• Date: 2014-01-01
• Publisher: Emory University Libraries
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Copyright © Taylor & Francis Group, LLC.
• Final Published Version (URL): http://dx.doi.org/10.1080/15257770.2014.880477
• Title of Journal or Parent Work: Nucleosides Nucleotides Nucleic Acids
• Conference or Event Name: 15th International Symposium on Purine and Pyrimidine Metabolism in Man
• Volume: 33
• Issue: 4-6
• Start Page: 208
• End Page: 217
• Grant/Funding Information: The authors thank the Lesch-Nyhan Association, AFM, Malaury Association, Foundation Louis D., NIH HD 053312 from Child Health and Development for financial support; Cécile Denis and Mathilde Girard (IStem) for providing iPS control cells.
• Keywords: DEFICIENCY; VARIANT; HPRT; CDK1; NEURONS; Science & Technology; transcriptome; MODEL; GENE; HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE; Life Sciences & Biomedicine; microarray, gene ontology; Biochemistry & Molecular Biology; CENTRAL-NERVOUS-SYSTEM; hypoxanthine phosphoribosyltransferase; Lesch-Nyhan disease; PLURIPOTENT STEM-CELLS; DISORDER
• Research Categories: Biology, Genetics; Chemistry, Biochemistry

Abstract

Lesch-Nyhan disease (LND) is an X-linked metabolic disease caused by various mutations in the gene HPRT1 encoding an enzyme of purine metabolism, hypoxanthine guanine phosphoribosyltransferase (HPRT). In its most severe form, LND patients suffer from overproduction of uric acid along with neurological or behavioural difficulties including self-injurious behaviours. To gain more insight into pathogenesis, we compared the transcriptome from human LND fibroblasts to normal human fibroblasts using a microarray with 60,000 probes corresponding to the entire human genome. Using stringent criteria, we identified 25 transcripts whose expression was significantly different between LND and control cells. These genes were confirmed by quantitative RT-PCR to be dysregulated in LND cells. Moreover, bioinformatic analysis of microarray data using gene ontology (GO) highlighted clusters of genes displaying biological processes most significantly affected in LND cells. These affected genes belonged to specific processes such as cell cycle and cell-division processes, metabolic and nucleic acid processes, demonstrating the specific nature of the changes and providing new insights into LND pathogenesis.