PRTFDC1 Is a Genetic Modifier of HPRT-Deficiency in the Mouse

• Type of Material: Article
• Authors: Alaine C. Keebaugh, Yerkes National Primate Research Center; Heather A. Mitchell, Emory University; Meriem Gaval-Cruz, Emory University; Kimberly G. Freeman, University of Georgia; Gaylen L. Edwards, University of Georgia; David Weinshenker, Emory University; James W. Thomas, Emory University
• Language: English
• Date: 2011-07-27
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Keebaugh et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0022381
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 6
• Issue: 7
• Start Page: e22381
• End Page: e22381
• Grant/Funding Information: This work was also supported in part by the National Institutes of Health (NIH)/National Institute on Drug Abuse (NIDA) (DA017963 to D.W., DA25040 to M.G.C.).; A.C.K., H.A.M., D.W. and J.W.T. were supported by a grant from the National Institutes of Health (1R21NS060935).
• Keywords: DISEASE; DOPAMINE; PROTEIN; PHOSPHORIBOSYLTRANSFERASE; Science & Technology; LESCH-NYHAN SYNDROME; MICE; MODEL; Science & Technology - Other Topics; Multidisciplinary Sciences; BACILLUS-SUBTILIS
• Research Categories: Biology, Genetics

Abstract

Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT-deficiency in the mouse does not result in the profound phenotypes such as self-injurious behavior observed in humans, and the genetic basis for this phenotypic disparity between HPRT-deficient humans and mice is unknown. To test the hypothesis that HPRT deficiency is modified by the presence/absence of phosphoribosyltransferase domain containing 1 (PRTFDC1), a paralog of HPRT that is a functional gene in humans but an inactivated pseudogene in mice, we created transgenic mice that express human PRTFDC1 in wild-type and HPRT-deficient backgrounds. Male mice expressing PRTFDC1 on either genetic background were viable and fertile. However, the presence of PRTFDC1 in the HPRT-deficient, but not wild-type mice, increased aggression as well as sensitivity to a specific amphetamine-induced stereotypy, both of which are reminiscent of the increased aggressive and self-injurious behavior exhibited by patients with LND. These results demonstrate that PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse and could therefore have important implications for unraveling the molecular etiology of LND.