title: PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse.
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.
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
authors.forename: Alaine C
authors.initials: AC
authors.lastname: Keebaugh
authors.forename: Heather A
authors.initials: HA
authors.lastname: Mitchell
authors.forename: Meriem
authors.initials: M
authors.lastname: Gaval-Cruz
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Freeman
authors.forename: Gaylen L
authors.initials: GL
authors.lastname: Edwards
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.forename: James W
authors.initials: JW
authors.lastname: Thomas
mesh_terms: D000374:Aggression / Q000187:drug effects; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005298:Fertility; D060045:Genes, Modifier; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018377:Neurotransmitter Agents / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D018377:Neurotransmitter Agents; D000661:Amphetamine; D007041:Hypoxanthine Phosphoribosyltransferase; C554253:PRTFDC1 protein, human; D004298:Dopamine