The identification of genes underlying disease susceptibility is of critical importance to human health. Equally important is the identification of genes that confer resistance to disease. The goal of this R21 proposal is to genetically and molecularly evaluate a candidate gene for the resistance to a human genetic disease, called Lesch-Nyhan disease, in mice. Lesch-Nyhan disease is an inborn error in metabolism caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT1), and leads to severe developmental, neurological, and behavioral disorders for which there is no cure. In contrast to the profound effect HPRT1-deficiency has in humans, loss of HPRT1 activity in mice does not result in the severe clinical phenotypes seen in HPRT1-deficient patients. Thus, because of their resistance to Lesch-Nyhan disease, mice provide a model system for identifying the gene(s) that can suppress the severe clinical symptoms of this human genetic disorder. We recently identified a novel candidate gene which could lead to the suppression of the Lesch-Nyhan disease phenotypes in mice. Specifically, a gene inactivation event in an uncharacterized member of the HPRT1-gene family, PRTFDC1, was found only in mice. Therefore, given the similarity of HPRT1 and PRTFDC1, we hypothesize that this difference in gene content between humans and mice contributes to the differential susceptibility these species have to the severe clinical phenotypes associated with Lesch-Nyhan disease. In order to test this hypothesis, 'humanized' transgenic mice expressing PRTFDC1 will be used to evaluate if expression of this gene in HPRT1-deficient mice leads to the manifestation of the severe clinical phenotypes associated with Lesch-Nyhan disease. In addition, the regulatory interactions between PRTFDC1 and HPRT1 will be characterized by gene expression and protein assays. In summary, there is no adequate animal model of Lesch-Nyhan disease. The experiments proposed here will genetically and molecularly evaluate a candidate gene for modulating the interspecies susceptibility to HPRT1-deficiency as a means to develop a novel animal model of Lesch-Nyhan disease, and dissect the basic etiology of this inborn error in metabolism. ? ? ?
| Keebaugh, Alaine C; Mitchell, Heather A; Gaval-Cruz, Meriem et al. (2011) PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse. PLoS One 6:e22381 |
| Keebaugh, Alaine C; Thomas, James W (2010) The evolutionary fate of the genes encoding the purine catabolic enzymes in hominoids, birds, and reptiles. Mol Biol Evol 27:1359-69 |
| Keebaugh, Alaine C; Thomas, James W (2009) The genomes of the South American opossum (Monodelphis domestica) and platypus (Ornithorhynchus anatinus) encode a more complete purine catabolic pathway than placental mammals. Comp Biochem Physiol Part D Genomics Proteomics 4:174-8 |
