Tissue-specific aberrations of gene expression in HPRT-deficient mice: functional complexity in a monogenic disease?

We have used the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme-deficient mouse model of human Lesch-Nyhan disease (LND) to examine the tissue-specificity of altered global gene expression in a genetically "simple" monogenic human disease. We have identified a number of genes and gene families whose expression is aberrant in the mouse knockout model of the LND, and we have identified different patterns of aberrant gene expression in two principal target tissues associated with the disease phenotype, i.e., the central nervous system and the liver. The major neurological phenotype reflects dysfunction of the dopamine neurotransmitter system in the basal ganglia, and we have now identified aberrant expression of a small number of genes in HPRT-deficient striata. The abnormal metabolic phenotype of hyperuricemia in HPRT-deficient mice is also reflected in an aberrant gene expression in the liver. We interpret these findings to suggest that the genetic consequences of a primary HPRT knockout in the mouse produces transcriptional aberrations in a number of other genes that may play a role in the disease phenotype. Knowledge of these secondary genetic defects may help in the identification of targets for drug- and gene-based therapy.