Homogentisic acid dioxygenase (HGD), maleylacetoacetate isomerase (MAI) and fumarylacetoacetate hydrolase (FAH) sequentially catalyze the terminal degradation of tyrosine into Krebs cycle intermediates. Deficiency of HGD causes the human disorder alkaptonuria, (AKU) deficiency of FAH causes tyrosinemia type I (HT1) and the phenotype of MAI deficiency in man is unknown. HT1 is characterized by severe liver dysfunction, renal tubular damage and finally liver cancer. Previously we have generated a murine model of HT 1 and shown that the drug NTBC can prevent the neonatal lethality and liver dysfunction of FAH deficient mice. We also demonstrated a strong selective growth advantage of FAH expressing cells in mutant liver. This in vivo selection resulted in a near complete repopulation of diseased liver with healthy tissue and raised the hope that human HT1 may be curable by gene therapy. To broaden our understanding of the pathophysiology and potential therapy of HT1we have now also established murine models of HGD and MAI deficiency. This application pertains to the use of murine models of enzyme deficiencies in tyrosine catabolism to explore the biology of novel strategies for liver and kidney gene therapy, to better understand the etiology of hepatic cancer in HT1 and dissect the pathophysiology of the diseases in this pathway.
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