In vivosuppressor mutations correct liver disease in a murine model of Hereditary Tyrosinemia type I. K. Manning¹, M. Al-Dhalimy¹, M. Finegold², M. Grompe¹. 1) Department of Molecular & Medical Genetics, Oregon Health Sciences University, Portland, OR; 2) Department of Pathology, Texas Children's Hospital, Houston, TX.

   Hereditary tyrosinemia type I (HTI) and alkaptonuria (aku) are disorders of tyrosine catabolism caused by deficiency of fumarylacetoacetate hydrolase (FAH) and homogentisic acid dioxygenase (HGD) respectively. HTI is a severe childhood disease that results in liver and kidney dysfunction and often liver cancer, due to the build-up of fumarylacetoacetate (FAA) and maleylacetoacetate (MAA), the two metabolites upstream of FAH in the pathway. Patients with aku, a much more benign adult disorder, have joint problems resulting from a build-up of HGA, the substrate of HGD, but no liver or kidney damage since FAA and MAA are downstream of HGD in the pathway. Mice doubly mutant in Hgdand Fahwere found to be protected from both the liver and renal damage of HTI. Interestingly, all mice that were deficient in Fah, but heterozygous for Hgdspontaneously developed clonal nodules of functionally normal hepatocytes that were able to divide and repopulate the whole liver. By analyzing RT-PCR products from corrected livers in Fahmutant, Hgdheterozygous mice, we determined that this rescue was due to inactivating mutations in the wild-type allele of Hgd. This model therefore represents the first example of phenotypic reversion by an in vivosuppressor mutation in a mammal. Analysis of the Hgd mutations in the corrected nodules showed that FAA and MAA can cause a wide spectrum of alterations. These included small deletions and insertions, base substitutions, and also larger alterations (whole gene deletions or gene conversion) resulting in the loss of the entire wild-type Hgdallele.