In vivo suppressor mutations correct a murine model of hereditary tyrosinemia type I

Hereditary tyrosinemia type I and alkaptonuria are disorders of tyrosine ca tabolism caused by deficiency of fumarylacetoacetate hydrolase (FAH) and ho mogentisic acid dioxygenase (HGD), respectively. Tyrosinemia is a severe ch ildhood disease that affects the liver and kidneys, but alkaptonuria is a m ore benign adult disorder in comparison. Because HGD is upstream of FAH in the tyrosine pathway, mice doubly mutant in both enzymes were found to he p rotected from the liver and renal damage of tyrosinemia as hypothesized. Mi ce mutant at the tyrosinemic locus but heterozygous for alkaptonuria sponta neously developed clonal nodules of functionally normal hepatocytes that we re able to rescue the livers of some mice with this genotype. This phenotyp ic rescue was a result of an inactivating mutation of the wild-type homogen tisic acid dioxygenase gene, thus presenting an example of an in vivo suppr essor mutation in a mammalian model.