The Fah(-/-) rats faithfully represented major phenotypic and biochemical manifestations of human HT1, including hypertyrosinemia, liver failure, and renal tubular damage.
We applied our delivery strategy to a mouse model of human hereditary tyrosinemia and show that the treatment generated fumarylacetoacetate hydrolase (Fah)-positive hepatocytes by correcting the causative Fah-splicing mutation.
Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder affecting fumarylacetoacetate hydrolase (FAH), the last enzyme in the tyrosine catabolism pathway.
This type of tyrosinemia is caused by a mutation in the gene coding for fumarylacetoacetate hydrolase; several mutations in this gene have been identified.
Both the 8.5-kb Tol2 transposon and 5.8-kb miniTol2 engineered elements readily function to revert the deficiency of fumarylacetoacetate hydrolase in an animal model of hereditary tyrosinemia type 1.
Tyrosinaemia I (fumarylacetoacetate hydrolase deficiency) is an autosomal recessive inborn error of tyrosine metabolism that produces liver failure in infancy or a more chronic course of liver disease with cirrhosis, often complicated by hepatocellular carcinoma, in childhood or early adolescence.
Patients with hereditary tyrosinemia type 1 have a deficiency of fumarylacetoacetate hydrolase (FAH) and develop progressive hepatocellular dysfunction with a high risk of malignant transformation.
The complete fumarylacetoacetate hydrolase (FAH) genotype of probands of thirteen unrelated families with hereditary tyrosinemia type 1 (HT 1) was established.
Frequency of the IVS12 + 5G-->A splice mutation of the fumarylacetoacetate hydrolase gene in carriers of hereditary tyrosinaemia in the French Canadian population of Saguenay-Lac-St-Jean.
In four patients exhibiting mosaicism of FAH protein, analysis for the tyrosinemia-causing mutations was performed in immunonegative and immunopositive areas of liver tissue by restriction digestion analysis and direct DNA sequencing.
The finding that the Fah gene in wild-type mice is highly expressed only in cell types that develop a phenotype in mutants, and the fact that Fah deficiency determines the human liver disease hereditary tyrosinemia type 1 (HT1), suggested that disruption of the Fah gene was responsible for the lethal albino phenotype.
These RFLPs were utilised in 3 tyrosinemia families in which one or both parents are carriers of both a tyrosinemia and a pseudodeficiency gene for FAH.
Immunoblot analyses with bovine fumarylacetoacetase antibodies have been performed in fibroblast extracts from 28 patients with hereditary tyrosinemia of various clinical phenotypes, in one healthy individual homozygous for a "pseudodeficiency" gene for fumarylacetoacetase, and in three tyrosinemia families in which one or both parents are compound heterozygotes for the tyrosinemia and pseudodeficiency genes.
The presence of FAH immunoreactivity in normal fetal tissues suggests that deficient FAH activity in tyrosinemia is not simply related to a developmentally regulated expression of the enzyme.
Recently, studies on hereditary tyrosinemias (Type I) have indicated that the primary enzyme defect in these diseases is a deficiency of liver and renal fumarylacetoacetase.