Fah-KO Mouse

The FAH gene encodes the fumarylacetoacetate hydrolase (FAH) protein, a key enzyme in the tyrosine catabolism pathway. FAH is expressed in many tissues throughout the body but is most abundant in the liver and kidneys. Mutations in the FAH gene can lead to a deficiency in FAH activity, which results in the accumulation of fumarylacetoacetate (FAA) and other toxic metabolites in the body. This can lead to a variety of health problems, including hereditary tyrosinemia type 1 (HT1) ^[1-2]. HT1 is a rare autosomal recessive genetic disorder that is characterized by a deficiency in FAH activity. Symptoms of HT1 typically appear in early infancy and can include vomiting, diarrhea, jaundice, and failure to thrive. If left untreated, HT1 can lead to severe liver and kidney damage, as well as intellectual disability.

This model is a Fah gene knockout (Fah-KO) mouse. The Fah gene in the mouse, which is homologous to the human FAH gene, has been knocked out using gene editing technology. Heterozygous Fah-KO mice are viable and fertile. These mice can exhibit the typical characteristics of hereditary tyrosinemia type 1 (HT1), that is, the metabolic disorder of tyrosine in the body, leading to the accumulation of fumarylacetoacetate (FAA), which in turn causes hepatocyte damage. Homozygous Fah-KO mice will die shortly after birth, manifesting as liver and kidney dysfunction, hypoglycemia, and significant changes in liver mRNA expression, and nitisinone (NTBC) is required to maintain their survival ^[3]. In addition, FRG mice (Fah-KO/Rag2 KO/Il2rg KO) constructed by crossing Fah-KO mice with Rag2 KO mice and Il2rg KO mice can be used for the study of human hepatocyte regeneration, thus creating mice "with a human liver" ^[4], which is of great significance for research on liver biology, stem cells, infectious diseases, metabolism, and gene therapy.