B6RG-Fah-KO Mouse

The FAH gene encodes fumarylacetoacetate hydrolase (FAH), an enzyme abundant in the liver and kidneys and involved in the final step of tyrosine degradation. Genetic changes in the FAH gene can lead to various health conditions, with the most relevant disease being Tyrosinemia Type I (HT1). This metabolic disorder, caused by mutations in the FAH gene, leads to the accumulation of toxic substances in the body, resulting in liver and kidney problems as well as other complications. Tyrosinemia Type I (HT1) is an autosomal recessive disorder resulting from the deficiency or dysfunction of FAH. Normally, tyrosine is ultimately metabolized to fumarylacetoacetate and acetoacetate. However, when the FAH gene is deficient, toxic fumarylacetoacetate and maleylacetoacetate accumulate, and secondary toxic metabolites such as succinylacetone are produced, which cause damage to the liver and kidneys. In the early stages, liver damage can lead to liver failure and cirrhosis, while kidney damage may result in rickets and developmental delays ^[1-2].

The IL2RG gene, also known as the CD132 gene, encodes the interleukin-2 receptor gamma chain (IL-2Rγ), which is a critical signaling component of several interleukin receptors and a common receptor subunit for many important immune factors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These interleukin receptors are located on the surface of immune cells, and when one of these interleukins binds to its receptor, it triggers a cascade of chemical reactions within the cell, promoting cell growth and division. Therefore, the interleukin-2 receptor gamma chain is also referred to as the common gamma chain (γc). Mutations in the IL2RG gene in humans can lead to X-linked severe combined immunodeficiency (X-SCID). This condition is characterized by the lack of T cells and natural killer cells and the dysfunction of B cells, making patients extremely susceptible to recurrent infections and preventing them from surviving beyond infancy ^[3-4]. In mice, knockout of the Il2rg gene leads to severe deficiencies of B cells, T cells, and NK cells in the bone marrow, peripheral blood, and spleen, resulting in a phenotype of severe immunodeficiency ^[4].

The RAG2 gene encodes a protein that, together with the RAG1 protein, forms the RAG complex, which plays a crucial role in V(D)J recombination during the maturation of B and T cells. It not only participates in catalyzing the reaction but also regulates the reaction by controlling access to specific gene loci ^[5]. Lack of functional RAG2 protein can also lead to severe combined immunodeficiency (SCID). The loss of the Rag2 gene in mice results in the absence of V(D)J recombination, which blocks the differentiation, development, and maturation of T and B cells, ultimately causing a severe combined immunodeficiency-like phenotype ^[6].

B6RG-Fah-KO mice are obtained by crossing Fah KO mice (Catalog No.: C001273) with B6RG mice (Rag2 and Il2rg double knockout mice, Catalog No.: C001367). Research shows that B6RG-Fah-KO mice (triple knockout of Fah, Rag, and Il2rg), developed by mating Fah KO mice with Rag2 KO and Il2rg KO mice, can be used to study human hepatocyte regeneration. After transplantation of human hepatocytes, these mice can develop "humanized livers" ^[7], which are of significant importance for research in liver biology, stem cells, infectious diseases, metabolism, and gene therapy.