Fumarylacetoacetate hydrolase gene (FAH)

The fumarylacetoacetate hydrolase (FAH) gene, located on chromosome 15q25.1, encodes the enzyme responsible for the final step of the tyrosine degradation pathway (NCBI Gene, 2023). Mutations in this gene lead to Hereditary Tyrosinemia Type I (HT1), a severe metabolic disorder characterized by the accumulation of toxic metabolites like succinylacetone, which cause progressive liver failure and a high risk of hepatocellular carcinoma (MedlinePlus, 2020). The genomic DNA at the FAH locus in hepatocytes is a primary target for in vivo gene editing and gene therapy approaches aimed at restoring enzymatic function. Experimental strategies using CRISPR-Cas9 or base editors aim to precisely correct pathogenic mutations, while AAV-mediated delivery can provide a functional FAH cDNA (Yin et al., Nature Biotechnology, 2014). A unique therapeutic advantage of targeting this locus is the selective growth advantage of FAH-positive hepatocytes, which can outcompete diseased cells and repopulate the liver (Grompe et al., Genes & Development, 1993). Current research focuses on optimizing delivery and precision to minimize off-target effects and ensure long-term safety in clinical applications.

Other names

FAH locusFumarylacetoacetate acetohydrolase geneFAATyrosinemia type I gene

Restoration of functional FAH enzyme production via genomic correction (e.g., homology-directed repair), gene insertion, or gene replacement within the hepatocyte genome.