Fumarylacetoacetate hydrolase (FAH) gene (FAH)

The fumarylacetoacetate hydrolase (FAH) genomic DNA locus, located on chromosome 15q25.1, encodes the enzyme responsible for the final step of the tyrosine catabolic pathway (NCBI Gene ID: 2184). In hepatocytes, the loss of FAH function due to genetic mutations results in Hereditary Tyrosinemia Type I (HT1), a severe metabolic disorder where the accumulation of toxic metabolites like fumarylacetoacetate and succinylacetone leads to progressive liver failure and a high risk of hepatocellular carcinoma (UniProt P16930; OMIM 276700). While current pharmacological management involves the drug nitisinone to block upstream metabolite production, the FAH genomic locus is a primary target for curative genetic interventions such as CRISPR/Cas9-mediated gene editing and base editing (Yin et al., Nature 2014). These therapies aim to restore endogenous enzyme production by correcting the underlying genetic defect. A unique therapeutic advantage of targeting this locus is that FAH-corrected hepatocytes exhibit a selective survival advantage, allowing them to repopulate the liver and restore metabolic function even if only a small fraction of cells are initially edited (Grompe et al., Genes & Development 1993).

Other names

Fumarylacetoacetase geneFAH locus15q25.1 locusTyrosinemia type I gene

Restoration of functional fumarylacetoacetate hydrolase expression through gene replacement, gene editing, or base editing to correct pathogenic mutations within the hepatocyte genome.