Fumarylacetoacetate hydrolase (FAH) gene locus (FAH)

The genomic DNA locus of the Fumarylacetoacetate hydrolase (FAH) gene, located on chromosome 15q25.1, encodes the final enzyme in the tyrosine catabolic pathway [1, 4]. Mutations within this locus, such as the common R341W substitution, lead to Hereditary Tyrosinemia Type 1 (HT1), a severe metabolic disorder characterized by the accumulation of toxic metabolites like succinylacetone [2, 4]. These metabolites cause progressive liver damage, renal tubular dysfunction, and a significantly increased risk of hepatocellular carcinoma [4]. While current treatments like Nitisinone manage the disease by inhibiting upstream enzymes, the FAH gene locus is the primary target for curative genetic interventions [3, 5]. Investigational therapies like BEAM-301 utilize base editing technology to directly correct pathogenic mutations within the genomic sequence, thereby restoring endogenous enzyme production [3]. Other approaches include CRISPR-Cas9 mediated gene correction and gene replacement strategies aimed at providing a permanent therapeutic solution [5]. These genetic medicines represent a shift from chronic symptom management to definitive genomic repair for patients with FAH deficiency.

Other names

Fumarylacetoacetase geneFAA geneHT1 gene locusFumarylacetoacetate hydrolase gene

Direct genomic correction of pathogenic mutations via base editing or homology-directed repair to restore functional enzyme expression [3, 5].