FH Gene (Fumarate Hydratase): Function, Mutations, and Associated Diseases

The FH gene encodes fumarate hydratase (also known as fumarase), an enzyme that catalyzes the reversible hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle. This mitochondrial enzyme plays a critical role in cellular energy metabolism. Germline mutations in FH are associated with hereditary leiomyomatosis and renal cell cancer (HLRCC), a syndrome characterized by cutaneous and uterine leiomyomas and an aggressive form of renal cell carcinoma. Additionally, biallelic mutations cause fumarase deficiency, a severe neurological disorder. FH acts as a tumor suppressor, and loss of function leads to accumulation of fumarate, which stabilizes hypoxia-inducible factors (HIF) and promotes tumorigenesis.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Tricarboxylic acid (TCA) cycle

• Metabolic reprogramming in cancer

• Hypoxia-inducible factor (HIF) signaling

Fumarate hydratase (FH) is a homotetrameric enzyme that catalyzes the reversible hydration of fumarate to L-malate in the TCA cycle. It is localized in the mitochondria, where it participates in energy production. The protein is also present in the cytosol, where it may play a role in DNA damage response. Mutations in FH lead to loss of enzymatic activity, causing accumulation of fumarate, which is an oncometabolite that stabilizes HIF-1α and promotes tumorigenesis. The protein is encoded by the FH gene located on chromosome 1q43.