Fumarate Hydratase (FH) [J13]

Fumarate hydratase (FH) or fumarase encoded by the FH gene and ubiquitously expressed mitochondrial enzyme, catalyses the reversible hydration of fumaric acid to yield l-malic acid during the Krebs cycle. Germline mutations in the fumarate hydratase gene cause a predisposition to renal defects such as multiple cutaneous and uterine leiomyoma (MCL) syndrome. Furthermore, mutations also correlate with renal and smooth muscle tumors, but not with prostate cancer. Additionally, like other metabolic diseases, fumarate hydratase deficiency correlates with seizures, due to prenatal brain dysgenesis. FH and succinate dehydrogenase are tumour suppressors and they are associated with metabolic dysfunction and tumorigenesis, providing biochemical evidence to explain enhanced glycolysis in tumours. Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant heritable syndrome with predisposition to development of Renal Cell Carcinoma and Smooth Muscle Tumors of the skin and uterus. Cells of individuals with HLRCC had lower fumarate hydratase antibody activity than cells from normal controls, making fumarate hydratase antibody activity testing a useful method for diagnosis and screening.