FH (fumarate hydratase).

2006-07-01   Allison M Lynch , Cynthia C Morton 

Brigham, Womens Hospital, Harvard New Research Building, 77 Avenue Louis Pasteur, Room 160, Boston, MA 02115, USA




Atlas Image
Fig1. Genomic structure of FH. Exons are represented by purple boxes with base pair number above and exon number below. Image is not drawn to scale.


10 exons; 22,152 base pairs.


1,1790 bp. Multiple RNA transcripts encode two FH gene products- one with a mitochondrial signal protein and the other lacking the signal sequence.


Atlas Image


FH encodes the homotetrameric enzyme, fumarase, composed of 510 amino acids (molecular weight 54,637 Da); four identical subunits (50 kDa each); three active DNA binding sites (site A) and one lower affinity substrate (site B). Isoenzyme products have nearly identical amino acid sequences, but vary at the amino terminus.


Widespread in both fetal and adult tissues; most abundantly expressed in the skin, parathyroid, lymph and colon (four highest NCBI expression profiles). Tumors: expression in benign mesenchymal tissue (e.g., uterine, cutaneous); malignant tumors: leiomyosarcoma and papillary (type II) renal cell carcinoma.


Mitochondrial and cytosolic. Subcellular localization is determined by presence or absence of a signal sequence at the amino terminus. Presence of the signal generates the mitochondrial-targeted form while absence of the signal results in the cytosolic form.


Fumarase plays a key enzymatic role in fundamental metabolic pathways. The mitochondrial isoenzyme catalyzes conversion of fumarate to malate in the Krebs, or tricarboxylic acid (TCA) cycle, in which acetyl-CoA produces CO2, reduced electron carriers (FADH2 and NADH) and ATP. The cytosolic isoenzyme is involved with amino acid metabolism.



Germline mutations in FH are associated with two distinct conditions:
  • Homozygous and compound heterozygous mutations (e.g., missense and in-frame deletions) of the 3 end result in fumarate hydratase deficiency (FHD).
  • Heterozygous 5 mutations (e.g., nonsense, missense and deletions ranging from one base pair to whole gene) predispose individuals to somatic mutations in the normal allele leading to Hereditary leiomyomatosis and renal cell carcinoma / multiple cutaneous and uterine leiomyomatosis (HLRCC/MCUL1).
  • Somatic

    Loss-of-heterozygosity of the wild type allele results in functional nullizygosity for fumarate hydratase. Malignant uterine and kidney tumors characteristic of HLRCC can subsequently develop.

    Implicated in

    Entity name
    Uterine Leiomyomata (UL)
    Synonyms include uterine fibroids, fibromas, myofibromas and myomas.
    Benign mesenchymal tumors of the uterus.
    Excellent, but may require surgical intervention as one- third of hysterectomies performed in the United States have a primary indication of UL.
    UL rarely associated with cytologically visible 1q42 deletions.
    Hybrid gene
    Deletions of FH from structural rearrangements of 1q42.1.
    Fusion protein
    Presumed haploinsufficiency or functional null if mutation in other FH allele occurs.
    Entity name
    Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)/ multiple cutaneous and uterine leiomyomatosis (MCUL1).
    Also known as Reeds syndrome.
    HLRCC is an autosomal dominant disorder, characterized by smooth muscle tumors of the skin and uterus and/or kidney.
    Good, if early diagnosis.
    Fusion protein
    Inherited mutations can predispose to somatic deletions resulting in truncated, non-functional or absent proteins.
    FH acts as classic tumor suppressor gene in HLRCC/MCUL1. Genetic or epigenetic alterations in FH resulting from substitution, deletion or methylation follow the Knudson two hit mechanism. The resulting functionally null state for fumarase can lead to subsequent oxidative tissue damage and tumorigenesis.
    Entity name
    Fumarate hydratase deficiency (FHD).
    Synonymous with fumarase deficiency and fumaric aciduria.
    Autosomal recessive condition characterized by delayed development, diminished muscle tone, and encephalopathy likely due to limited energy generation during development.
    Poor. FHD is a rare condition, but reported cases indicate most affected individuals survive only several months while very few survive into their third decade.
    Hybrid gene
    The most common allelic abnormality is a 3 base pair- AAA insertion.
    Fusion protein
    Mutations near fumarase active site result in absent or truncated protein.


    Pubmed IDLast YearTitleAuthors
    127610392003Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.Alam NA et al
    121777822002Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas.Barker KT et al
    153345412004Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies.Gross KL et al
    115495742001Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.Kiuru M et al
    121834042002Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families.Kiuru M et al
    112480882001Inherited susceptibility to uterine leiomyomas and renal cell cancer.Launonen V et al
    165821322006The genetics of uterine leiomyomata: what clinicians need to know.Stewart EA et al
    118653002002Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.Tomlinson IP et al
    127720872003Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.Toro JR et al
    163191282006Distinct expression profile in fumarate-hydratase-deficient uterine fibroids.Vanharanta S et al
    89092931996Crystallographic studies of the catalytic and a second site in fumarase C from Escherichia coli.Weaver T et al
    30407361987Mitochondrial and cytoplasmic fumarases in Saccharomyces cerevisiae are encoded by a single nuclear gene FUM1.Wu M et al

    Other Information

    Locus ID:

    NCBI: 2271
    MIM: 136850
    HGNC: 3700
    Ensembl: ENSG00000091483


    dbSNP: 2271
    ClinVar: 2271
    TCGA: ENSG00000091483


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Citrate cycle (TCA cycle)KEGGko00020
    Pyruvate metabolismKEGGko00620
    Renal cell carcinomaKEGGko05211
    Citrate cycle (TCA cycle)KEGGhsa00020
    Pyruvate metabolismKEGGhsa00620
    Pathways in cancerKEGGhsa05200
    Renal cell carcinomaKEGGhsa05211
    Metabolic pathwaysKEGGhsa01100
    Citrate cycle, second carbon oxidation, 2-oxoglutarate => oxaloacetateKEGGhsa_M00011
    Citrate cycle (TCA cycle, Krebs cycle)KEGGM00009
    Citrate cycle, second carbon oxidation, 2-oxoglutarate => oxaloacetateKEGGM00011
    Carbon metabolismKEGGhsa01200
    Carbon metabolismKEGGko01200
    Citrate cycle (TCA cycle, Krebs cycle)KEGGhsa_M00009
    The citric acid (TCA) cycle and respiratory electron transportREACTOMER-HSA-1428517
    Pyruvate metabolism and Citric Acid (TCA) cycleREACTOMER-HSA-71406
    Citric acid cycle (TCA cycle)REACTOMER-HSA-71403

    Protein levels (Protein atlas)

    Not detected


    Pubmed IDYearTitleCitations
    118653002002Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.351
    160984672005HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.294
    226775462012Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors.274
    187282832008Germline SDHB mutations and familial renal cell carcinoma.106
    192761582009LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer.97
    194707622009Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species.93
    243347672014Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.76
    126126542003A role for mitochondrial enzymes in inherited neoplasia and beyond.72
    219079232011The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels.71
    202318752010Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response.63


    Allison M Lynch ; Cynthia C Morton

    FH (fumarate hydratase).

    Atlas Genet Cytogenet Oncol Haematol. 2006-07-01

    Online version: http://atlasgeneticsoncology.org/gene/40573/fh