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FH (fumarate hydratase).

Written2006-07Allison M Lynch, Cynthia C Morton
Brigham, Women's Hospital, Harvard New Research Building, 77 Avenue Louis Pasteur, Room 160, Boston, MA 02115, USA

(Note : for Links provided by Atlas : click)


HGNC (Hugo) FH
HGNC Alias namefumarase
LocusID (NCBI) 2271
Atlas_Id 40573
Location 1q43  [Link to chromosome band 1q43]
Location_base_pair Starts at 241497603 and ends at 241519755 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping FH.png]
Local_order Telomeric to RGS7, centromeric to KMO
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


  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.
Description 10 exons; 22,152 base pairs.
Transcription 1,1790 bp. Multiple RNA transcripts encode two FH gene products- one with a mitochondrial signal protein and the other lacking the signal sequence.


Description 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.
Expression 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: and .
Localisation 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.
Function 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.


Germinal 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 Uterine Leiomyomata (UL)
    Note Synonyms include uterine fibroids, fibromas, myofibromas and myomas.
    Disease Benign mesenchymal tumors of the uterus.
    Prognosis Excellent, but may require surgical intervention as one- third of hysterectomies performed in the United States have a primary indication of UL.
    Cytogenetics UL rarely associated with cytologically visible 1q42 deletions.
    Hybrid/Mutated Gene Deletions of FH from structural rearrangements of 1q42.1.
    Abnormal Protein Presumed haploinsufficiency or functional null if mutation in other FH allele occurs.
    Entity Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)/ multiple cutaneous and uterine leiomyomatosis (MCUL1).
    Note Also known as Reed's syndrome.
    Disease HLRCC is an autosomal dominant disorder, characterized by smooth muscle tumors of the skin and uterus and/or kidney.
    Prognosis Good, if early diagnosis.
    Abnormal Protein Inherited mutations can predispose to somatic deletions resulting in truncated, non-functional or absent proteins.
    Oncogenesis 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 Fumarate hydratase deficiency (FHD).
    Note Synonymous with fumarase deficiency and fumaric aciduria.
    Disease Autosomal recessive condition characterized by delayed development, diminished muscle tone, and encephalopathy likely due to limited energy generation during development.
    Prognosis 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/Mutated Gene The most common allelic abnormality is a 3 base pair- AAA insertion.
    Abnormal Protein Mutations near fumarase active site result in absent or truncated protein.


    Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
    Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts ED, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, Tomlinson IP
    Human molecular genetics. 2003 ; 12 (11) : 1241-1252.
    PMID 12761039
    Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas.
    Barker KT, Bevan S, Wang R, Lu YJ, Flanagan AM, Bridge JA, Fisher C, Finlayson CJ, Shipley J, Houlston RS
    British journal of cancer. 2002 ; 87 (4) : 446-448.
    PMID 12177782
    Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies.
    Gross KL, Panhuysen CI, Kleinman MS, Goldhammer H, Jones ES, Nassery N, Stewart EA, Morton CC
    Genes, chromosomes & cancer. 2004 ; 41 (3) : 183-190.
    PMID 15334541
    Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.
    Kiuru M, Launonen V, Hietala M, Aittomäki K, Vierimaa O, Salovaara R, Arola J, Pukkala E, Sistonen P, Herva R, Aaltonen LA
    The American journal of pathology. 2001 ; 159 (3) : 825-829.
    PMID 11549574
    Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families.
    Kiuru M, Lehtonen R, Arola J, Salovaara R, Järvinen H, Aittomäki K, Sjöberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA
    Cancer research. 2002 ; 62 (16) : 4554-4557.
    PMID 12183404
    Inherited susceptibility to uterine leiomyomas and renal cell cancer.
    Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA
    Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (6) : 3387-3392.
    PMID 11248088
    The genetics of uterine leiomyomata: what clinicians need to know.
    Stewart EA, Morton CC
    Obstetrics and gynecology. 2006 ; 107 (4) : 917-921.
    PMID 16582132
    Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
    Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomäki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Multiple Leiomyoma Consortium, Aaltonen LA
    Nature genetics. 2002 ; 30 (4) : 406-410.
    PMID 11865300
    Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
    Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B
    American journal of human genetics. 2003 ; 73 (1) : 95-106.
    PMID 12772087
    Distinct expression profile in fumarate-hydratase-deficient uterine fibroids.
    Vanharanta S, Pollard PJ, Lehtonen HJ, Laiho P, Sjöberg J, Leminen A, Aittomäki K, Arola J, Kruhoffer M, Orntoft TF, Tomlinson IP, Kiuru M, Arango D, Aaltonen LA
    Human molecular genetics. 2006 ; 15 (1) : 97-103.
    PMID 16319128
    Crystallographic studies of the catalytic and a second site in fumarase C from Escherichia coli.
    Weaver T, Banaszak L
    Biochemistry. 1996 ; 35 (44) : 13955-13965.
    PMID 8909293
    Mitochondrial and cytoplasmic fumarases in Saccharomyces cerevisiae are encoded by a single nuclear gene FUM1.
    Wu M, Tzagoloff A
    The Journal of biological chemistry. 1987 ; 262 (25) : 12275-12282.
    PMID 3040736


    This paper should be referenced as such :
    Lynch, AM ; Morton, CC
    FH (fumarate hydratase)
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(4):247-250.
    Free journal version : [ pdf ]   [ DOI ]

    Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
      Hereditary multiple cutaneous leiomyomatosis

    External links


    HGNC (Hugo)FH   3700
    LRG (Locus Reference Genomic)LRG_504
    Atlas Explorer : (Salamanque)FH
    Entrez_Gene (NCBI)FH    fumarate hydratase
    AliasesFMRD; HLRCC; HsFH; LRCC; 
    MCL; MCUL1
    GeneCards (Weizmann)FH
    Ensembl hg19 (Hinxton)ENSG00000091483 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000091483 [Gene_View]  ENSG00000091483 [Sequence]  chr1:241497603-241519755 [Contig_View]  FH [Vega]
    ICGC DataPortalENSG00000091483
    TCGA cBioPortalFH
    AceView (NCBI)FH
    Genatlas (Paris)FH
    SOURCE (Princeton)FH
    Genetics Home Reference (NIH)FH
    Genomic and cartography
    GoldenPath hg38 (UCSC)FH  -     chr1:241497603-241519755 -  1q43   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)FH  -     1q43   [Description]    (hg19-Feb_2009)
    GoldenPathFH - 1q43 [CytoView hg19]  FH - 1q43 [CytoView hg38]
    Genome Data Viewer NCBIFH [Mapview hg19]  
    OMIM136850   150800   606812   
    Gene and transcription
    Genbank (Entrez)AA669797 AK312415 AW611924 BC003108 BC017444
    RefSeq transcript (Entrez)NM_000143
    Consensus coding sequences : CCDS (NCBI)FH
    Gene ExpressionFH [ NCBI-GEO ]   FH [ EBI - ARRAY_EXPRESS ]   FH [ SEEK ]   FH [ MEM ]
    Gene Expression Viewer (FireBrowse)FH [ Firebrowse - Broad ]
    GenevisibleExpression of FH in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)2271
    GTEX Portal (Tissue expression)FH
    Human Protein AtlasENSG00000091483-FH [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP07954   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP07954  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP07954
    Domaine pattern : Prosite (Expaxy)FUMARATE_LYASES (PS00163)   
    Domains : Interpro (EBI)Fum_hydII    Fumarase/histidase_N    Fumarase_C_C    Fumarate_lyase_CS    Fumarate_lyase_fam    Fumarate_lyase_N    L-Aspartase-like   
    Domain families : Pfam (Sanger)FumaraseC_C (PF10415)    Lyase_1 (PF00206)   
    Domain families : Pfam (NCBI)pfam10415    pfam00206   
    Conserved Domain (NCBI)FH
    PDB (RSDB)3E04    5D6B    5UPP    6EBT   
    PDB Europe3E04    5D6B    5UPP    6EBT   
    PDB (PDBSum)3E04    5D6B    5UPP    6EBT   
    PDB (IMB)3E04    5D6B    5UPP    6EBT   
    Structural Biology KnowledgeBase3E04    5D6B    5UPP    6EBT   
    SCOP (Structural Classification of Proteins)3E04    5D6B    5UPP    6EBT   
    CATH (Classification of proteins structures)3E04    5D6B    5UPP    6EBT   
    AlphaFold pdb e-kbP07954   
    Human Protein Atlas [tissue]ENSG00000091483-FH [tissue]
    Protein Interaction databases
    DIP (DOE-UCLA)P07954
    IntAct (EBI)P07954
    Ontologies - Pathways
    Ontology : AmiGOfumarate hydratase activity  fumarate hydratase activity  fumarate hydratase activity  protein binding  nucleus  chromosome  cytoplasm  mitochondrion  mitochondrion  mitochondrion  mitochondrial matrix  cytosol  tricarboxylic acid cycle  tricarboxylic acid cycle  fumarate metabolic process  fumarate metabolic process  malate metabolic process  malate metabolic process  DNA repair  tricarboxylic acid cycle enzyme complex  homeostasis of number of cells within a tissue  extracellular exosome  positive regulation of cold-induced thermogenesis  
    Ontology : EGO-EBIfumarate hydratase activity  fumarate hydratase activity  fumarate hydratase activity  protein binding  nucleus  chromosome  cytoplasm  mitochondrion  mitochondrion  mitochondrion  mitochondrial matrix  cytosol  tricarboxylic acid cycle  tricarboxylic acid cycle  fumarate metabolic process  fumarate metabolic process  malate metabolic process  malate metabolic process  DNA repair  tricarboxylic acid cycle enzyme complex  homeostasis of number of cells within a tissue  extracellular exosome  positive regulation of cold-induced thermogenesis  
    REACTOMEP07954 [protein]
    REACTOME PathwaysR-HSA-71403 [pathway]   
    NDEx NetworkFH
    Atlas of Cancer Signalling NetworkFH
    Wikipedia pathwaysFH
    Orthology - Evolution
    GeneTree (enSembl)ENSG00000091483
    Phylogenetic Trees/Animal Genes : TreeFamFH
    Homologs : HomoloGeneFH
    Homology/Alignments : Family Browser (UCSC)FH
    Gene fusions - Rearrangements
    Fusion : FusionGDB4.2.1.2   
    Fusion : FusionHubARRDC3--FH    BMPR2--FH    C1ORF131--FH    EFCAB2--FH    FH--HSP90B1    FH--NCOR2    HNRNPU--FH    RMDN1--FH    RRP15--FH   
    Fusion : QuiverFH
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerFH [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)FH
    Exome Variant ServerFH
    GNOMAD BrowserENSG00000091483
    Varsome BrowserFH
    ACMGFH variants
    Genomic Variants (DGV)FH [DGVbeta]
    DECIPHERFH [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisFH 
    ICGC Data PortalFH 
    TCGA Data PortalFH 
    Broad Tumor PortalFH
    OASIS PortalFH [ Somatic mutations - Copy number]
    Cancer Gene: CensusFH 
    Somatic Mutations in Cancer : COSMICFH  [overview]  [genome browser]  [tissue]  [distribution]  
    Somatic Mutations in Cancer : COSMIC3DFH
    Mutations and Diseases : HGMDFH
    LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
    DgiDB (Drug Gene Interaction Database)FH
    DoCM (Curated mutations)FH
    CIViC (Clinical Interpretations of Variants in Cancer)FH
    NCG (London)FH
    Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    OMIM136850    150800    606812   
    Orphanet3376    8775    8649   
    Genetic Testing Registry FH
    NextProtP07954 [Medical]
    Target ValidationFH
    Huge Navigator FH [HugePedia]
    ClinGenFH (curated)
    Clinical trials, drugs, therapy
    Protein Interactions : CTDFH
    Pharm GKB GenePA28139
    Clinical trialFH
    canSAR (ICR)FH
    DataMed IndexFH
    PubMed153 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Thu Jan 20 14:07:28 CET 2022

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