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FH (fumarate hydratase).

Identity

HGNC (Hugo) FH
Location 1q42.1
Location_base_pair Starts at 239727527 and ends at 239749677 bp from pter ( according to hg18-Mar_2006)  [Mapping]
Local_order Telomeric to RGS7, centromeric to KMO

DNA/RNA

 
  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.

Protein

 
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: leiomyosarcoma and papillary (type II) renal cell carcinoma.
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.

Mutations

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 (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 Reed¹s 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 ³two hit² 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.
      

    External links

    Nomenclature
    HGNC (Hugo)FH   3700
    Entrez_Gene (NCBI)FH  2271  fumarate hydratase
    Cards
    AtlasFHID40573ch1q42
    GeneCards (Weizmann)FH
    Ensembl (Hinxton)ENSG00000091483 [Gene_View]  FH [Vega]
    AceView (NCBI)FH
    Genatlas (Paris)FH
    euGene (Indiana)2271
    SOURCE (Stanford)NM_000143
    Gene Expression (Array Express) ENSG00000091483
    Genomic and cartography
    GoldenPath (UCSC)FH  -  1q42.1   chr1:239727527-239749677 -  1q42.1   [Description]    (hg18-Mar_2006)
    EnsemblFH - 1q42.1 [CytoView]
    Mapping of homologs : NCBIFH [Mapview]
    OMIM136850   150800   605839   606812   
    Gene and transcription
    Gene : Genbank (Entrez)AK312415 BC003108 BC017444 BT009839 CR590170
    Reference sequence (RefSeq transcript) :SRSNM_000143
    Reference transcript : EntrezNM_000143
    RefSeq genomic : SRSAC_000044 AC_000133 NC_000001 NG_012338 NT_167186 NW_001838549 NW_927128
    RefSeq genomic : EntrezAC_000044 AC_000133 NC_000001 NG_012338 NT_167186 NW_001838549 NW_927128
    Consensus coding sequences : CCDS NCBIFH
    Cluster EST : UnigeneHs.592490 [ SRS ] Hs.592490 [ NCBI ]
    Alternative Splicing : Fast-db (Paris)17963
    Protein : pattern, domain, 3D structure
    Protein : UniProt/SwissProtP07954 (SRS) P07954 (Expasy) P07954 (Uniprot)
    With graphics : InterProP07954
    Splice isoforms : VarSplice FASTAP07954(VarSplice FASTA)
    Domaine pattern : Prosite (SRS)FUMARATE_LYASES (PS00163)   
    Domain pattern : Prosite (Expaxy)FUMARATE_LYASES (PS00163)   
    Domains : Interpro (SRS)Fum_hydII    Fumarase_C_C    Fumarate_lyase    Fumarate_lyase_CS    L-Aspartase-like   
    Domains : Interpro (EBI)Fum_hydII    Fumarase_C_C    Fumarate_lyase    Fumarate_lyase_CS    L-Aspartase-like   
    Related proteins : CluSTrP07954
    Domain families : Pfam SRSFumaraseC_C (PF10415)    Lyase_1 (PF00206)   
    Domain families : Pfam SangerFumaraseC_C (PF10415)    Lyase_1 (PF00206)   
    Domain families : Pfam NCBIpfam10415    pfam00206   
    Blocks (Seattle)P07954
    Crystal structure of protein : PDB SRS3.00E+04   
    Crystal structure of protein : PDBSum3.00E+04   
    Crystal structure of protein : IMB3.00E+04   
    Crystal structure of protein : PDB RSDB3.00E+04   
    HPRD00652
    Protein Interaction databases
    DIP (DOE-UCLA)P07954
    IntAct (EBI)P07954
    Polymorphism : SNP, mutations, diseases
    Single Nucleotide Polymorphism (SNP) : dbSNP NCBIFH
    SNP : GeneSNP UtahFH
    SNP : HGBaseFH
    Genetic variants : HAPMAPFH
    Cancer Gene: CensusFH 
    Somatic Mutations in Cancer : COSMICFH 
    Mutations and Diseases : HGMDFH
    Hereditary diseases : OMIM136850    150800    605839    606812   
    Hereditary diseases : GENETests136850    150800    605839    606812   
    Diseases : Genetic AssociationFH
    General knowledge
    Homologs : HomoloGeneFH
    Homology/Alignments : Family Browser UCSCFH
    Phylogenetic Trees/Animal Genes : TreeFamFH
    Catalytic activity : Enzyme4.2.1.2 [ Enzyme-Expasy ]   4.2.1.2 [ Enzyme-SRS ]   4.2.1.2 [ IntEnz-EBI ]   4.2.1.2 [ BRENDA ]   4.2.1.2 [ KEGG ]   
    Chemical/Protein Interactions : CTD2271
    Keywords Ontology : AmiGOfumarate hydratase activity  cytoplasm  mitochondrion  mitochondrial matrix  tricarboxylic acid cycle  fumarate metabolic process  malate metabolic process  lyase activity  tricarboxylic acid cycle enzyme complex  homeostasis of number of cells within a tissue  
    Keywords Ontology : EGO-EBIfumarate hydratase activity  cytoplasm  mitochondrion  mitochondrial matrix  tricarboxylic acid cycle  fumarate metabolic process  malate metabolic process  lyase activity  tricarboxylic acid cycle enzyme complex  homeostasis of number of cells within a tissue  
    Pathways : BIOCARTA
    Pathways : KEGGCitrate cycle (TCA cycle)Reductive carboxylate cycle (CO2 fixation)
    Other databases
    Probes
    Probes : ImagenesFH Related clones (RZPD - Berlin)
    Literature
    PubMed44 Pubmed reference(s) in Entrez
    PubGeneFH

    Bibliography

    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
     
    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
     
    Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.
    Kiuru M, Launonen V, Hietala M, Aittomˆ§ki 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
     
    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
     
    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
     
    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, Jˆ§rvinen H, Aittomˆ§ki K, Sjˆberg 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
     
    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, Aittomˆ§ki 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
     
    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
     
    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
     
    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
     
    The genetics of uterine leiomyomata: what clinicians need to know.
    Stewart EA, Morton CC
    Obstetrics and gynecology. 2006 ; 107 (4) : 917-921.
    PMID 16582132
     
    Distinct expression profile in fumarate-hydratase-deficient uterine fibroids.
    Vanharanta S, Pollard PJ, Lehtonen HJ, Laiho P, Sjˆberg J, Leminen A, Aittomˆ§ki 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
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written07-2006Allison M Lynch, Cynthia C Morton
    Brigham and Women's Hospital, Harvard New Research Building, 77 Avenue Louis Pasteur, Room 160, Boston, MA 02115, USA

    Citation

    This paper should be referenced as such :
    Lynch AM, Morton CC . FH (fumarate hydratase).. Atlas Genet Cytogenet Oncol Haematol. July 2006 .
    URL : http://AtlasGeneticsOncology.org/Genes/FHID40573ch1q42.html

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    indexed on : Sat Feb 27 10:48:04 CET 2010
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