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Taking over the Atlas
Dear Colleagues,
The Atlas, once more, is in great danger, and I will have to proceed to a collective economic lay-off of all the team involved in the Atlas before the begining of April 2015 (a foundation having suddenly withdrawn its commitment to support the Atlas). I ask you herein if any Scientific Society (a Society of Cytogenetics, of Clinical Genetics, of Hematology, or a Cancer Society, or any other...), any University and/or Hospital, any Charity, or any database would be interested in taking over the Atlas, in whole or in part. If taking charge of the whole lot is too big, a consortium of various actors could be the solution (I am myself trying to find partners). Could you please spread the information, contact the relevant authorities, and find partners.
Survival of the Atlas will be critically dependant upon your ability to find solutions (and urgently!).
Kind regards.
Jean-Loup Huret
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FH (fumarate hydratase).


HGNC (Hugo) FH
LocusID (NCBI) 2271
Location 1q43
Location_base_pair Starts at 241660857 and ends at 241683085 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Telomeric to RGS7, centromeric to KMO


  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: 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.


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 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.

    Other Solid tumors implicated (Data extracted from papers in the Atlas)

    Solid Tumors AmeloblastomID5945 MedulloblastomaID5065

    External links

    HGNC (Hugo)FH   3700
    Entrez_Gene (NCBI)FH  2271  fumarate hydratase
    GeneCards (Weizmann)FH
    Ensembl hg19 (Hinxton)ENSG00000091483 [Gene_View]  chr1:241660857-241683085 [Contig_View]  FH [Vega]
    Ensembl hg38 (Hinxton)ENSG00000091483 [Gene_View]  chr1:241660857-241683085 [Contig_View]  FH [Vega]
    ICGC DataPortalENSG00000091483
    AceView (NCBI)FH
    Genatlas (Paris)FH
    SOURCE (Princeton)FH
    Genomic and cartography
    GoldenPath hg19 (UCSC)FH  -     chr1:241660857-241683085 -  1q42.1   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)FH  -     1q42.1   [Description]    (hg38-Dec_2013)
    EnsemblFH - 1q42.1 [CytoView hg19]  FH - 1q42.1 [CytoView hg38]
    Mapping of homologs : NCBIFH [Mapview hg19]  FH [Mapview hg38]
    OMIM136850   606812   
    Gene and transcription
    Genbank (Entrez)AA669797 AK312415 AW611924 BC003108 BC017444
    RefSeq transcript (Entrez)NM_000143
    RefSeq genomic (Entrez)NC_000001 NC_018912 NG_012338 NT_167186 NW_004929294
    Consensus coding sequences : CCDS (NCBI)FH
    Cluster EST : UnigeneHs.592490 [ NCBI ]
    CGAP (NCI)Hs.592490
    Alternative Splicing : Fast-db (Paris)GSHG0003081
    Alternative Splicing GalleryENSG00000091483
    Gene ExpressionFH [ NCBI-GEO ]     FH [ SEEK ]   FH [ MEM ]
    SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP07954 (Uniprot)
    NextProtP07954  [Medical]
    With graphics : InterProP07954
    Splice isoforms : SwissVarP07954 (Swissvar)
    Catalytic activity : Enzyme4.2.1.2 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   
    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   
    Related proteins : CluSTrP07954
    Domain families : Pfam (Sanger)FumaraseC_C (PF10415)    Lyase_1 (PF00206)   
    Domain families : Pfam (NCBI)pfam10415    pfam00206   
    DMDM Disease mutations2271
    Blocks (Seattle)P07954
    PDB (SRS)3.00E+04   
    PDB (PDBSum)3.00E+04   
    PDB (IMB)3.00E+04   
    PDB (RSDB)3.00E+04   
    Human Protein AtlasENSG00000091483
    Peptide AtlasP07954
    IPIIPI00296053   IPI00759715   
    Protein Interaction databases
    DIP (DOE-UCLA)P07954
    IntAct (EBI)P07954
    Ontologies - Pathways
    Ontology : AmiGOfumarate hydratase activity  protein binding  cytoplasm  mitochondrion  mitochondrial matrix  tricarboxylic acid cycle  tricarboxylic acid cycle  fumarate metabolic process  cellular metabolic process  small molecule metabolic process  tricarboxylic acid cycle enzyme complex  homeostasis of number of cells within a tissue  extracellular exosome  
    Ontology : EGO-EBIfumarate hydratase activity  protein binding  cytoplasm  mitochondrion  mitochondrial matrix  tricarboxylic acid cycle  tricarboxylic acid cycle  fumarate metabolic process  cellular metabolic process  small molecule metabolic process  tricarboxylic acid cycle enzyme complex  homeostasis of number of cells within a tissue  extracellular exosome  
    Pathways : KEGGCitrate cycle (TCA cycle)    Pathways in cancer    Renal cell carcinoma   
    REACTOMEP07954 [protein]
    REACTOME PathwaysREACT_111217 Metabolism [pathway]
    Protein Interaction DatabaseFH
    DoCM (Curated mutations)FH
    Wikipedia pathwaysFH
    Gene fusion - rearrangements
    Polymorphisms : SNP, variants
    NCBI Variation ViewerFH [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)FH
    Exome Variant ServerFH
    SNP (GeneSNP Utah)FH
    SNP : HGBaseFH
    Genetic variants : HAPMAPFH
    Genomic Variants (DGV)FH [DGVbeta]
    ICGC Data PortalENSG00000091483 
    Cancer Gene: CensusFH 
    Somatic Mutations in Cancer : COSMICFH 
    CONAN: Copy Number AnalysisFH 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    LOVD (Leiden Open Variation Database)Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)
    LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
    LOVD (Leiden Open Variation Database)TCA Cycle Gene Mutation Database
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
    DECIPHER (Syndromes)1:241660857-241683085
    Mutations and Diseases : HGMDFH
    OMIM136850    606812   
    NextProtP07954 [Medical]
    Disease Genetic AssociationFH
    Huge Navigator FH [HugePedia]  FH [HugeCancerGEM]
    snp3D : Map Gene to Disease2271
    DGIdb (Drug Gene Interaction db)FH
    General knowledge
    Homologs : HomoloGeneFH
    Homology/Alignments : Family Browser (UCSC)FH
    Phylogenetic Trees/Animal Genes : TreeFamFH
    Chemical/Protein Interactions : CTD2271
    Chemical/Pharm GKB GenePA28139
    Clinical trialFH
    Cancer Resource (Charite)ENSG00000091483
    Other databases
    PubMed86 Pubmed reference(s) in Entrez


    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, Sjˆberg 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, Sjˆberg 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
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    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


    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 ]
    URL :

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    indexed on : Sat Mar 28 12:17:00 CET 2015

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