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Genetics Home Reference: your guide to understanding genetic conditions
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FH

Reviewed April 2008

What is the official name of the FH gene?

The official name of this gene is “fumarate hydratase.”

FH is the gene's official symbol. The FH gene is also known by other names, listed below.

What is the normal function of the FH gene?

The FH gene provides instructions for making an enzyme called fumarase (also known as fumarate hydratase). Fumarase participates in an important series of reactions known as the citric acid cycle or Krebs cycle, which allows cells to use oxygen and generate energy. Specifically, fumarase helps convert a molecule called fumarate to a molecule called malate.

How are changes in the FH gene related to health conditions?

fumarase deficiency - caused by mutations in the FH gene

Approximately 17 FH gene mutations that cause fumarase deficiency have been reported. Fumarase deficiency occurs in individuals who inherit two mutated copies of the FH gene in each cell. Most of these mutations replace one protein building block (amino acid) with another amino acid in the fumarase enzyme. These changes disrupt the ability of the enzyme to help convert fumarate to malate, interfering with the function of this reaction in the citric acid cycle. Impairment of the process that generates energy for cells is particularly harmful to cells in the developing brain, and this impairment results in the signs and symptoms of fumarase deficiency.

hereditary leiomyomatosis and renal cell cancer - caused by mutations in the FH gene

Approximately 50 mutations in the FH gene that cause hereditary leiomyomatosis and renal cell cancer (HLRCC) have been reported. Most of these mutations replace one amino acid with another amino acid in the fumarase enzyme.

People with HLRCC are born with one mutated copy of the FH gene in each cell. The second copy of the FH gene in certain cells may also acquire mutations as a result of environmental factors such as ultraviolet radiation from the sun or a mistake that occurs as DNA copies itself during cell division. These changes are called somatic mutations and are not inherited.

FH gene mutations may interfere with the enzyme's role in the citric acid cycle, resulting in a buildup of fumarate. Researchers believe that the excess fumarate may interfere with the regulation of oxygen levels in the cell. Chronic oxygen deficiency (hypoxia) in cells with two mutated copies of the FH gene may encourage tumor formation and result in the tendency to develop leiomyomas and renal cell cancer.

Where is the FH gene located?

Cytogenetic Location: 1q42.1

Molecular Location on chromosome 1: base pairs 241,497,556 to 241,519,784

The FH gene is located on the long (q) arm of chromosome 1 at position 42.1.

The FH gene is located on the long (q) arm of chromosome 1 at position 42.1.

More precisely, the FH gene is located from base pair 241,497,556 to base pair 241,519,784 on chromosome 1.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about FH?

You and your healthcare professional may find the following resources about FH helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the FH gene or gene products?

  • fumarase
  • fumarase hydratase
  • FUMH_HUMAN
  • HLRCC
  • LRCC
  • MCL
  • MCUL1

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding FH?

amino acid ; cancer ; cell ; cell division ; chronic ; deficiency ; DNA ; enzyme ; gene ; hereditary ; hypoxia ; inherit ; inherited ; molecule ; oxygen ; oxygen deficiency ; protein ; radiation ; renal ; tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • 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. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet. 2003 Jun 1;12(11):1241-52. (http://www.ncbi.nlm.nih.gov/pubmed/12761039?dopt=Abstract)
  • Badeloe S, van Geel M, van Steensel MA, Bastida J, Ferrando J, Steijlen PM, Frank J, Poblete-Gutiérrez P. Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature. Exp Dermatol. 2006 Sep;15(9):735-41. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16881969?dopt=Abstract)
  • Deschauer M, Gizatullina Z, Schulze A, Pritsch M, Knöppel C, Knape M, Zierz S, Gellerich FN. Molecular and biochemical investigations in fumarase deficiency. Mol Genet Metab. 2006 Jun;88(2):146-52. Epub 2006 Feb 28. (http://www.ncbi.nlm.nih.gov/pubmed/16510303?dopt=Abstract)
  • OMIM: FUMARATE HYDRATASE (http://omim.org/entry/136850)
  • King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006 Aug 7;25(34):4675-82. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16892081?dopt=Abstract)
  • Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK, Salovaara R, Herva R, Koivisto PA, Vierimaa O, Aittomäki K, Pukkala E, Launonen V, Aaltonen LA. Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet. 2006 Jun;43(6):523-6. Epub 2005 Sep 9. (http://www.ncbi.nlm.nih.gov/pubmed/16155190?dopt=Abstract)
  • Lorenzato A, Olivero M, Perro M, Brière JJ, Rustin P, Di Renzo MF. A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein. Int J Cancer. 2008 Feb 15;122(4):947-51. (http://www.ncbi.nlm.nih.gov/pubmed/17960613?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/2271)
  • Raimundo N, Ahtinen J, Fumić K, Barić I, Remes AM, Renkonen R, Lapatto R, Suomalainen A. Differential metabolic consequences of fumarate hydratase and respiratory chain defects. Biochim Biophys Acta. 2008 May;1782(5):287-94. doi: 10.1016/j.bbadis.2008.01.008. Epub 2008 Feb 14. (http://www.ncbi.nlm.nih.gov/pubmed/18313410?dopt=Abstract)
  • Ratcliffe PJ. Fumarate hydratase deficiency and cancer: activation of hypoxia signaling? Cancer Cell. 2007 Apr;11(4):303-5. (http://www.ncbi.nlm.nih.gov/pubmed/17418405?dopt=Abstract)
  • Sudarshan S, Linehan WM, Neckers L. HIF and fumarate hydratase in renal cancer. Br J Cancer. 2007 Feb 12;96(3):403-7. Epub 2007 Jan 9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17211469?dopt=Abstract)
  • Sudarshan S, Pinto PA, Neckers L, Linehan WM. Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer. Nat Clin Pract Urol. 2007 Feb;4(2):104-10. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17287871?dopt=Abstract)
  • Zeman J, Krijt J, Stratilová L, Hansíková H, Wenchich L, Kmoch S, Chrastina P, Houstek J. Abnormalities in succinylpurines in fumarase deficiency: possible role in pathogenesis of CNS impairment. J Inherit Metab Dis. 2000 Jun;23(4):371-4. (http://www.ncbi.nlm.nih.gov/pubmed/10896297?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: April 2008
Published: October 20, 2014