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SDHC gene

succinate dehydrogenase complex subunit C
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Normal Function

The SDHC gene provides instructions for making one of four subunits of the succinate dehydrogenase (SDH) enzyme. The SDH enzyme plays a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells can use. The SDHC protein helps anchor the SDH enzyme in the mitochondrial membrane.

Within mitochondria, the SDH enzyme links two important cellular pathways in energy conversion: the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Negatively charged particles called electrons are released during this reaction. The electrons are transferred through the SDH subunits, including the SDHC protein, to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons help create an electrical charge that provides energy for the production of adenosine triphosphate (ATP), the cell's main energy source.

Succinate, the compound on which the SDH enzyme acts, is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia). In particular, succinate stabilizes a protein called hypoxia-inducible factor (HIF) by preventing a reaction that would allow HIF to be broken down. HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment.

The SDHC gene is a tumor suppressor, which means it prevents cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Hereditary paraganglioma-pheochromocytoma

More than 30 mutations in the SDHC gene have been found to increase the risk of hereditary paraganglioma-pheochromocytoma type 3. People with this condition have paragangliomas, pheochromocytomas, or both. An inherited SDHC gene mutation predisposes an individual to the condition, and a somatic mutation that deletes the normal copy of the SDHC gene is needed to cause hereditary paraganglioma-pheochromocytoma type 3.

Most of the inherited SDHC gene mutations change single protein building blocks (amino acids) in the SDHC protein sequence or result in a shortened protein. As a result, there is little or no SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. The excess succinate abnormally stabilizes HIF, which also builds up in cells. Excess HIF stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development of tumors in people with hereditary paraganglioma-pheochromocytoma.

More About This Health Condition

Gastrointestinal stromal tumor

MedlinePlus Genetics provides information about Gastrointestinal stromal tumor

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Cancers

Mutations in the SDHC gene have been found in a small number of people with gastrointestinal stromal tumor (GIST), which is a cancer of the gastrointestinal tract. SDHC gene mutations have also been identified in people with noncancerous tumors associated with the nervous system called paragangliomas or pheochromocytomas (a type of paraganglioma). Some affected individuals have both paraganglioma and GIST, which is called Carney-Stratakis syndrome. An inherited SDHC gene mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to cause these forms of GIST and paraganglioma. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.

Mutations of the SDHC gene lead to loss of SDH enzyme activity, which results in abnormal hypoxia signaling and formation of tumors.

Other Names for This Gene

  • C560_HUMAN
  • CYB560
  • CYBL
  • cytochrome B large subunit of complex II
  • integral membrane protein CII-3
  • integral membrane protein CII-3b
  • PGL3
  • QPs-1
  • QPS1
  • SDH3
  • succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa
  • succinate dehydrogenase cytochrome b560 subunit, mitochondrial
  • succinate-ubiquinone oxidoreducatase cytochrome B large subunit
  • succinate-ubiquinone oxidoreductase cytochrome B large subunit

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Research Resources

References

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  • Janeway KA, Kim SY, Lodish M, Nosé V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL; NIH Pediatric and Wild-Type GIST Clinic, O'Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):314-8. doi: 10.1073/pnas.1009199108. Epub 2010 Dec 20. Citation on PubMed or Free article on PubMed Central
  • Müller U. Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). Neurogenetics. 2011 Aug;12(3):175-81. doi: 10.1007/s10048-011-0280-y. Epub 2011 Mar 9. Review. Citation on PubMed
  • Niemann S, Müller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000 Nov;26(3):268-70. Citation on PubMed
  • Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008 Jan;16(1):79-88. Epub 2007 Aug 1. Citation on PubMed
  • Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med. 2009 Jul;266(1):19-42. doi: 10.1111/j.1365-2796.2009.02111.x. Review. Citation on PubMed or Free article on PubMed Central
  • Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005 Aug 1;14(15):2231-9. Epub 2005 Jun 29. Citation on PubMed
  • Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005 Jan;7(1):77-85. Citation on PubMed
  • Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 2009 Jul;266(1):43-52. doi: 10.1111/j.1365-2796.2009.02110.x. Review. Citation on PubMed or Free article on PubMed Central
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