Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 869 word(s) 869 2020-12-15 08:08:28

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Chen, K. SDHD Gene. Encyclopedia. Available online: https://encyclopedia.pub/entry/5216 (accessed on 15 April 2024).
Chen K. SDHD Gene. Encyclopedia. Available at: https://encyclopedia.pub/entry/5216. Accessed April 15, 2024.
Chen, Karina. "SDHD Gene" Encyclopedia, https://encyclopedia.pub/entry/5216 (accessed April 15, 2024).
Chen, K. (2020, December 24). SDHD Gene. In Encyclopedia. https://encyclopedia.pub/entry/5216
Chen, Karina. "SDHD Gene." Encyclopedia. Web. 24 December, 2020.
SDHD Gene
Edit

succinate dehydrogenase complex subunit D

genes

1. Normal Function

The SDHD 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 SDHD protein helps anchor the SDH enzyme in the mitochondrial membrane.

Within mitochondria, the SDH enzyme links two important 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 SDHD protein, to the oxidative phosphorylation pathway. In oxidative phosphorylation, the electrons 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 SDHD gene is a tumor suppressor, which means it prevents cells from growing and dividing in an uncontrolled way.

2. Health Conditions Related to Genetic Changes

2.1. Hereditary paraganglioma-pheochromocytoma

More than 100 mutations in the SDHD gene have been identified in people with hereditary paraganglioma-pheochromocytoma type 1. People with this condition have paragangliomas, pheochromocytomas, or both. These noncancerous (benign) tumors are associated with the nervous system. An inherited SDHD gene mutation predisposes an individual to the condition. An additional mutation that deletes the normal copy of the gene is needed to cause hereditary paraganglioma-pheochromocytoma type 1. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.

Most of the inherited SDHD gene mutations change single protein building blocks (amino acids) in the SDHD 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.

2.2. Nonsyndromic paraganglioma

Mutations in the SDHD gene are found in some cases of nonsyndromic paraganglioma or pheochromocytoma, which are non-hereditary forms of the condition. Most of these mutations change single amino acids in the SDHD protein. As in hereditary paraganglioma-pheochromocytoma type 1, these mutations are expected to decrease SDH enzyme activity, which stabilizes the HIF protein, causing it to build up in cells. Excess HIF protein abnormally stimulates cell division and the formation of blood vessels, which can lead to tumor formation.

2.3. Cowden syndrome

At least five variants in the SDHD gene have been identified in people with Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by multiple tumor-like growths called hamartomas and an increased risk of developing certain cancers. When Cowden syndrome and Cowden-like syndrome are caused by SDHD gene mutations, the conditions are associated with a particularly high risk of developing breast and thyroid cancers.

The SDHD gene variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the SDHD protein, which likely alters the function of the SDH enzyme. Studies suggest that the defective enzyme could allow cells to grow and divide unchecked, leading to the formation of hamartomas and cancerous tumors. However, researchers are uncertain whether the identified SDHD gene variants are directly associated with Cowden syndrome and Cowden-like syndrome. Some of the variants described above have rarely been found in people without the features of these conditions.

2.4. Other cancers

Mutations in the SDHD gene have been found in a small number of people with Carney-Stratakis syndrome. People with this condition have a type of cancer of the gastrointestinal tract called gastrointestinal stromal tumor (GIST) and a noncancerous tumor associated with the nervous system called paraganglioma or pheochromocytoma (a type of paraganglioma). An inherited SDHD gene mutation predisposes an individual to cancer formation. An additional mutation that deletes the normal copy of the gene is needed to cause Carney-Stratakis syndrome. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.

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

3. Other Names for This Gene

  • CBT1
  • CII-4
  • cybS
  • DHSD_HUMAN
  • PGL
  • PGL1
  • QPs3
  • SDH4
  • succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial
  • succinate dehydrogenase complex subunit D, integral membrane protein
  • succinate dehydrogenase complex, subunit D, integral membrane protein
  • succinate dehydrogenase ubiquinone cytochrome B small subunit
  • succinate-ubiquinone oxidoreductase cytochrome b small subunit
  • succinate-ubiquinone reductase membrane anchor subunit

References

  1. Ayala-Ramirez M, Callender GG, Kupferman ME, Rich TA, Chuang HH, Trent J,Perrier ND, Goodarzi M, Jimenez C. Paraganglioma syndrome type 1 in a patientwith Carney-Stratakis syndrome. Nat Rev Endocrinol. 2010 Feb;6(2):110-5. doi:10.1038/nrendo.2009.250.
  2. Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P,Gaillard D, Chabrier G, Chabolle F, Coupier I, Thieblot P, Lecomte P, BertheratJ, Wion-Barbot N, Murat A, Venisse A, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP; PGL.NET network. The succinate dehydrogenase genetic testing in a largeprospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009Aug;94(8):2817-27. doi: 10.1210/jc.2008-2504.
  3. Douwes Dekker PB, Hogendoorn PC, Kuipers-Dijkshoorn N, Prins FA, van DuinenSG, Taschner PE, van der Mey AG, Cornelisse CJ. SDHD mutations in head and neckparagangliomas result in destabilization of complex II in the mitochondrialrespiratory chain with loss of enzymatic activity and abnormal mitochondrialmorphology. J Pathol. 2003 Nov;201(3):480-6.
  4. Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, RötigA, Jeunemaitre X. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratorychain and activates the hypoxia pathway. Am J Hum Genet. 2001 Dec;69(6):1186-97.
  5. Gimm O, Armanios M, Dziema H, Neumann HP, Eng C. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilialpheochromocytoma. Cancer Res. 2000 Dec 15;60(24):6822-5.
  6. Müller U. Pathological mechanisms and parent-of-origin effects in hereditaryparaganglioma/pheochromocytoma (PGL/PCC). Neurogenetics. 2011 Aug;12(3):175-81.doi: 10.1007/s10048-011-0280-y.
  7. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J,Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T,Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M,Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peçzkowska M, Szmigielski C,Eng C; Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. Germ-line mutationsin nonsyndromic pheochromocytoma. N Engl J Med. 2002 May 9;346(19):1459-66.
  8. Ni Y, He X, Chen J, Moline J, Mester J, Orloff MS, Ringel MD, Eng C. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-likesyndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet. 2012 Jan15;21(2):300-10. doi: 10.1093/hmg/ddr459.
  9. Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS,Waite KA, Eng C. Germline mutations and variants in the succinate dehydrogenasegenes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008 Aug;83(2):261-8. doi: 10.1016/j.ajhg.2008.07.011.
  10. Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, BoikosSA, 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 andmolecular genetics of patients with the Carney-Stratakis syndrome and germlinemutations of the genes coding for the succinate dehydrogenase subunits SDHB,SDHC, and SDHD. Eur J Hum Genet. 2008 Jan;16(1):79-88.
  11. Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrinetumours: 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.
  12. 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, TomlinsonIP. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha intumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005 Aug 1;14(15):2231-9.
  13. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, PanY, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction tooncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005Jan;7(1):77-85.
More
Information
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 360
Entry Collection: MedlinePlus
Revision: 1 time (View History)
Update Date: 24 Dec 2020
1000/1000