SDHB Gene

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1		Karina Chen	+ 900 word(s)	900	2020-12-15 08:08:25

This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/sdhb

succinate dehydrogenase complex iron sulfur subunit B

genes

1. Normal Function

The SDHB 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.

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 SDHB protein provides an attachment site for electrons as they are transferred 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 SDHB 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 150 mutations in the SDHB gene have been identified in people with hereditary paraganglioma-pheochromocytoma type 4. People with this condition have paragangliomas, pheochromocytomas, or both. Paragangliomas and pheochromocytomas (a type of paraganglioma) are noncancerous tumors associated with the nervous system. An inherited SDHB gene mutation predisposes an individual to the condition, and a somatic mutation that deletes the normal copy of the gene is needed to cause hereditary paraganglioma-pheochromocytoma type 4.

Most of the inherited SDHB gene mutations change single protein building blocks (amino acids) in the SDHB 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 SDHB 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 SDHB protein. As in hereditary paraganglioma-pheochromocytoma type 4, 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 10 variants in the SDHB 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, particularly breast cancer, thyroid cancer, and cancer of the uterine lining (endometrial cancer).

The SDHB gene variants associated with Cowden syndrome and Cowden-like syndrome change single amino acids in the SDHB 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 SDHB 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.

2.3. Other cancers

The SDHB gene is involved in several cancers. Mutations in the SDHB gene have been found in a small number of people with gastrointestinal stromal tumors (GISTs), which are a type of tumor that occurs in the gastrointestinal tract, or renal cell carcinoma, which is a type of kidney cancer. SDHB gene mutations have been identified in people a condition called Carney-Stratakis syndrome in which affected individuals have both paraganglioma and GIST or in people with both renal cell cancer and paraganglioma. An inherited SDHB 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, renal cell cancer, 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 SDHB gene lead to a reduction in the amount of SDHB protein in the cell and loss of SDH enzyme activity. Furthermore, even without a SDHB gene mutation, a subset of gastrointestinal stromal tumors have reduced SDHB protein and loss of SDH enzyme activity. Lack of SDH enzyme activity results in abnormal hypoxia signaling and formation of tumors.

3. Other Names for This Gene

DHSB_HUMAN
FLJ92337
IP
iron-sulfur subunit of complex II
PGL4
SDH
SDH1
SDH2
SDHIP
succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial
succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial precursor
succinate dehydrogenase complex subunit B, iron sulfur (Ip)
succinate dehydrogenase complex, subunit B, iron sulfur (Ip)

References

Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Sköldberg F,Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenasesubunit SDHB cause susceptibility to familial pheochromocytoma and to familialparaganglioma. Am J Hum Genet. 2001 Jul;69(1):49-54.in: Am J Hum Genet 2002 Feb;70(2):565.
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.
Gill AJ, Pachter NS, Clarkson A, Tucker KM, Winship IM, Benn DE, Robinson BG, Clifton-Bligh RJ. Renal tumors and hereditary pheochromocytoma-paragangliomasyndrome type 4. N Engl J Med. 2011 Mar 3;364(9):885-6. doi:10.1056/NEJMc1012357.
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 GISTClinic, O'Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR,Fletcher JA, Helman L, Stratakis CA. Defects in succinate dehydrogenase ingastrointestinal 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.
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.
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.
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.
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.
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.
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.
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.
Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER.Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst.2008 Sep 3;100(17):1260-2. doi: 10.1093/jnci/djn254.
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.
Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas andgastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics andclinical implications. J Intern Med. 2009 Jul;266(1):43-52. doi:10.1111/j.1365-2796.2009.02110.x. Review.
Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peçzkowska M, Morrison CD,Lehtonen R, Januszewicz A, Järvinen H, Juhola M, Mecklin JP, Pukkala E, Herva R, Kiuru M, Nupponen NN, Aaltonen LA, Neumann HP, Eng C. Early-onset renal cellcarcinoma as a novel extraparaganglial component of SDHB-associated heritableparaganglioma. Am J Hum Genet. 2004 Jan;74(1):153-9.

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Subjects: Genetics & Heredity

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Karina Chen

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Update Date: 24 Dec 2020

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