View source for SDHD

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{{short description|Protein-coding gene in the species Homo sapiens}}
{{Use dmy dates|date=April 2017}}
{{Infobox gene}}

'''Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial''' (CybS), also known as '''succinate dehydrogenase complex subunit D''' (SDHD), is a [[protein]] that in humans is encoded by the ''SDHD'' [[gene]]. Names previously used for SDHD were '''PGL''' and '''PGL1'''. Succinate dehydrogenase is an important [[enzyme]] in both the [[citric acid cycle]] and the [[electron transport chain]].<ref name="entrez">{{cite web | title = Entrez Gene: succinate dehydrogenase complex| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6392}}</ref><ref name="pmid1301144">{{cite journal | vauthors = Heutink P, van der Mey AG, Sandkuijl LA, van Gils AP, Bardoel A, Breedveld GJ, van Vliet M, van Ommen GJ, Cornelisse CJ, Oostra BA | title = A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter | journal = Human Molecular Genetics | volume = 1 | issue = 1 | pages = 7–10 | date = April 1992 | pmid = 1301144 | doi = 10.1093/hmg/1.1.7 }}</ref><ref name="pmid9533030">{{cite journal | vauthors = Hirawake H, Taniwaki M, Tamura A, Kojima S, Kita K | title = Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23 | journal = Cytogenetics and Cell Genetics | volume = 79 | issue = 1–2 | pages = 132–8 | year = 1997 | pmid = 9533030 | doi = 10.1159/000134700 }}</ref> Hereditary PGL-PCC syndrome is caused by a parental imprint of the SDHD gene. Screening can begin by 6 years of age. 

== Structure ==
The SDHD [[gene]] is  located on [[chromosome 11]] at [[Locus (genetics)|locus]] 11q23 and it spans 8,978 [[base pairs]]. There are [[pseudogenes]] for this gene on [[chromosome 1|chromosomes 1]], [[chromosome 2|2]], [[chromosome 3|3]], [[chromosome 7|7]], and [[chromosome 18|18]].<ref name = "entrez" />  The SDHD gene produces a 17 kDa protein composed of 159 [[amino acids]].<ref name=COPaKB>{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = https://amino.heartproteome.org/web/protein/O14521 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = SDHD - Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial }}</ref>

The SDHD protein is one of the two integral transmembrane subunits anchoring the four-subunit [[succinate dehydrogenase]] (Complex II) [[protein complex]] to the matrix side of the [[mitochondrial inner membrane]]. The other [[transmembrane]] subunit is [[Succinate dehydrogenase complex subunit C|SDHC]]. The [[SDHC (gene)|SDHC]]/SDHD [[protein dimer|dimer]] is connected to the [[SDHB]] electron transport subunit which, in turn, is connected to the [[SDHA]] subunit.<ref>{{cite journal | vauthors = Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z | title = Crystal structure of mitochondrial respiratory membrane protein complex II | journal = Cell | volume = 121 | issue = 7 | pages = 1043–57 | date = July 2005 | pmid = 15989954 | doi = 10.1016/j.cell.2005.05.025 | s2cid = 16697879 | doi-access = free }}</ref>

== Function ==
SDHD forms part of the transmembrane [[protein dimer]] with [[SDHC (gene)|SDHC]] that anchors [[Complex II]] to the inner mitochondrial membrane. The SDHC/SDHD dimer provides binding sites for [[ubiquinone]] and water during electron transport at Complex II. Initially, [[SDHA]] oxidizes [[succinate]] via [[deprotonation]] at the [[flavin adenine dinucleotide|FAD]] binding site, leaving [[fumarate]], loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in the [[SDHB]] subunit until they reach the [3Fe-4S] [[iron–sulfur cluster]]. The electrons are then transferred to an awaiting [[ubiquinone]] molecule at the active site in the SDHC/SDHD dimer. The O1 [[carbonyl]] oxygen of ubiquinone is oriented at the active site (image 4) by [[hydrogen bond]] interactions with Tyr83 of SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of subunit C. Following the first single electron reduction step, a [[semiquinone]] radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to [[ubiquinol]].<ref>{{cite journal | vauthors = Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, Byrne B, Cecchini G, Iwata S | title = Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction | journal = The Journal of Biological Chemistry | volume = 281 | issue = 11 | pages = 7309–16 | date = March 2006 | pmid = 16407191 | doi = 10.1074/jbc.m508173200 | doi-access = free }}</ref>

==Clinical significance==
Mutations in the ''SDHD'' [[gene]] can cause familial [[paraganglioma]].<ref name = "entrez" /> [[Germline mutation]]s in ''SDHD'' were first linked to hereditary paraganglioma in 2000.<ref name="Baysal">{{cite journal | vauthors = Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW, Cornelisse CJ, Devilee P, Devlin B | title = Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma | journal = Science | volume = 287 | issue = 5454 | pages = 848–51 | date = February 2000 | pmid = 10657297 | doi = 10.1126/science.287.5454.848 | bibcode = 2000Sci...287..848B }}</ref>  Since then, it has been shown that mutations in ''SDHB'' and to a lesser degree ''SDHC'' can cause paranglioma as well as familial [[pheochromocytoma]]. Notably, the tumor spectrum is different for the different mutations. ''SDHB'' mutations often lead to metastatic disease that is extra-adrenal, while ''SDHD'' mutation related tumors are more typically benign, originating in the head and neck.<ref name = GHR-HPP>{{cite web|title=Hereditary paraganglioma-pheochromocytoma|url=http://ghr.nlm.nih.gov/condition/hereditary-paraganglioma-pheochromocytoma|website=Genetics Home Reference|publisher=U.S. National Library of Medicine|access-date=26 March 2015}}</ref>

The exact mechanism for tumorigenesis is not determined, but it is suspected that malfunction of the SDH complex can cause a [[Hypoxia (medical)|hypoxic]] response in the cell that leads to tumor formation. Mutations in the [[SDHB]], [[SDHC (gene)|SDHC]], SDHD, and [[SDHAF2]] genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.<ref name = GHR-HPP /> People living at higher altitudes (for example, the Andes mountains) are known to have an increased rate of benign paraganglioma, with the rate of disease increasing with the altitude of the population.

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 cancer|breast]] and [[thyroid cancer|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.<ref name = GHR-SDHD>{{cite web|title=SDHD|url=http://ghr.nlm.nih.gov/gene/SDHD|website=Genetics Home Reference|publisher=U.S. National Library of Medicine|access-date=26 March 2015}}</ref>

Mutations in the ''SDHD'' gene have been found in a small number of people with [[Carney–Stratakis syndrome]], a hereditary form of a cancer of the gastrointestinal tract called [[gastrointestinal stromal tumor]] (GIST). Those with Carney-Stratakis syndrome present with a noncancerous tumor associated with the nervous system called a [[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.<ref name="GHR-SDHD"/>

Mitochondrial complex II deficiency (MT-C2D), a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, has also been associated with mutations in the ''SDHD'' gene. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia, dystonia, progressive leukoencephalopathy, muscle weakness, exercise intolerance, cardiomyopathy. Some patients manifest [[Leigh syndrome]] or [[Kearns–Sayre syndrome]].<ref>{{cite web |title=SDHD Gene |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=SDHD |website=www.genecards.org |publisher=GeneCards Human Gene Database |access-date=30 July 2018}}</ref><ref>{{cite journal | vauthors = Jackson CB, Nuoffer JM, Hahn D, Prokisch H, Haberberger B, Gautschi M, Häberli A, Gallati S, Schaller A | title = Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency | journal = Journal of Medical Genetics | volume = 51 | issue = 3 | pages = 170–5 | date = March 2014 | pmid = 24367056 | doi = 10.1136/jmedgenet-2013-101932 | s2cid = 25057245 }}</ref><ref>{{cite journal | vauthors = Alston CL, Ceccatelli Berti C, Blakely EL, Oláhová M, He L, McMahon CJ, Olpin SE, Hargreaves IP, Nolli C, McFarland R, Goffrini P, O'Sullivan MJ, Taylor RW | title = A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency | journal = Human Genetics | volume = 134 | issue = 8 | pages = 869–79 | date = August 2015 | pmid = 26008905 | pmc = 4495259 | doi = 10.1007/s00439-015-1568-z }}</ref>

== Interactive pathway map ==
{{TCACycle_WP78|highlight=SDHD}}

== References ==
{{Reflist|33em}}

{{NLM content}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Bayley JP, Weiss MM, Grimbergen A, van Brussel BT, Hes FJ, Jansen JC, Verhoef S, Devilee P, Corssmit EP, Vriends AH | title = Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients | journal = Endocrine-Related Cancer | volume = 16 | issue = 3 | pages = 929–37 | date = September 2009 | pmid = 19546167 | doi = 10.1677/ERC-09-0084 | doi-access = free }}
* {{cite journal | vauthors = Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF, de Krijger RR, Gimenez-Roqueplo AP, Dinjens WN | title = Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 95 | issue = 3 | pages = 1274–8 | date = March 2010 | pmid = 19915015 | doi = 10.1210/jc.2009-2170 | doi-access = free }}
* {{cite journal | vauthors = Milosevic D, Lundquist P, Cradic K, Vidal-Folch N, Huynh T, Pacak K, Grebe SK | title = Development and validation of a comprehensive mutation and deletion detection assay for SDHB, SDHC, and SDHD | journal = Clinical Biochemistry | volume = 43 | issue = 7–8 | pages = 700–4 | date = May 2010 | pmid = 20153743 | pmc = 3419008 | doi = 10.1016/j.clinbiochem.2010.01.016 }}
* {{cite journal | vauthors = Janecke AR, Willett-Brozick JE, Karas C, Hasipek M, Loeffler-Ragg J, Baysal BE | title = Identification of a 4.9-kilo base-pair Alu-mediated founder SDHD deletion in two extended paraganglioma families from Austria | journal = Journal of Human Genetics | volume = 55 | issue = 3 | pages = 182–5 | date = March 2010 | pmid = 20111059 | doi = 10.1038/jhg.2009.142 | doi-access = free }}
* {{cite journal | vauthors = Cascón A, López-Jiménez E, Landa I, Leskelä S, Leandro-García LJ, Maliszewska A, Letón R, de la Vega L, García-Barcina MJ, Sanabria C, Alvarez-Escolá C, Rodríguez-Antona C, Robledo M | title = Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma | journal = Hormone and Metabolic Research | volume = 41 | issue = 9 | pages = 672–5 | date = September 2009 | pmid = 19343621 | doi = 10.1055/s-0029-1202814 | s2cid = 24979281 }}
* {{cite journal | vauthors = Waldmann J, Langer P, Habbe N, Fendrich V, Ramaswamy A, Rothmund M, Bartsch DK, Slater EP | title = Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas | journal = Endocrine | volume = 35 | issue = 3 | pages = 347–55 | date = June 2009 | pmid = 19399650 | doi = 10.1007/s12020-009-9178-y | s2cid = 8986765 }}
* {{cite journal | vauthors = Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, Cole TR, Armstrong R, Kumar VK, Morrison PJ, Atkinson AB, Douglas F, Ball SG, Cook J, Srirangalingam U, Killick P, Kirby G, Aylwin S, Woodward ER, Evans DG, Hodgson SV, Murday V, Chew SL, Connell JM, Blundell TL, Macdonald F, Maher ER | title = Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD | journal = Human Mutation | volume = 31 | issue = 1 | pages = 41–51 | date = January 2010 | pmid = 19802898 | doi = 10.1002/humu.21136 | s2cid = 22888808 | doi-access = free }}
* {{cite journal | vauthors = Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow GY, Richardson AL, Sidhu SB, Robinson BG, Clifton-Bligh RJ | title = Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes | journal = Human Pathology | volume = 41 | issue = 6 | pages = 805–14 | date = June 2010 | pmid = 20236688 | doi = 10.1016/j.humpath.2009.12.005 }}
* {{cite journal | vauthors = Martin TP, Irving RM, Maher ER | title = The genetics of paragangliomas: a review | journal = Clinical Otolaryngology | volume = 32 | issue = 1 | pages = 7–11 | date = February 2007 | pmid = 17298303 | doi = 10.1111/j.1365-2273.2007.01378.x | doi-access = free }}
* {{cite journal | vauthors = Eng C, Kiuru M, Fernandez MJ, Aaltonen LA | title = A role for mitochondrial enzymes in inherited neoplasia and beyond | journal = Nature Reviews. Cancer | volume = 3 | issue = 3 | pages = 193–202 | date = March 2003 | pmid = 12612654 | doi = 10.1038/nrc1013 | s2cid = 20549458 }}
* {{cite journal | vauthors = Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, Gaunt TR, Pallas J, Lovering R, Li K, Casas JP, Sofat R, Kumari M, Rodriguez S, Johnson T, Newhouse SJ, Dominiczak A, Samani NJ, Caulfield M, Sever P, Stanton A, Shields DC, Padmanabhan S, Melander O, Hastie C, Delles C, Ebrahim S, Marmot MG, Smith GD, Lawlor DA, Munroe PB, Day IN, Kivimaki M, Whittaker J, Humphries SE, Hingorani AD | title = Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip | journal = American Journal of Human Genetics | volume = 85 | issue = 5 | pages = 628–42 | date = November 2009 | pmid = 19913121 | pmc = 2775832 | doi = 10.1016/j.ajhg.2009.10.014 }}
* {{cite journal | vauthors = Hermsen MA, Sevilla MA, Llorente JL, Weiss MM, Grimbergen A, Allonca E, Garcia-Inclán C, Balbín M, Suárez C | title = Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management | journal = Cellular Oncology | volume = 32 | issue = 4 | pages = 275–83 | date = January 2010 | pmid = 20208144 | pmc = 4619289 | doi = 10.3233/CLO-2009-0498 }}
* {{cite journal | vauthors = Hensen EF, Jansen JC, Siemers MD, Oosterwijk JC, Vriends AH, Corssmit EP, Bayley JP, van der Mey AG, Cornelisse CJ, Devilee P | title = The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family | journal = European Journal of Human Genetics | volume = 18 | issue = 1 | pages = 62–6 | date = January 2010 | pmid = 19584903 | pmc = 2987152 | doi = 10.1038/ejhg.2009.112 }}
* {{cite journal | vauthors = Brière JJ, Favier J, El Ghouzzi V, Djouadi F, Bénit P, Gimenez AP, Rustin P | title = Succinate dehydrogenase deficiency in human | journal = Cellular and Molecular Life Sciences | volume = 62 | issue = 19–20 | pages = 2317–24 | date = October 2005 | pmid = 16143825 | doi = 10.1007/s00018-005-5237-6 | s2cid = 23793565 | pmc = 11139140 }}
* {{cite journal | vauthors = Richalet JP, Gimenez-Roqueplo AP, Peyrard S, Vénisse A, Marelle L, Burnichon N, Bouzamondo A, Jeunemaitre X, Azizi M, Elghozi JL | title = A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia? | journal = Clinical Autonomic Research | volume = 19 | issue = 6 | pages = 335–42 | date = December 2009 | pmid = 19768395 | doi = 10.1007/s10286-009-0028-z | s2cid = 2265162 }}
* {{cite journal | vauthors = Sevilla MA, Hermsen MA, Weiss MM, Grimbergen A, Balbín M, Llorente JL, Rodrigo JP, Suárez C | title = Chromosomal changes in sporadic and familial head and neck paragangliomas | journal = Otolaryngology–Head and Neck Surgery | volume = 140 | issue = 5 | pages = 724–9 | date = May 2009 | pmid = 19393419 | doi = 10.1016/j.otohns.2009.01.004 | s2cid = 5393912 | hdl = 10651/35694 | hdl-access = free }}
* {{cite journal | vauthors = Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA, Goedert JJ, Kirk GD, Gomperts ED, Buchbinder SP, Troyer JL, O'Brien SJ | title = Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression | journal = PLOS ONE | volume = 5 | issue = 9 | pages = e12862 | date = September 2010 | pmid = 20877624 | pmc = 2943476 | doi = 10.1371/journal.pone.0012862 | bibcode = 2010PLoSO...512862H | doi-access = free }}
* {{cite journal | vauthors = Erlic Z, Rybicki L, Peczkowska M, Golcher H, Kann PH, Brauckhoff M, Müssig K, Muresan M, Schäffler A, Reisch N, Schott M, Fassnacht M, Opocher G, Klose S, Fottner C, Forrer F, Plöckinger U, Petersenn S, Zabolotny D, Kollukch O, Yaremchuk S, Januszewicz A, Walz MK, Eng C, Neumann HP | title = Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients | journal = Clinical Cancer Research | volume = 15 | issue = 20 | pages = 6378–85 | date = October 2009 | pmid = 19825962 | doi = 10.1158/1078-0432.CCR-09-1237 | s2cid = 6225809 | doi-access =  }}
* {{cite journal | vauthors = Krawczyk A, Hasse-Lazar K, Pawlaczek A, Szpak-Ulczok S, Krajewska J, Paliczka-Cieślak E, Jurecka-Lubieniecka B, Roskosz J, Chmielik E, Ziaja J, Cierpka L, Peczkowska M, Preibisz A, Januszewicz A, Otto M, Jarzab B | title = Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas | journal = Endokrynologia Polska | volume = 61 | issue = 1 | pages = 43–8 | year = 2010 | pmid = 20205103 }}
* {{cite journal | vauthors = Bailey SD, Xie C, Do R, Montpetit A, Diaz R, Mohan V, Keavney B, Yusuf S, Gerstein HC, Engert JC, Anand S | title = Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study | journal = Diabetes Care | volume = 33 | issue = 10 | pages = 2250–3 | date = October 2010 | pmid = 20628086 | pmc = 2945168 | doi = 10.2337/dc10-0452 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1548/  GeneReviews/NCBI/NIH/UW entry on Hereditary Paraganglioma-Pheochromocytoma Syndromes]
* [http://www.gene.ucl.ac.uk/nomenclature/data/get_data.php?hgnc_id=10683 SDHD from the HUGO Gene Nomenclature Committee]

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