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SDHB

HGNC:10681 1p36.1-p35 Entrez:6390 MIM.185470

Friday 21 September 2007

Definition: One the four genes (SDHA, SDHB, SDHC, SDHD) that encode mitochondrial succinate dehydrogenase.

Complex II in mitochondria, of which succinate dehydrogenase (EC 1.3.99.1) is a component, has 4 subunits. In order of decreasing molecular mass, they are the flavoprotein (SDHA; MIM.600857), the iron sulfur protein (SDHB), and the 2 integral membrane proteins, SDHC (MIM.602413) and SDHD (MIM.602690).

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types.

Pathology

Germline mutations in the genes encoding the B (SDHB) and D (SDHD) subunits of the heterotetrameric protein succinate dehydrogenase (mitochondrial complex II) are important causes of inherited and apparently sporadic paragangliomas.

- germline mutations of SDHB in:

- tumors

Germ-line mutations of the SDHs genes have been found to account for nearly 10% of apparently sporadic paragangliomas.

An excess of SDHB mutations in paragangliomas versus pheochromocytomas is found, with no difference in the frequency of mutations in malignant versus benign paragangliomas. (18382370)

Risks of HNPGL and pheochromocytoma in SDHB mutation carriers are 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. (19802898)

Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) are higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) have been identified in a study. (19802898)

No clear genotype-phenotype correlations are detected for SDHB mutations. (19802898)

However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein are associated with a significantly increased risk of pheochromocytoma compared to missense mutations that are not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). (19802898)

The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma. (19802898)

Immunochemistry

- Negative staining for SDHB is characteristic of the gastrointestinal stromal tumors (GISTs) of Carney triad and the subgroup of pediatric GISTs which it resembles.

- Furthermore, when negative staining occurs in apparently sporadic GISTs in adults, the GISTs show morphologic and clinical features similar to pediatric and CT type GISTs. GISTs may therefore be divided into type 1 (SDHB positive) and type 2 (SDHB negative) subtypes. (20305538)

Nota bene: The Carney triad (CT) is gastrointestinal stromal tumor (GIST), paraganglioma, and pulmonary chondroma. The GISTs of CT show different clinical, molecular, and morphologic features to usual adult GISTs but are similar to the majority of pediatric GISTs. GISTs show negative staining for succinate dehydrogenase B (SDHB).

References

- Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. 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. Hum Mutat. 2010 Jan;31(1):41-51. PMID: 19802898

- Immunohistochemistry for SDHB Divides Gastrointestinal Stromal Tumors (GISTs) into 2 Distinct Types. Gill AJ, Chou A, Vilain R, Clarkson A, Lui M, Jin R, Tobias V, Samra J, Goldstein D, Smith C, Sioson L, Parker N, Smith RC, Sywak M, Sidhu SB, Wyatt JM, Robinson BG, Eckstein RP, Benn DE, Clifton-Bligh RJ. Am J Surg Pathol. 2010 May;34(5):636-44. PMID: 20305538

- Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. Armstrong R, Greenhalgh KL, Rattenberry E, Judd B, Shukla R, Losty PD, Maher ER. J Med Genet. 2009 Mar;46(3):215-6. PMID: 19251979

- Germline SDHB mutations are common in patients with apparently sporadic sympathetic paragangliomas. Klein RD, Jin L, Rumilla K, Young WF Jr, Lloyd RV. Diagn Mol Pathol. 2008 Jun;17(2):94-100. PMID: 18382370

- 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 dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008 Aug;83(2):261-8. PMID: 18678321

- Cascon A, Montero-Conde C, Ruiz-Llorente S, Mercadillo F, Leton R, Rodriguez-Antona C, Martinez-Delgado B, Delgado M, Diez A, Rovira A, Diaz JA, Robledo M. Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot? Genes Chromosomes Cancer. 2006 Mar;45(3):213-9. PMID: 16258955

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