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SDHD

MIM.602690 11q23

Wednesday 22 September 2004

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

Function

Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms.

Pathology

- susceptibility to head and neck paraganglioma
- familial and isolated phaeochromocytoma
- pheochromocytoma-paraganglioma syndrome
- Cowden disease (16258955)
- Cowden-like syndrome (16258955)

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:

  • paragangliomas (16258955)
  • susceptibility to head and neck paraganglioma
  • familial and isolated phaeochromocytoma
  • early onset renal cell carcinoma (RCC)
  • Cowden disease (16258955)
  • Cowden-like syndromes (16258955)
  • Carney triad

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)

NB: No evidence of SDHD in neuroblastoma pathogenesis (15331017).

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

- A novel mutation in the SDHD gene in a family with inherited paragangliomas—implications of genetic diagnosis for follow up and treatment. Renard L, Godfraind C, Boon LM, Vikkula M. Head Neck. 2003 Feb;25(2):146-51. PMID: 12509798