SDH Genes: From Glomic Tumours to Pheochromocytomas

Alexander      Persu; Miikka      Vikkula

Abstract

The four SDH genes encode succinate dehydrogenase (SDHA and SDHB) and its anchoring subunits (SDHC and SDHD), which constitute complex II of the mitochondrial membrane, involved both in the respiratory chain and the Krebs cycle. Mutations of SDHD and less frequently SDHB and SDHC are at the origin of rare hereditary forms of head and neck paraganglioma. Interestingly, SDHB mutations are also a major cause of sporadic and familial pheochromocytomas, which have the same embryonic origin as head and neck paragangliomas. Patients with SDHB mutations are at higher risk of developing malignant and recurrent forms of pheochromocytoma. SDHB mutations have also been found in pedigrees harbouring both paragangliomas and renal cell carcinomas. This association reminds us of the Von Hippel-Lindau syndrome caused by mutations in the VHL gene. It should be pointed out that several angiogenic factors (HIFa, VEGF) are overexpressed both in tumours associated with paraganglioma and Von Hippel-Lindau syndrome. Though the different steps leading from SDH mutations to paraganglioma remain obscure, it is tempting to hypothesise that SDH gene products, VHL and angiogenic factors belong to the same functional pathway. The story of SDH genes is an impressive example of how the unravelling of the genetic basis of a rare disease i.e. familial head and neck paraganglioma can provide new insights into mechanisms involved in more frequent conditions such as endocrine hypertension, tumourigenesis, angiogenesis and adaptation to hypoxia.

Keywords: sdhd, sdhb, complex II, mitochondrial respiratory chain, paraganglioma, pheochromocytoma, mutation

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