The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway

Hereditary paragangliomas are usually benign tumors of the autonomic nervou s system that are composed of cells derived from the primitive neural crest . Even though three genes (SDHD, SDHC, and SDHB), which encode three protei n subunits of cytochrome b of complex II in the mitochondrial respiratory c hain, have been identified, the molecular mechanisms leading to tumorigenes is are unknown. We studied a family in which the father and his eldest son had bilateral neck paragangliomas, whereas the second son had a left caroti d-body paraganglioma and an ectopic mediastinal pheochromocytoma. A nonsens e mutation (R22X) in the SDHD gene was found in these three affected subjec ts. Loss of heterozygosity was observed for the maternal chromosome 11q21-q 25 within the tumor but not in peripheral leukocytes. Assessment of the act ivity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, that was n ot detected in six sporadic pheochromocytomas. In situ hybridization and im munohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. Real-time quantitative reverse transcriptase (R T)-PCR measurements confirmed that vascular endothelial growth factor and e ndothelial PAS domain protein 1 mRNA levels were significantly higher (thre e-and sixfold, respectively) than those observed in three sporadic benign p heochromocytomas. Thus, inactivation of the SDHD gene in hereditary paragan glioma is associated with a complete loss of mitochondrial complex II activ ity and with a high expression of angiogenic factors.