Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma.
Three genes encoding for mitochondrial complex II proteins are linked to hereditary paraganglioma. We have recently shown that an inactivation of the SDHD gene is associated with a complete loss of mitochondrial complex II activity and a stimulation of the angiogenic pathway (Gimenez-Roqueplo, A. P., J. Favier, P. Rustin, J. J. Mourad, P. F. Plouin, P. Corvol, A. Rötig, and X. Jeunemaitre, 2001, Am J Hum Genet 69:1186-1197). Here, we relate the case of a malignant sporadic pheochromocytoma induced by a germline missense mutation of the SDHB gene. Within the tumor, a loss of heterozygosity at chromosome 1pter led to a null SDHB allele and to a complete loss of complex II enzymatic activity. In situ hybridization and immunohistochemistry experiments showed a high expression of hypoxic-angiogenic responsive genes, similar to that previously observed in inherited-SDHD tumors. This observation highlights the role of the complex II mitochondrial genes in the oxygen-sensing pathway and in the regulation of angiogenesis of neural crest-derived tumors.
D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins; D002878:Chromosomes, Human, Pair 1; D004252:DNA Mutational Analysis; D042963:Electron Transport Complex II; D016228:Endothelial Growth Factors / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007506:Iron-Sulfur Proteins / Q000235:genetics* / Q000502:physiology; D019656:Loss of Heterozygosity; D008222:Lymphokines / Q000235:genetics; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics; D010673:Pheochromocytoma / Q000201:enzymology / Q000235:genetics*; D021122:Protein Subunits; D012333:RNA, Messenger / Q000032:analysis; D017422:Sequence Analysis, DNA; D013385:Succinate Dehydrogenase / Q000172:deficiency / Q000235:genetics; D014057:Tomography, X-Ray Computed; D015534:Trans-Activators / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D042963:Electron Transport Complex II; D016228:Endothelial Growth Factors; D007506:Iron-Sulfur Proteins; D008222:Lymphokines; D009097:Multienzyme Complexes; D010088:Oxidoreductases; D021122:Protein Subunits; D012333:RNA, Messenger; D013385:Succinate Dehydrogenase; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C108095:SDHB protein, human