title: SDHA is a tumor suppressor gene causing paraganglioma.
abstract: Mitochondrial succinate-coenzyme Q reductase (complex II) consists of four subunits, SDHA, SDHB, SDHC and SDHD. Heterozygous germline mutations in SDHB, SDHC, SDHD and SDHAF2 [encoding for succinate dehydrogenase (SDH) complex assembly factor 2] cause hereditary paragangliomas and pheochromocytomas. Surprisingly, no genetic link between SDHA and paraganglioma/pheochromocytoma syndrome has ever been established. We identified a heterozygous germline SDHA mutation, p.Arg589Trp, in a woman suffering from catecholamine-secreting abdominal paraganglioma. The functionality of the SDHA mutant was assessed by studying SDHA, SDHB, HIF-1alpha and CD34 protein expression using immunohistochemistry and by examining the effect of the mutation in a yeast model. Microarray analyses were performed to study gene expression involved in energy metabolism and hypoxic pathways. We also investigated 202 paragangliomas or pheochromocytomas for loss of heterozygosity (LOH) at the SDHA, SDHB, SDHC and SDHD loci by BAC array comparative genomic hybridization. In vivo and in vitro functional studies demonstrated that the SDHA mutation causes a loss of SDH enzymatic activity in tumor tissue and in the yeast model. Immunohistochemistry and transcriptome analyses established that the SDHA mutation causes pseudo-hypoxia, which leads to a subsequent increase in angiogenesis, as other SDHx gene mutations. LOH was detected at the SDHA locus in the patient's tumor but was present in only 4.5% of a large series of paragangliomas and pheochromocytomas. The SDHA gene should be added to the list of genes encoding tricarboxylic acid cycle proteins that act as tumor suppressor genes and can now be considered as a new paraganglioma/pheochromocytoma susceptibility gene.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, 20-40 rue Leblanc, F-75015 Paris, France. nelly.burnichon@inserm.fr
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Brière
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Laure
authors.initials: L
authors.lastname: Vescovo
authors.forename: Julie
authors.initials: J
authors.lastname: Rivière
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouanno
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.forename: Alexander
authors.initials: A
authors.lastname: Tzagoloff
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D042963:Electron Transport Complex II / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D016147:Genes, Tumor Suppressor; D056426:Genetic Loci / Q000235:genetics; D005838:Genotype; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000235:genetics; D019656:Loss of Heterozygosity / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000150:complications / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D010235:Paraganglioma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase