SDHA is a tumor suppressor gene causing paraganglioma.
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.
Burnichon
Nelly
N
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, 20-40 rue Leblanc, F-75015 Paris, France. nelly.burnichon@inserm.fr
Brière
Jean-Jacques
JJ
Libé
Rossella
R
Vescovo
Laure
L
Rivière
Julie
J
Tissier
Frédérique
F
Jouanno
Elodie
E
Jeunemaitre
Xavier
X
Bénit
Paule
P
Tzagoloff
Alexander
A
Rustin
Pierre
P
Bertherat
Jérôme
J
Favier
Judith
J
Gimenez-Roqueplo
Anne-Paule
AP
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
D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase