Functional Consequences of aSDHBGene Mutation in an Apparently Sporadic Pheochromocytoma

Abstract

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.

R46Q Mutation in the Succinate Dehydrogenase B Gene (SDHB) in a Japanese Family with both Abdominal and Thoracic Paraganglioma Following Metastasis

“…Current evidence suggests that the mutation of SDHB is more frequently related to abdominal (or thoracic) paraganglioma and the following distant metastasis, in agreement with our case presented here [3][4][5][6][7][8]. Therefore, it is recommended that all patients with metastatic disease, especially from paraganglioma, be tested for SDHB mutations.…”

“…ment with previous reports [3][4][5][6][7][8]. Furthermore, clinical phenotypes were found to differ significantly between family members carrying the same mutation.…”

“…More recently, nuclear genes encoding two mitochondrial complex II subunit proteins, SDHD and SDHB, have been associated with the development of familial pheochromocytomas and paragangliomas (hereditary pheochromocytoma/ paraganglioma syndrome: HPPS) [1,2]. Growing evidence suggests that a mutation of SDHB is highly associated with abdominal (or thoracic) paraganglioma and the following distant metastasis (malignant paraganglioma) [3][4][5][6][7][8]. Indeed, it has been found that malignant pheochromocytoma/paraganglioma is associated with 38 to 83% of patients with SDHB germline mutations, indicating a much higher rate of malignancy compared with other mutations or sporadic adrenal pheochromocytoma where the rate is <10%.…”

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

“…The observation that loss of function of the SDH complex is mostly associated with paraganglioma, regardless of the SDH subunit involved, suggests that tumorigenesis because of these mutations stems from a common biochemical pathway. This is supported by the observation that mutations in either SDHB or SDHD result in the disintegration of the SDH complex and a complete loss of SDH enzymatic activity (Gimenez-Roqueplo et al, 2001;Gimenez-Roqueplo et al, 2002;Douwes Dekker et al, 2003). However, a closer examination of the genotype-phenotype link revealed several differences between the different SDH genes.…”

“…The majority of tumours derived from SDHB or SDHD mutations have a very weak to non-detectable activity of SDH (Gimenez-Roqueplo et al, 2001;Gimenez-Roqueplo et al, 2002;Douwes Dekker et al, 2003). This indicates that the SDH complex in these tumours is incapable of oxidizing succinate, a required enzymatic reaction for ROS generation.…”