Gene Mutations in the Succinate Dehydrogenase Subunit SDHB Cause Susceptibility to Familial Pheochromocytoma and to Familial Paraganglioma

Abstract

The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…ncbi.nlm.nih.gov/pubmed) from 2000, the year of the first published mutation in a paraganglioma, to April 2014. 1,2,[4][5][6] The following search terms were used: SDHA, SDHB, SDHC, SDHD, and SDHAF2, in combination with the tumor type names pheochromocytomas, paragangliomas (sympathetic and parasympathetic), gastrointestinal stromal tumors, renal-cell carcinomas, and pituitary adenomas. 20 With the aim of predicting the functional impact of the SDH mutations on the corresponding proteins, a bioinformatics analysis was performed using the ANNOVAR software.…”

“…SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas.…”

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

“…Following this initial discovery, it did not take long to identify the genes of two other HPGL-associated loci, PGL4 (1p36) and PGL3 (1q21), to be SDHB and SDHC, respectively (Niemann and Muller, 2000;Astuti et al, 2001). Germ line heterozygous mutations of these genes generally follow the classic Knudson's 'two hits' sequence of tumour suppressor inactivation and are usually, but not always, associated with loss of heterozygosity (LOH) in the tumours (Pawlu et al, 2005).…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…Mutations in SDHD were the first to be identified as causative in patients with hereditary paragangliomas and later pheochromocytomas, rare neuroendocrine neoplasms of the chromaffin tissue of the adrenal medulla and the parasympathetic tissue of the head and neck paraganglioma, respectively 50. Since the initial discovery of SDHD mutations in 2000, mutations in SDHB and SDHC , and more recently, SDHA and SDHAF2 (encoding the protein responsible for FAD incorporation into SDH) have been identified with the same syndrome 47, 48, 49, 60. These mutations are found as heterozygous germline mutations, which means that loss of protein function and neoplastic transformation develops as a result of loss of heterozygosity, resulting in the complete loss of enzyme function by a second ‘hit.’61 Inactivating mutations of SDH subunits have since been reportedly associated with other tumor types including gastrointestinal stromal tumors,62 renal cell carcinoma,63, 64 and neuroblastoma 65, 66.…”