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.

Figure 1

Electropherograms, showing germline SDHB mutations (arrowheads), and simplified pedigrees for families K1–K3 (A) and family K4 (B). The affected codon and the amino acids are depicted below the electropherograms. In pedigrees, symbols with horizontal bars indicate pheochromocytoma (intra- or extra-adrenal), symbols with vertical bars indicate cervical paraganglioma, and symbols with checkered pattern indicate both pheochromocytoma and paraganglioma.

Figure 2

Locations of germline mutations and missense substitution, detected in the highly conserved SDHB coding sequence (HS = Homo sapiens; DM = Drosophila melanogaster). Multiple-sequence alignment was performed by the ClustalW program, available from BCM Search Launcher. The mutations are shown with respect to the functional domains of the protein, as predicted by the InterPro program. The black dots represent the four germline mutations described in the text. The yellow screen indicates the predicted ferredoxin domain (54–119 amino acids; GenBank accession number NP_002991), the green screen indicates the 2Fe-2S ferredoxin domain (93–101 amino acids), and the blue screen indicates the 4Fe-4S ferredoxin iron-sulfur–binding domain (186–197 amino acids).