Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma

The pheochromocytomas are an important cause of secondary hypertension. Alt hough pheochromocytoma susceptibility may be associated with germline mutat ions in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RE T, the genetic basis for most cases of nonsyndromic familial pheochromocyto ma is unknown. Recently, pheochromocytoma susceptibility has been associate d with germline SDHD mutations. Germline SDHD mutations were originally des cribed in hereditary paraganglioma, a dominantly inherited disorder charact erized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehyd rogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial me mbrane. Although mutations in SDHC and in SDHD may cause hereditary paragan glioma, 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 th at germline SDHB mutations are an important cause of pheochromocytoma susce ptibility.