title: 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.
authors.affiliation: Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Astuti
authors.forename: F
authors.initials: F
authors.lastname: Latif
authors.forename: A
authors.initials: A
authors.lastname: Dallol
authors.forename: P L
authors.initials: PL
authors.lastname: Dahia
authors.forename: F
authors.initials: F
authors.lastname: Douglas
authors.forename: E
authors.initials: E
authors.lastname: George
authors.forename: F
authors.initials: F
authors.lastname: Sköldberg
authors.forename: E S
authors.initials: ES
authors.lastname: Husebye
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: E R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010235:Paraganglioma / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D010673:Pheochromocytoma / Q000201:enzymology* / Q000235:genetics*; D021122:Protein Subunits; D000090063:Proto-Oncogene Mas; D016415:Sequence Alignment; D013385:Succinate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D021122:Protein Subunits; D000090063:Proto-Oncogene Mas; D013385:Succinate Dehydrogenase