title: Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.
abstract: BACKGROUND
  Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors. Succinate dehydrogenase is a heterotetrameric protein complex and a component of both the Krebs cycle and the mitochondrial respiratory chain (succinate:ubiquinone oxidoreductase or complex II).
  
  
  METHODS
  Using conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing to analyse genomic DNA from peripheral blood lymphocytes, here we describe the mutation analysis of the SDHB and SDHC genes in 37 patients with sporadic (i.e. no known family history) head and neck paraganglioma and five pheochromocytoma and/or paraganglioma families.
  
  
  RESULTS
  Two sporadic patients were found to have a SDHB splice site mutation in intron 4, c.423+1G>A, which produces a mis-spliced transcript with a 54 nucleotide deletion, resulting in an 18 amino acid in-frame deletion. A third patient was found to carry the c.214C>T (p.Arg72Cys) missense mutation in exon 4 of SDHC, which is situated in a highly conserved protein motif that constitutes the quinone-binding site of the succinate: ubiquinone oxidoreductase (SQR) complex in E. coli. Together with our previous results, we found 27 germline mutations of SDH genes in 95 cases (28%) of sporadic head and neck paraganglioma. In addition all index patients of five families showing hereditary pheochromocytoma-paraganglioma were found to carry germline mutations of SDHB: four of which were novel, c.343C>T (p.Arg115X), c.141G>A (p.Trp47X), c.281G>A (p.Arg94Lys), and c.653G>C (p.Trp218Ser), and one reported previously, c.136C>T, p.Arg46X.
  
  
  CONCLUSIONS
  In conclusion, these data indicate that germline mutations of SDHB and SDHC play a minor role in sporadic head and neck paraganglioma and further underline the importance of germline SDHB mutations in cases of familial pheochromocytoma-paraganglioma.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. J.P.L.Bayley@lumc.nl
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bayley
authors.forename: Ivonne
authors.initials: I
authors.lastname: van Minderhout
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Jansen
authors.forename: Peter H N
authors.initials: PH
authors.lastname: Oomen
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
authors.forename: Barbara
authors.initials: B
authors.lastname: Ferrando
authors.forename: Nora
authors.initials: N
authors.lastname: Wong
authors.forename: Lesley C
authors.initials: LC
authors.lastname: Alpert
authors.forename: Rosie
authors.initials: R
authors.lastname: Williams
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Peter E M
authors.initials: PE
authors.lastname: Taschner
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics*; D022821:RNA Splice Sites; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D007506:Iron-Sulfur Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; D022821:RNA Splice Sites; C108096:SDHC protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase