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Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.

AbstractBACKGROUND:
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.
CONCLUSION:
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.
AuthorsJean-Pierre Bayley, Ivonne van Minderhout, Marjan M Weiss, Jeroen C Jansen, Peter H N Oomen, Fred H Menko, Barbara Pasini, Barbara Ferrando, Nora Wong, Lesley C Alpert, Rosie Williams, Edward Blair, Peter Devilee, Peter E M Taschner
JournalBMC medical genetics (BMC Med Genet) Vol. 7 Pg. 1 (Jan 11 2006) ISSN: 1471-2350 [Electronic] England
PMID16405730 (Publication Type: Journal Article)
Chemical References
  • Iron-Sulfur Proteins
  • Membrane Proteins
  • Protein Subunits
  • RNA Splice Sites
  • SDHC protein, human
  • SDHB protein, human
  • Succinate Dehydrogenase
Topics
  • Adolescent
  • Adrenal Gland Neoplasms (genetics)
  • Adult
  • Aged
  • DNA Mutational Analysis
  • Female
  • Germ-Line Mutation
  • Head and Neck Neoplasms (genetics)
  • Humans
  • Iron-Sulfur Proteins (genetics)
  • Male
  • Membrane Proteins (genetics)
  • Middle Aged
  • Paraganglioma (genetics)
  • Pheochromocytoma (genetics)
  • Protein Subunits (genetics)
  • RNA Splice Sites
  • Succinate Dehydrogenase (genetics)

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