title: Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas.
abstract: Pheochromocytomas are neural crest-derived tumors that occur mostly sporadically, but may also be part of inherited syndromes. The molecular pathogenesis of sporadic pheochromocytomas remains unknown. Recently, the susceptibility gene for familial paraganglioma syndrome, a disorder embryologically related to pheochromocytomas, was characterized and shown to encode the small subunit of succinate dehydrogenase (SDHD), which is part of the mitochondrial complex II. This complex regulates oxygen-sensing signals. Importantly, hypoxic signals also appear to be related to the pathogenesis of pheochromocytomas associated with von Hippel-Lindau syndrome. We sequenced the entire coding region of the SDHD gene in a series of pheochromocytomas. Although we did not find mutations in the gene, we identified a new intronic single nucleotide polymorphism in 15% of the samples (g.97739A-->G). We also confirmed the existence of a sequence highly homologous to the SDHD complementary DNA in chromosome 1p34--36, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of our samples that was also present in the germline. This sequence does not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this series of sporadic pheochromocytomas. The existence of SDHD pseudogenes should be considered when analyzing complementary DNA-based samples.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115-6084, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Aguiar
authors.forename: G
authors.initials: G
authors.lastname: Cox
authors.forename: S L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: P L
authors.initials: PL
authors.lastname: Dahia
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011544:Pseudogenes / Q000235:genetics; D013385:Succinate Dehydrogenase; D013577:Syndrome; D014158:Transcription, Genetic
chemical_list: D008565:Membrane Proteins; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase