Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas

Pheochromocytomas are neural crest-derived tumors that occur mostly sporadi cally, but may also be part of inherited syndromes. The molecular pathogene sis of sporadic pheochromocytomas remains unknown. Recently, the susceptibi lity gene for familial paraganglioma syndrome, a disorder embryologically r elated to pheochromocytomas, was characterized and shown to encode the smal l subunit of succinate dehydrogenase (SDHD), which is part of the mitochond rial complex II. This complex regulates oxygen-sensing signals. Importantly , hypoxic signals also appear to be related to the pathogenesis of pheothro mocytomas associated with von Hippel-Lindau syndrome. We sequenced the enti re coding region of the SDHD gene in a series of pheochromocytomas. Althoug h we did not find mutations in the gene, we identified a new intronic singl e nucleotide polymorphism in 15% of the samples (g.97739A-->G). We also con firmed the existence of a sequence highly homologous to the SDHD complement ary DNA in chromosome 1p34-36, a region commonly deleted in pheochromocytom as. Full analysis of this sequence revealed a heterozygous single base subs titution 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 pseu dogene. Therefore, despite its chromosomal location, it is unlikely that th is sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this serie s of sporadic pheochromocytomas. The existence of SDHD pseudogenes should b e considered when analyzing complementary DNA-based samples.