Mutation screening in the VHL, SDHB and SDHD genes in patients with sporadic pheochromocytoma and/or paraganglioma / Rastreamento de mutações nos genes VHL, SDHB e SDHD em pacientes portadores de feocromocitoma ou também, paraganglioma esporádico

AUTOR(ES)
DATA DE PUBLICAÇÃO

2007

RESUMO

Pheochromocytomas are neuroendocrine tumors composed of chromaffin cells that produce and secrete catecholamines as well as a variety of neuropeptides, whose most common clinical manifestation is arterial hypertension. Twelve to 24% of the apparently sporadic pheochromocytomas, present germline mutations in genes previously associated to inherited familiar syndromes, such as, RET, VHL, SDHB e SDHD. The von Hippel-Lindau (VHL) disease occurs upon the VHL gene mutation - a tumor suppressor gene whose product encodes complexes with other proteins leading proteic substracts to the proteolysis. The proteins encoded by the SDHD and SDHB genes are parts of the complex mitochondrial II, as well as the aerobic chain of the electron transport. The aim of the present study was the screening of mutations in the VHL, SDHB and SDHD genes in patients harboring sporadic pheochromocytoma and/or paraganglioma, followed by the Endocrinology Service of Hospital das Clínicas of the University of São Paulo School of Medicine. All the three studied gene exons were amplified by polymerase chain reaction (PCR) and were analyzed by dHPLC, which was the method used for screen mutations. The samples with altered eluting progress were directly sequenced. No mutations were found in the VHL gene, only two polymorphisms previously described in the exon 1, c. -77 C>T in two patients and c - 195 G>in 58.6% out of the total alleles of the studied patients. Two polymorphisms previously described (c. 201-36 G>T and c.487 T>C) in the SDHB gene were found in four patients, as well as silent mutation not yet described (c.540 G>A) and a mutation previously described in patients with pheochromocytoma (c. 293 G>A). A particular patient presented the silent mutation c.540 G>A and the polymorphism c.201-36 G>T. In the SDHD gene two polymorpfisms previously described (c.204 C>T and c.315-32 T>C) were found, one in each patient, as well as an allelic variant previously described in the 3non-coding region whose frequency has never been studied in other populations (c.*612 C>T) and two substitutions never described in the 3non-coding region (c.*799 T>C and c.*803 A>G). The variants c.*612 C>T and c.*799 T>C were detected in only one patient each and have not been found in 200 alleles of normal control subjects studied. The variant c.*803 A>G was found in nine out of 76 alleles from 38 patients (11.8%) and in five out of 200 alleles from 100 non-affected subjects (2.5%), being, then, a polymorphism significantly more frequent among patients with pheochromocytoma or paraganglioma. Among those seven patients with the polymorphism c.*803 A>G, three patients heterozygotous for the polymorphism presented a second polymorphism in the SDHD gene and one of those patients also presented a mutation in the SDHB gene. Out of the other four patients, two presented the polymorphism c.*803 A>G in heterozygosis. This polymorphism occurs in the nucleotide localized in the position -1 immediately 5to the site where the pre-mRNA is cleaved for the insertion of the poly(A) tail, which is essencial to the mRNA stability. The substitution of the A to the G probably presents a functional repercussion, because the A in the position -1 is considered as the most efficient nucleotide in the pre-mRNA cleavage promotion, while the G is considered the least efficient one (scale of cleavage efficiency A >U >C >G). Therefore, the possibility of this polymorphism be associated with susceptibility to the development of pheochromocytoma and paraganglioma is not discarded, being possible that other genetic events are necessary to promote tumorigenesis. In conclusion, this study evidenced a low frequency of mutations in the coding regions of the genes VHL (mutations not detected), SDHB (5,2%) and SDHD (mutations not detected) in this series of patients with sporadic pheochromocytomas and paragangliomas, however, a polymorphism significantly more frequent in patients harboring those tumors was found in the 3non-coding region of the SDHD gene and, for its specific characteristics, it can very well be related to the etiopathogenesis of the pheochromocytoma and paraganglioma

ASSUNTO(S)

mutações paraganglioma doença de hippel-lindau feocromocitoma succinato desidrogenase hipertensão paraganglioma succinate dehydrogenase hipertension mutation pheochromocytoma hippel-lindau disease

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