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SDH Mutations in Patients Affected by Paraganglioma Syndromes

2006; Wiley; Volume: 1073; Issue: 1 Linguagem: Inglês

10.1196/annals.1353.019

1749-6632

Massimo Mannelli, Lisa Simi, Tonino Ercolino, Maria Sole Gaglianò, Lucia Becherini, Serena Vinci, Roberta Sestini, Francesca Gensini, Pamela Pinzani, Mario Mascalchi, Luisa Guerrini, Carlo Pratesi, Gabriella Nesi, Frank M. Torti, Franco Cipollini, G Bernini, Maurizio Genuardi,

Cancer, Hypoxia, and Metabolism

Abstract: Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest‐derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL. Haplotype analysis showed the presence of a founder effect. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumors, variably associated or not with PGLs or PHEOs. A novel missense SDHD variant, T112I, was also found in one of our families. A new missense G106D mutation, involving a highly conserved amino acid, was found in two sisters affected by bilateral glomus tumors. A P81L mutation associated with abdominal and head and neck PGL was detected in three families. A G12S variant of the SDHD gene was found in one patient affected by a PHEO. The finding of this variant in 3 of 100 control subjects suggests that it is a polymorphism and not a mutation. A novel IVS2‐1G>T variant was found at intron 2 of SDHD gene in one patient affected by a glomus tumor. All the tumors associated with SDHD mutations were benign. Conversely, the only mutation we found in SDHB gene (IVS3 + 1G>A) was associated with a malignant PHEO.