SDH mutations in patients affected by paraganglioma syndromes: a personal experience.
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.
Mannelli
M
M
Endocrinology Section, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6 50139, Florence, and Internal Medicine 2, Pistoia Hospital, Italy. m.mannelli@dfc.unifi.it
Simi
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Ercolino
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T
Gaglianò
M S
MS
Becherini
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Vinci
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Sestini
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R
Gensini
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F
Pinzani
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P
Mascalchi
M
M
Guerrini
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Pratesi
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C
Nesi
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G
Torti
F
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Cipollini
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Bernini
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Genuardi
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D000595:Amino Acid Sequence; D000818:Animals; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D010235:Paraganglioma / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013385:Succinate Dehydrogenase / Q000737:chemistry / Q000235:genetics*
D013385:Succinate Dehydrogenase