Human Molecular Genetics Advance Access originally published online on March 4, 2009
Human Molecular Genetics 2009 18(10):1860-1868; doi:10.1093/hmg/ddp102
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Functional study in a yeast model of a novel succinate dehydrogenase subunit B gene germline missense mutation (C191Y) diagnosed in a patient affected by a glomus tumor
1 Department of Genetics, Biology of Microorganisms, Anthropology and Evolution, University of Parma, Viale Usberti 11/A, 43100 Parma, Italy 2 Section of Endocrinology, Department of Clinical Pathophysiology, University of Florence Medical School, 50139 Florence, Italy 3 Department of Preclinical and Clinical Pharmacology, University of Florence, 50139 Florence, Italy
* To whom correspondence should be addressed. Tel: +39 0521905600; Fax: +39 0521905604; Email: iferrero{at}unipr.it
Received January 30, 2009; Accepted March 2, 2009
Mutations of succinate dehydrogenase (SDH) subunits B, C and D are associated to pheochromocytoma/paraganglioma (PGL) development. The mechanisms linking SDH mutations to tumorigenesis are currently unknown. We report a novel germline missense SDHB mutation (C191Y) in a patient affected by a glomus tumor. The missense mutation hits an amino acid residue conserved from mammals to the yeast Saccharomyces cerevisiae. The pathogenic significance of the human mutation was validated in a yeast model. SDH2C184Y mutant allele equivalent to human SDHBC191Y did not restore the OXPHOS phenotype of the 
sdh2 null mutant. In the mutant, SDH activity was also abolished along with a reduction in respiration. Sensitivity to oxidative stress was increased in the mutant, as revealed by reduced growth in the presence of menadione. Remarkably, the frequency of petite colony formation was increased in the mutant yeast strain, indicating an increased mtDNA mutability. Histochemistry demonstrates that SDH activity was selectively absent in the patient tumor tissue. Overall, our results demonstrate that the C191Y SDHB mutation suppresses SDH enzyme activity leading to increased ROS formation and mtDNA mutability in our yeast model. These findings further our understanding of the mechanisms underlying PGL development and point to the yeast model as a valid tool to investigate on the possible pathogenic relevance of SDH novel mutations and/or rare polymorphism.
The authors wish to be known that, in their opinion, the first two authors should be regarded as joint First Authors.