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.

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. SDH2(C184Y) mutant allele equivalent to human SDHB(C191Y) did not restore the OXPHOS phenotype of the Deltasdh2 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.

Histochemical evidence of adenosine triphosphatase activity in glomus tumor--report of a case.

A case of glomus tumor was studied by light and electron microscopic enzyme histochemistry. Histologically, this case was classified as glomangioma or vascular form of glomus tumor. The tumor cells had ultrastructural characteristics of smooth muscle cells such as large amount of thin filaments with dense bodies, basal lamina and numerous pinocytotic vesicles. Among the 3 membrane associated enzymes, namely alkaline phosphatase, adenosine triphosphatase (ATPase) and 5'nucleotidase, only ATPase was detectable in the cell membrane and pinocytotic vesicles. It is suggested that the ATPase activity of the tumor cells shows additional evidence of smooth muscle character of glomus tumor.