Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome

• Published in: Human molecular genetics Vol. 22; no. 4; pp. 804 - 815
• Main Authors: Panizza, Elena, Ercolino, Tonino, Mori, Luigi, Rapizzi, Elena, Castellano, Maurizio, Opocher, Giuseppe, Ferrero, Ileana, Neumann, Hartmut P H, Mannelli, Massimo, Goffrini, Paola
• Format: Journal Article
• Language: English
• Published: England 15.02.2013
• Subjects: Genetic Complementation Test; Humans; Membrane Proteins - genetics; Mutation, Missense; Oxidative Phosphorylation; Oxidative Stress; Paraganglioma - enzymology; Paraganglioma - genetics; Phenotype; Pheochromocytoma - enzymology; Pheochromocytoma - genetics; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins - genetics; Succinate Dehydrogenase - genetics; Syndrome
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/dds487

SDH genes, encoding succinate dehydrogenase, act as tumour suppressor genes, linking mitochondrial dysfunction with tumourigenesis. Heterozygous germline mutations in SDHA, SDHB, SDHC, SDHD and in the assembly factor encoding gene SDHAF2 have all been shown to predispose to heritable endocrine neoplasias such as pheochromocytomas (PHEO) and paragangliomas (PGLs) called 'PHEO-PGL syndrome'. SDH genes mutations, in addition to deletions or truncations which are most likely pathogenic, often include missense substitutions which can be of uncertain significance. Unclassified missense substitutions may be difficult to interpret unless the cause-effect link between mutation and the disease is established by functional and in silico studies or by the familial segregation with the phenotype. Using the yeast model, here, we report functional investigations on several missense SDH mutations found in patients affected by pheochromocytomas or paragangliomas. The aim of this study was to evaluate whether and to which extent the yeast model may be useful for establishing the pathological significance of missense SDH mutations in humans. The results of our study demonstrate that the yeast is a good functional model to validate the pathogenic significance of SDHB missense mutations while, for missense mutations in SDHC and SDHD genes, the model can be informative only when the variation involves a conserved residue in a conserved domain.