Abstract
We have investigated genetic/pathogenetic factors associated with a new clinical entity in patients presenting with pheochromocytoma/paraganglioma (PHEO/PGL) and polycythemia. Two patients without hypoxia-inducible factor 2α (HIF2A) mutations, who presented with similar clinical manifestations, were analyzed for other gene mutations, including prolyl hydroxylase (PHD) mutations. We have found for the first time a germ-line mutation in PHD1 in one patient and a novel germ-line PHD2 mutation in a second patient. Both mutants exhibited reduced protein stability with substantial quantitative protein loss and thus compromised catalytic activities. Due to the unique association of patients’ polycythemia with borderline or mildly elevated erythropoietin (EPO) levels, we also performed an in vitro sensitivity assay of erythroid progenitors to EPO and for EPO receptor (EPOR) expression. The results show inappropriate hypersensitivity of erythroid progenitors to EPO in these patients, indicating increased EPOR expression/activity. In addition, the present study indicates that HIF dysregulation due to PHD mutations plays an important role in the pathogenesis of these tumors and associated polycythemia. The PHD1 mutation appears to be a new member contributing to the genetic landscape of this novel clinical entity. Our results support the existence of a specific PHD1- and PHD2-associated PHEO/PGL-polycythemia disorder.
Key message
• A novel germ-line PHD1 mutation causing pheochromocytoma/paraganglioma and polycythemia.
• Increased EPOR activity and inappropriate hypersensitivity of erythroid progenitors to EPO.
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Acknowledgments
We would like to acknowledge the clinical and technical assistance of Victoria Martucci, Karen Adams, Pauline Dmitriev, and Joan Nambuba in the production of this manuscript. We also thank both patients and their families for their participation and assistance. This research was supported, in part, by the Intramural Research Program of the NIH, Eunice Kennedy Shriver NICHD, NINDS, NCI, and NHGRI.
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The authors declare no conflict of interests related to this study.
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Chunzhang Yang and Zhengping Zhuang contributed equally to this article.
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Yang, C., Zhuang, Z., Fliedner, S.M.J. et al. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. J Mol Med 93, 93–104 (2015). https://doi.org/10.1007/s00109-014-1205-7
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DOI: https://doi.org/10.1007/s00109-014-1205-7