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Germline mutations in TMEM127 confer susceptibility to pheochromocytoma


Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary1. However, the molecular basis of the majority of these tumors is unknown2. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations and, similarly, show hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Accordingly, in vitro gain-of-function and loss-of-function analyses indicate that TMEM127 is a negative regulator of mTOR. TMEM127 dynamically associates with the endomembrane system and colocalizes with perinuclear (activated) mTOR, suggesting a subcompartmental-specific effect. Our studies identify TMEM127 as a tumor suppressor gene and validate the power of hereditary tumors to elucidate cancer pathogenesis.

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Figure 1: TMEM127 localizes to the plasma membrane and cytoplasm.
Figure 2: TMEM127 colocalizes with multiple components of the endomembrane system.
Figure 3: TMEM127 modulates mTORC1 signaling in vitro and in vivo.
Figure 4: TMEM127 colocalizes with amino acid–activated mTORC1.

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We thank S. Jiang for technical assistance, V. Frohlich and J. Wewer for help with optical imaging, J. Blenis for kindly providing the 293E cell line, W. Kaelin Jr. for his comments and suggestions, and M. Jech, C. Colin, N.V. Nguyen, M. Pujana, M. Vidal, D. Hill, J. Bruder and the Familial Pheochromocytoma Consortium members for their contribution to earlier phases of this project. We also thank the subjects and families that participated in the study for their cooperation. P.L.M.D. is a Kimmel Foundation Scholar and a recipient of a Voelcker Foundation Young Investigator Award and is supported by the Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (UTHSCSA) (NIH-P30 CA54174). R.C.T.A. is supported by the Voelcker Fund. Immunofluorescence images were generated in the Core Optical Imaging Facility which is supported by UTHSCSA, US National Institutes of Health (NIH)-National Cancer Institute P30 CA54174 (CTRC), NIH-National Institute on Aging (NIA) P30 AG013319 (Nathan Shock Center) and NIH-NIA P01AG19316.

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Y.Q., L.Y., E.E.K., K.B., R.E.L., E.S.C., J.D.L., F.S., R.A.T., R.C.T.A. and P.L.M.D. performed and analyzed experiments. M.S., N.A., F.S., F.B., G.O., R.A.T., S.P.A.T. and C.S. contributed reagents, clinical information and discussions. R.C.T.A., J.D.L. and P.L.M.D. designed experiments. R.C.T.A. and P.L.M.D. wrote the manuscript.

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Correspondence to Patricia L M Dahia.

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The authors declare no competing financial interests.

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Qin, Y., Yao, L., King, E. et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 42, 229–233 (2010).

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