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Germline mutations in TMEM127 confer susceptibility to pheochromocytoma

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Qin, Yuejuan, Yao, Li, King, Elizabeth E, Buddavarapu, Kalyan, Lenci, Romina E, Chocron, E Sandra, Lechleiter, James D, Sass, Meghan +9 more·2010·Nature Genetics
DOI 10.1038/ng.533PMC PMC2998199
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Abstract

Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary. However, the molecular basis of the majority of these tumors is unknown. 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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  • The SNV rs121908813 is implicated in familial pheochromocytoma, a condition characterized by tumors found in the neuroendocrine system that secrete high levels of catecholamines.

    “Another SNV, rs121908813, is implicated in familial pheochromocytoma, a condition characterized by tumors found in the neuroendocrine system that secrete high levels of catecholamines43.”

    From Human 5′ UTR design and variant effect prediction from a massively parallel translation assay (2019) · cites this paper as [43]

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Authors
Qin, Y., Yao, L., King, E. E., Buddavarapu, K., Lenci, R. E., Chocron, E. S., Lechleiter, J. D., Sass, M., Aronin, N., Schiavi, F., Boaretto, F., Opocher, G., Toledo, R. A., Toledo, S. P. A., Stiles, C., Aguiar, R. C. T., & Dahia, P. L. M.
Affiliations
  • The University of Texas at San Antonio Health Science Center (US)
  • University of Massachusetts Chan Medical School (US)
  • Istituto Oncologico Veneto (IT)
  • Universidade de São Paulo (BR)
  • Harvard University (US)
Corresponding author
Dahia, Patricia L M
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2010-02-14
Volume
42
Issue
3
Pages
229-233
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.533
PMC
PMC2998199
OpenAlex
W1992804184
Cited by
379
References
4
Citations by year
2026: 9 · 2025: 4 · 2024: 6 · 2023: 16 · 2022: 13 · 2021: 20 · 2020: 18 · 2019: 21 · 2018: 19 · 2017: 33 · 2016: 24 · 2015: 29 · 2014: 38 · 2013: 41 · 2012: 53
FWCI
41.16
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • National Institutes of Health (8ul1tr000149-05)
  • National Institute on Aging (P01AG019316, P30AG013319)
  • National Cancer Institute (P30CA054174, NIH-P30 CA54174)
  • National Center for Research Resources (UL1RR025767)
  • National Center for Advancing Translational Sciences (UL1-TR000149)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
  • Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
Keywords
pheochromocytoma, TMEM127, germline mutations, tumor suppressor, hereditary cancer predisposition, mTOR, neurofibromatosis type 1, catecholamine-secreting tumors, endomembrane system
MeSH terms
Adrenal Gland Neoplasms, Adult, Aged, Cells, Cultured, DNA Mutational Analysis, Family, Humans, Membrane Proteins, Middle Aged, Pheochromocytoma, Cohort Studies, Germ-Line Mutation, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide

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