Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 105, Issue 9, Pages E3142-E3156Publisher
ENDOCRINE SOC
DOI: 10.1210/clinem/dgaa396
Keywords
TMEM127; tumor suppressor gene; variant classification; pheochromocytoma; paraganglioma; transmembrane protein; germline variant; endocytic motif
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Funding
- National Institutes of Health (NIH) National Institute of General Medical Sciences (NIH/NIGMS) [F31GM131634]
- National Cancer Institute (NCI) [T32CA148724]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP140105]
- NIGMS [R01GM114102]
- CPRIT [RP140743, RP190043]
- Clinical and Translational Science Award (CTSA) from the National Center for Advancing Translational Sciences (NCATS) [UL1TR001120, UL1TR002645]
- Alex's Lemonade Stand Foundation (Northwest Mutual and Flashes of Hope) research grants
- National Institute of Environmental Health Sciences (NIEHS) [R01ES031522]
- Veterans Administration Merit Award [I01BX001882]
- Central South University Xiangya School of Medicine (Changsha, Hunan, China)
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Context: TMEM127 is a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas, and renal carcinomas. Our incomplete understanding of TMEM127 function has limited our ability to predict variant pathogenicity. Purpose: To better understand the function of the transmembrane protein TMEM127 we undertook cellular and molecular evaluation of patient-derived germline variants. Design: Subcellular localization and steady-state levels of tumor-associated, transiently expressed TMEM127 variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed. Results: We identified 3 subgroups of mutations and determined that 71% of the variants studied are pathogenic or likely pathogenic through loss of membrane-binding ability, stability, and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a 4-transmembrane, not a 3-transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrin-mediated endocytosis. Conclusion: We characterized the functional deficits of several germline TMEM127 variants and identified novel structure-function features of TMEM127. These findings will assist in determining pathogenicity of TMEM127 variants and will help guide future studies investigating the cellular role of TMEM127.
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