Apr 9, 2020

Functional characterization of germline variants in the TMEM127 tumor suppressor reveals novel insights into its membrane topology and trafficking

BioRxiv : the Preprint Server for Biology
Shahida K FloresPatricia L M Dahia


Purpose: To better understand the function of the transmembrane protein TMEM127, a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas and renal carcinomas, we evaluated patient-derived germline variants. Methods: Subcellular localization and steady-state levels of 21 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 three subgroups of mutations and determined that 15 of the 21 variants (71%), including 9 of 15 missense variants (60%), 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 four-, not a three-, 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 throug...Continue Reading

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Mentioned in this Paper

Tissue Membrane
Protein Secretion by the Type III Secretion System
Outer Membrane
Protein Secretion
Process of Secretion
Genetic Activator
Type V Protein Secretion System Complex

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