{"doi":"10.1210/clinem/dgaa396","title":"Functional Characterization of <i>TMEM127</i> Variants Reveals Novel Insights into Its Membrane Topology and Trafficking","abstract":"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.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2020,"id":78762,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":409521,"name":"Yilun Deng","orcid":"0000-0002-7209-7855","position":1,"is_corresponding":false},{"id":409522,"name":"Ziming Cheng","orcid":"0009-0006-4316-0903","position":2,"is_corresponding":false},{"id":409523,"name":"Xingyu Zhang","orcid":"0009-0005-6361-1145","position":3,"is_corresponding":false},{"id":410595,"name":"Sifan Tao","orcid":null,"position":4,"is_corresponding":false},{"id":410596,"name":"Afaf Saliba","orcid":null,"position":5,"is_corresponding":false},{"id":410597,"name":"Irene Chu","orcid":null,"position":6,"is_corresponding":false},{"id":399749,"name":"Nelly Burnichon","orcid":"0000-0001-7972-5845","position":7,"is_corresponding":false},{"id":70235,"name":"Anne‐Paule Gimenez‐Roqueplo","orcid":"0000-0002-4816-670X","position":8,"is_corresponding":false},{"id":410598,"name":"Exing Wang","orcid":null,"position":9,"is_corresponding":false},{"id":409524,"name":"Ricardo C.T. Aguiar","orcid":"0000-0002-8791-5849","position":10,"is_corresponding":false},{"id":399750,"name":"Patricia L. M. Dahia","orcid":"0000-0002-7757-370X","position":11,"is_corresponding":false},{"id":400949,"name":"Shahida K. Flores","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T21:50:09.793321Z","pmid":"32575117","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}