Submission Details

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] describes susceptibility to Paraganglioma such as head and neck, retroperitoneum [PMID: 21613359], or Renal cell carcinomas (RCCs) [PMID 24334765] and Pheochromocytoma [MIM#171300, PMID: 21156949] with autosomal dominant inheritance. TMEM127 [MIM# 613403] gene encodes the transmembrane protein 127. Heterozygous germline loss of function variants in TMEM127 were first described in 2005 [Dahia PL, et al.; PMID 16266984]. The LOH (loss of heterozygosity) at the TMEM127 locus in tumors examined suggests TMEM127 is a tumor suppressor gene. Genetic evidence from studies on familial and patients with sporadic Pheochromocytomas, as well as RCC are used in this curation [PMID 16266984, 25389632, 20154675 and 28384794]. Experimental evidences such as reduced TMEM127 transcription levels of TMEM127-mutant tumor samples in Pheochromocytomas and Renal cell carcinomas; reduced mTOR signaling, enlarged cells, reduced vesicles and/or increased cell growth compared to non mutant controls in various human cells and murine model cells with reduced or depleted TMEM127 are included for this curation. Evidence that the enlarged cells and increased cell proliferation were rescued by enforced expression of TMEM127 is also included [PMID 20154675, 21156949, 24334765]. In summary, TMEM127 gene is definitely associated with autosomal dominant HPGL/PCC syndrome, most commonly pheochromocytoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.