TMEM127

TMEM127, or transmembrane protein 127, is a human gene that encodes a small multi-pass transmembrane protein located on intracellular membranes, particularly lysosomes and endosomes. It functions as a tumor suppressor, with germline mutations associated with hereditary pheochromocytoma and paraganglioma (PGL/PCC).

The TMEM127 protein is thought to regulate cellular growth signaling, notably the mTOR pathway, by residing on lysosomal membranes and influencing mTORC1 activity. Loss of TMEM127 function can disrupt this regulation and contribute to tumor development. The detailed molecular interactions and partners are an active area of research.

Genetics and clinical significance: Heterozygous TMEM127 mutations confer predisposition to PGL and PCC in families, with variable penetrance and age of onset. A second somatic hit or loss of heterozygosity at the TMEM127 locus is typically required for tumor formation, consistent with a classic tumor suppressor mechanism. Somatic TMEM127 alterations have been observed in pheochromocytomas and paragangliomas, though germline mutations are most strongly linked to familial cases. Mutations are usually loss-of-function, including frameshift, nonsense, splice-site, and some missense changes. Genotype-phenotype correlations remain incompletely defined.

Genetic testing and clinical management: Testing for TMEM127 mutations is considered in individuals with a family history of PGL/PCC or related tumors. Diagnosis involves biochemical evaluation for catecholamines and appropriate imaging, with treatment guided by established guidelines for pheochromocytoma and paraganglioma.