Gene TMEM127
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Also known as
Transmembrane Protein 127, RCC-associated protein, PPGL3Overview
TMEM127 (Transmembrane Protein 127) encodes an endosomal membrane protein that functions as a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. The protein localizes to endomembranes and plays a role in controlling cell growth and proliferation by modulating mTOR activity, which integrates signals from nutrients, growth factors, and cellular energy status. TMEM127 interacts with mTOR and contributes to the proper localization and regulation of mTORC1 signaling. Loss of TMEM127 function results in constitutive activation of mTOR signaling, promoting cell growth and survival.Germline mutations in TMEM127 are associated with hereditary pheochromocytoma and paraganglioma (PCC/PGL), neuroendocrine tumors arising from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. These tumors can cause episodic or sustained hypertension due to excessive catecholamine secretion and carry risks of malignancy and metastasis. TMEM127-related PCC/PGL typically presents with solitary adrenal pheochromocytomas and shows autosomal dominant inheritance with incomplete penetrance. Genetic testing for TMEM127 mutations is important for individuals with personal or family history of these tumors, enabling early detection, appropriate surveillance, and surgical intervention when indicated. Understanding TMEM127 function has also provided insights into mTOR pathway dysregulation in cancer.