Tmem63a, or transmembrane protein 63A, functions as a mechanosensitive ion channel. It is involved in processes like mechanotransduction, and is associated with pathways such as autophagic degradation. It has significance in various biological functions and diseases, with genetic models like knockout mice being crucial for its study [1,2,3,4,5,6,7,8,9].

In triple-negative breast cancer (TNBC), Tmem63a acts as an oncogene promoting cell proliferation, migration, invasion, and metastasis. It localizes in endoplasmic reticulum and lysosome membranes, interacting with VCP and DERL1, and undergoes TOLLIP-mediated autophagic degradation [1].

In the context of lysosomal function, Drosophila Tmem63 and mouse Tmem63a are lysosomal mechanosensory ion channels, with Tmem63 mutant flies showing impaired lysosomal degradation and related phenotypes [2].

In lung function, loss of Tmem63a and Tmem63b results in atelectasis and respiratory failure due to surfactant secretion deficit, as they are involved in releasing surfactant and ATP from lamellar bodies in alveolar type 2 epithelial cells [3].

In the nervous system, Tmem63a deficiency causes hypomyelination in mice due to impaired oligodendrocyte precursor cell differentiation, and a patient with a Tmem63a mutation showed similar hypomyelination phenotypes [8]. Also, Tmem63a in nociceptors and infiltrated macrophages in the dorsal root ganglion work together to promote chronic post-amputation pain [7].

In summary, Tmem63a is essential for multiple biological processes. Its functions range from cancer progression in TNBC to lysosomal function, lung surfactant secretion, myelination in the nervous system, and pain modulation. Gene knockout mouse models have been instrumental in revealing its role in these disease-related conditions, providing insights into potential therapeutic targets for TNBC, respiratory disorders, leukodystrophies, and chronic pain.