Table 1. Physiological roles of TMEM63... | Rockefeller University Press

Table 1.

Physiological roles of TMEM63 protein family

Member	Expression	Related physiology/pathology	Ref
TMEM63A	Oligodendrocytes and central nervous system	Mutations cause infantile hypomyelinating leukodystrophy	Yan et al. (2019)
		Mutation identified in infantile hypomyelinating leukodystrophy	Tonduti et al. (2021)
		Mutations cause infantile hypomyelinating leukodystrophy with global developmental delay	Fukumura et al. (2022)
		Modulates myelin and myelin-associated protein production	Halford et al. (2025)
	Triple-negative breast cancer	Acts as an oncogene; involved in autophagy-mediated degradation pathway	Zhang et al. (2023b)
	Diffuse large B cell lymphoma	Potential therapeutic target; knockout inhibits diffuse large B cell lymphoma proliferation	Wu et al. (2022)
	Dorsal root ganglion neurons	Mediates macrophage infiltration and pro-inflammatory cytokine release, leading to pain hypersensitivity in chronic postamputation pain	Pu et al. (2023)
	Alveolar type 2 epithelial cells, lung	Mediates lung inflation-induced surfactant and ATP release	Chen et al. (2024)
TMEM63B	Alveolar type 2 epithelial cells, lung	Mediates lung inflation-induced surfactant and ATP release	Chen et al. (2024)
	Intestinal stem cells and small intestine	Regulates intestinal stem cell proliferation and motility	Tu et al. (2024)
	Subfornical organ neurons	Directly responds to hyperosmolarity in thirst	Zou et al. (2025)
	Subfornical organ neurons	Osmosensor detecting systemic hyperosmolality for thirst drive	Yang et al. (2024)
	Cochlear sensory epithelial cells, inner ear	Regulates the regression of the greater epithelial ridge for normal onset of hearing	Ye et al. (2024)
	Outer hair cells and inner ear	Osmosensing regulates cell volume	Du et al. (2020)
	Brain	Gain-of-function variants cause neurodevelopmental disorder with epilepsy and neurodegeneration	Vetro et al. (2023)
	Pancreatic β-cells	Responds to glucose-induced swelling, triggering depolarization and insulin secretion	Tu et al. (2025)
	Olfactory interneurons	Mediates mechanical signaling for somal translocation during neuronal migration	Minegishi et al. (2025)
TMEM63C	Podocytes and kidney	Downregulated in angiotensin II-induced podocyte apoptosis	Eisenreich et al. (2020)
		Downregulation causes podocyte loss; restoring TMEM63C rescues their viability	Orphal et al. (2020)
		Essential for normal kidney filtration barrier function	Schulz et al. (2019)
	Nervous system	Dysfunction disrupts ER-mitochondrial contact sites in hereditary spastic paraplegia	Tábara et al. (2022)

Member	Expression	Related physiology/pathology	Ref
TMEM63A	Oligodendrocytes and central nervous system	Mutations cause infantile hypomyelinating leukodystrophy	Yan et al. (2019)
		Mutation identified in infantile hypomyelinating leukodystrophy	Tonduti et al. (2021)
		Mutations cause infantile hypomyelinating leukodystrophy with global developmental delay	Fukumura et al. (2022)
		Modulates myelin and myelin-associated protein production	Halford et al. (2025)
	Triple-negative breast cancer	Acts as an oncogene; involved in autophagy-mediated degradation pathway	Zhang et al. (2023b)
	Diffuse large B cell lymphoma	Potential therapeutic target; knockout inhibits diffuse large B cell lymphoma proliferation	Wu et al. (2022)
	Dorsal root ganglion neurons	Mediates macrophage infiltration and pro-inflammatory cytokine release, leading to pain hypersensitivity in chronic postamputation pain	Pu et al. (2023)
	Alveolar type 2 epithelial cells, lung	Mediates lung inflation-induced surfactant and ATP release	Chen et al. (2024)
TMEM63B	Alveolar type 2 epithelial cells, lung	Mediates lung inflation-induced surfactant and ATP release	Chen et al. (2024)
	Intestinal stem cells and small intestine	Regulates intestinal stem cell proliferation and motility	Tu et al. (2024)
	Subfornical organ neurons	Directly responds to hyperosmolarity in thirst	Zou et al. (2025)
	Subfornical organ neurons	Osmosensor detecting systemic hyperosmolality for thirst drive	Yang et al. (2024)
	Cochlear sensory epithelial cells, inner ear	Regulates the regression of the greater epithelial ridge for normal onset of hearing	Ye et al. (2024)
	Outer hair cells and inner ear	Osmosensing regulates cell volume	Du et al. (2020)
	Brain	Gain-of-function variants cause neurodevelopmental disorder with epilepsy and neurodegeneration	Vetro et al. (2023)
	Pancreatic β-cells	Responds to glucose-induced swelling, triggering depolarization and insulin secretion	Tu et al. (2025)
	Olfactory interneurons	Mediates mechanical signaling for somal translocation during neuronal migration	Minegishi et al. (2025)
TMEM63C	Podocytes and kidney	Downregulated in angiotensin II-induced podocyte apoptosis	Eisenreich et al. (2020)
		Downregulation causes podocyte loss; restoring TMEM63C rescues their viability	Orphal et al. (2020)
		Essential for normal kidney filtration barrier function	Schulz et al. (2019)
	Nervous system	Dysfunction disrupts ER-mitochondrial contact sites in hereditary spastic paraplegia	Tábara et al. (2022)

Summary of all established physiological and pathological functions of TMEM63s, including mechanosensation and osmoregulation processes in specific cell types.

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