TMEM16F is supported by strong human genetic and functional evidence as the causal gene for Scott syndrome, a rare bleeding disorder. Expression cloning in mouse lymphocyte cell lines identified TMEM16F as a Ca²⁺-dependent phospholipid scramblase; TMEM16F directly mediated phosphatidylserine exposure in cells loaded with a Ca²⁺ ionophore, whereas TMEM16F-deficient cells failed to expose phosphatidylserine, and a TMEM16F mutation was identified in cells from a patient with Scott syndrome (51). Pathogenic TMEM16F variants identified in affected individuals are associated with defective Ca²⁺-dependent phospholipid scrambling and impaired phosphatidylserine exposure in platelets. Platelets from patients with Scott syndrome fail to externalize aminophospholipids (phosphatidylserine and phosphatidylethanolamine) even after stimulation with thrombin and rotenone. This finding directly links TMEM16F deficiency to defective procoagulant membrane remodeling and highlights its potential relevance to the management of bleeding disorders and to transfusion therapy (45,52). TMEM16F-mediated phosphatidylserine exposure has also been described in activated mast cells (in vitro studies summarized in a previous review) (45). Mechanistically, TMEM16F acts as a PLSCR in the plasma membrane, and five acidic amino acids within TMEM16F are critical for Ca²⁺ binding and PLSCR activity, indicating that Ca²⁺ binds directly to TMEM16F to induce its activity (10).

In the gastrointestinal tract, TMEM16A functions as a CaCC in the interstitial cells of Cajal, where Cl⁻ efflux depolarizes these pacemaker cells to generate the slow waves that drive rhythmic smooth muscle contraction, and TMEM16A knockout mice show diminished rhythmic gastrointestinal contraction (53). Consistent with a role for this conductance in intestinal motility, TMEM16A has emerged as a potential regulator of intestinal motility in microarray screening. In rats, both the jejunum and ileum express TMEM16A mRNA and protein, and both levels are reduced in rats with short bowel syndrome showing dysmotility, including enlarged intestinal loops and delayed emptying (54). These findings suggest that reduced TMEM16A-mediated Cl⁻ conductance contributes to intestinal dysmotility after bowel resection, although the evidence is correlative and causality has not been established.

TMEM16A expression was detected in the skin and apical ectodermal ridge at embryonic day E10.5 in mice using whole-mount RNA in situ hybridization (55), in the human sweat gland cell line NCL-SG3 and in isolated human eccrine sweat gland biopsy samples (56). In human sweat gland cells, Ca²⁺ influx through SOCE is required to activate TMEM16A and trigger agonist-induced Cl⁻ secretion. Accordingly, patients with loss-of-function mutations in ORAI1 or stromal interaction molecule (STIM)1 (skin biopsies from three patients) (57) and mice with ectodermal tissue-specific deletion of Orai1 or Stim1/Stim2 fail to sweat despite normal sweat gland development (57). Notably, expression of TMEM16A and the water channel aquaporin 5 (AQP5) was preserved in the absence of SOCE, indicating that the impaired chloride secretion lies in TMEM16A activation rather than in TMEM16A expression. Thus, TMEM16A functions as the Cl⁻ channel downstream of SOCE in sweat production in humans and mice (57).

TMEM16A is present in numerous cell types and plays essential roles in smooth muscle contraction, sensory signal transduction and epithelial secretion (11,53,58). CaCCs regulate the excitability of several classes of sensory neuron, including olfactory sensory neurons, somatosensory neurons and photoreceptors (53). TMEM16A has been observed in airway smooth muscle cells, the smooth muscle of the reproductive tracts, including the oviduct and ductus epididymis, the gastrointestinal tract and the interstitial cells of Cajal (the pacemaker cells whose depolarization governs rhythmic smooth muscle contraction) rather than in gastrointestinal smooth muscle cells themselves (53). These observations underscore the physiological importance of TMEM16A as an essential component of CaCCs (11). TMEM16A is also present in smooth muscle myocytes of the carotid artery, thoracic aorta and portal vein of mice, and TMEM16A-GFP transfected into 293 cells produces currents closely resembling native CaCCs, with steep outward rectification, slow kinetics and sensitivity to niflumic acid, supporting a role in murine vascular smooth muscle cells (58). Dysregulation of TMEM16A has been linked to nociception, hypertension and gastrointestinal dysfunction, as well as to several cancer types that are outside the scope of the present review, as summarized in a previous review article (59).

TMEM163 functions as a zinc transporter. Decreased levels of TMEM163 RNA and protein were observed in cultured fibroblasts from patients with mucolipidosis type IV, a condition associated with elevated tissue zinc levels, and knockdown of TMEM163 increased intracellular zinc levels in 293 cells. These findings indicate an important role of TMEM163 in regulating cellular zinc balance (60,61). TMEM163 variants have also been reported in Parkinson's disease (47).

Mass spectrometric analysis revealed that TMEM263 co-purifies with both anti-Slick and anti-Slack antibodies in the mouse brain. Slick and Slack are sodium-activated potassium channels found throughout the mammalian central nervous system that contribute to hyperpolarization, depolarization and stabilization of the resting potential, and human mutations in Slack are associated with learning and developmental defects (49). It was therefore proposed that TMEM263 directly partners with Slick and Slack in the mouse brain (50), although direct evidence linking TMEM263 to human learning disorders is lacking.

Analysis of The Genotype-Tissue Expression RNA-sequencing database (bioinformatics study) revealed that TMEM52, TMEM233, TMEM38A/TRIC-A and TMEM38B/TRIC-B are preferentially transcribed in skeletal muscle (62). Skeletal muscle loss is a critical contributor to aging and various diseases, including drug-induced myopathy, myotonia, cachexia, sarcopenia and muscular dystrophy. TMEM233 is preferentially expressed in skeletal muscle, myoblasts and myotubes, while the neighboring genes TMEM52 and CALML6 share a 6-kb skeletal-muscle super-enhancer that appears to upregulate TMEM52 preferentially, as reflected by their skeletal-muscle expression levels (82 vs. ~7 TPM) and by the strong promoter chromatin present at TMEM52 but not CALML6 (62). TMEM38A/TRIC-A and TMEM38B/TRIC-B encode trimeric intracellular cation channels of the sarcoplasmic and endoplasmic reticulum that conduct K⁺ as counter-ions, supporting Ca²⁺ release through ryanodine and IP₃ receptors. TRIC-A is enriched in excitable tissues including skeletal and cardiac muscle, whereas loss-of-function mutations in TMEM38B cause autosomal recessive osteogenesis imperfecta type XIV through dysregulated endoplasmic reticulum Ca²⁺ handling in osteoblasts. Consistent with this, TMEM38A-null mice show a subtle skeletal-muscle phenotype, whereas TMEM38B-null mice die of respiratory failure (62). The preferential skeletal-muscle expression of these genes suggests roles in muscle differentiation and maintenance, with potential implications for exercise, aging and muscle-related disease, although the strength of the supporting evidence differs among them (62) (Table SII). TMEM38 proteins have also been implicated in the regulation of SOCE (14) (discussed below).

ORAI1 (TMEM142A) forms the pore of the Ca²⁺ release-activated Ca²⁺ (CRAC) channel, which opens when STIM1 senses ER Ca²⁺ depletion. Patients with a hereditary form of severe combined immunodeficiency were homozygous for a single missense mutation in ORAI1 (R91W) (63), which abolished store-operated Ca²⁺ influx and CRAC currents in their T cells, and re-expression of wild-type ORAI1 in patient T cells restored these responses (63,64). Consistent with these findings, Orai1-deficient mice showed markedly reduced SOCE, CRAC currents and cytokine production in T cells, as well as impaired Ca²⁺ influx and proliferation of B cells (65), and mast cells derived from Orai1-deficient mice showed defective degranulation, leukotriene C4 release and TNF-α production (66). Loss of ORAI1-mediated SOCE also abolishes thermoregulatory sweating through failure to activate TMEM16A in sweat glands (57), illustrating how two TMEM-dependent mechanisms, Ca²⁺ entry and Ca²⁺-activated Cl⁻ conductance, operate in series to support a single physiological function.

SARAF (TMEM66) is an ER membrane protein that associates with STIM1 to promote slow Ca²⁺-dependent inactivation of SOCE, thereby limiting refilling of intracellular Ca²⁺ stores and protecting cells from Ca²⁺ overload, as demonstrated by overexpression, RNA interference-mediated knockdown and electrophysiological experiments in 293 and Jurkat T cells (67). Excessive Ca²⁺ influx into pancreatic acinar cells is a central event in acute pancreatitis. Saraf knockout mice developed more severe caerulein- or L-arginine-induced pancreatitis, with increased Ca²⁺ influx in acinar cells, whereas overexpression of SARAF in acinar cells reduced Ca²⁺ influx, inflammation and disease severity (68). In addition, SARAF mRNA levels were reduced in pancreatic tissues from patients with pancreatitis (68). These findings suggest that SARAF protects against pancreatitis by restraining SOCE, although human evidence is currently limited to expression data.

TMEM106B, a lysosomal protein, has been identified as a risk factor for frontotemporal lobar degeneration (FTLD) characterized by transactive response DNA-binding protein 43 kDa (TDP-43) accumulation, and upregulation of TMEM106B leads to lysosomal dysfunction. Neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder to which progranulin (GRN) deficiency may contribute. Both GRN and TMEM106B exhibit elevated levels in mouse models of NCL, and increased levels of TMEM106B were observed in the brains of patients with FTLD-TDP/GRN. Consequently, TMEM106B was proposed as an important factor in FTLD-TDP/GRN and NCL (69).

Antibodies that recognize the C-terminal fragment of TMEM106B, termed TMEM106B C-terminal immunoreactive (TMEM-ir), can detect TMEM106B in human post-mortem brain tissue using immunohistochemistry. TMEM-ir accumulates in Alzheimer's disease, tauopathies, synucleinopathies, FTLD-TDP and aging brain tissue alike, and the presence of TMEM-ir aggregates appears to correlate with patient age in most cases. These results suggest that the accumulation of TMEM106B C-terminal fragments is an age-related phenomenon with potential utility as a biomarker for neurodegenerative diseases (38,70), although these data do not by themselves establish causality.

Missense and nonsense mutations in TMEM240 have been identified in patients with SCA21 (71,72). Models of the SCA21 mutants T80M and R116C have been established using HeLa cells, primary cultured cerebellar Purkinje cells and mice. Although the SCA21 mutants did not appear to disrupt clathrin-mediated endocytosis, they impaired the degradation of autophagic lysosomal proteins in HeLa cells. In cultured cerebellar Purkinje cells from rat embryos, the SCA21 mutants hindered dendritic development through lysosomal dysfunction. In addition, mice expressing SCA21 with mutant TMEM240 exhibited activated microglia and astrocytes and impaired motor coordination, and chaperone-mediated autophagy was compromised in their cerebella. These results suggest that mutant TMEM240 drives SCA21 pathogenesis through lysosomal dysfunction and early glial activation (73).

In Caenorhabditis elegans, mutations in the TMEM39A ortholog result in lysosome tubularization, reduced lysosome mobility and accumulation of the lysosome-associated membrane protein LMP-1. Similarly, knockout of TMEM39A in 293T cells results in the redistribution of lysosomes from the perinuclear region to the cell periphery. TMEM39A binds the dynein intermediate chain DYNC1I2 to regulate lysosome distribution through mTOR signaling. These findings suggest that TMEM39A maintains proper lysosome distribution, which may be relevant to the lysosomal abnormalities observed in human autoimmune diseases (74).

Through whole-exome sequencing in a patient cohort study, a total of 45 rare variants spanning six TMEMs were identified among 743 patients with unrelated early-onset Parkinson's disease. Notably, variants affecting TMEM175 at position 176 (K>E) and TMEM163 at position 33 (P>R) were linked to Parkinson's disease at the allele level, and three missense variants of TMEM163 were observed exclusively in patients. Hence, these variants of TMEM175 and TMEM163 may serve as risk factors for Parkinson's disease (47). TMEM175 functions as a K⁺ channel in endosomes and lysosomes and regulates lysosomal function (75), and TMEM163 regulates cellular zinc balance (60,61), suggesting that these variants may act through lysosomal and ion homeostasis; however, causality and disease mechanisms remain insufficiently established.

TMEM126B encodes a mitochondrial complex I assembly factor. Deficiencies in mitochondrial complex I result in a range of clinical manifestations, including respiratory chain defects, neuropathy, hypotonia, retinopathy, seizures, developmental delay, cardiomyopathy and optic atrophy (76). Targeted exome sequencing followed by whole-exome sequencing in three adults with complex I-deficient phenotypes implicated TMEM126B defects in mitochondrial complex I deficiency (a case series of affected patients) (76). Mitochondrial complex I is also an important source of ROS, which are required for inflammasome activation and cytokine production in physiological and pathological contexts. Knockdown of TMEM126B in human macrophage-like cells in vitro reduced mitochondrial ROS production and the oxidation of succinate dehydrogenase flavoprotein subunit A (SDHA); oxidized SDHA maintains interleukin-1β (IL-1β) expression and stabilizes hypoxia-inducible factor-1α, underscoring the role of TMEM126B in ROS generation (32).

TMEM135 acts as a regulator of mitochondrial dynamics and has been implicated in obesity and non-alcoholic fatty liver disease, as well as in breast cancer prognosis (31). Through its colocalization with the mitochondrial fission mediator dynamin-related protein 1, TMEM135 influences mitochondrial fission (31). Disruption of TMEM135 alters mitochondrial size and number, and its upregulation increases membrane potential and mitochondrial fragmentation. Conversely, loss of TMEM135 reduces oxygen consumption and mitochondrial membrane potential, suggesting its involvement in mitochondrial fusion/fission dynamics and related functions such as lipid metabolism and peroxisomal activity, as summarized in a review of cellular and animal studies (31). In mice, an N-ethyl-N-nitrosourea-induced Tmem135 mutation caused enlarged mitochondria through an imbalance between mitochondrial fission and fusion, together with accelerated age-dependent retinal pathologies, including early photoreceptor loss and features resembling age-related macular degeneration, whereas Tmem135 overexpression caused excessive mitochondrial fragmentation (77). Transgenic mice overexpressing Tmem135 also showed fragmented mitochondria in the heart, accompanied by cardiac hypertrophy and fibrosis (78).

TMEM70 and TMEM242 interact with subunit c of ATP synthase and with assembly factors for mitochondrial complex I, and deletion of TMEM70 and TMEM242 in human cell lines impedes the assembly of ATP synthase and mitochondrial complex I. Specifically, the removal of TMEM242 decreases the incorporation of subunits ATP6, ATP8, j and k into ATP synthase, highlighting the role of TMEM70 and TMEM242 in the assembly of these complexes (33).

TMEM39 localizes within the ER to regulate the production and trafficking of procollagen, the precursor of collagen. Dysregulation of collagen synthesis has been observed in aging and tissue fibrosis in different organs (22). Knockdown of TMEM39 via RNA interference in C. elegans and Drosophila leads to defects in collagen secretion and induces a high ER stress response (22). In human cells, TMEM39 modulates collagen secretion and vesicular trafficking by binding to the cytosolic domain of Sec23A, a coat protein complex II vesicle coat protein. These findings suggest that the functions of TMEM39 in collagen processing and ER homeostasis are evolutionarily conserved (22).

TMEM45A, also termed DERP7, DNAPTP4 or FLJ10134, is highly expressed in epidermal keratinocytes; its expression is increased in human primary cultured keratinocytes and within the granular layer of the epidermis of normal human abdominal skin (25). TMEM45A is primarily localized to the Golgi apparatus, particularly the trans-Golgi network, and accumulates in both native and reconstructed epidermis in association with the keratinocyte differentiation markers KRT10 and FLG. These findings suggest the involvement of TMEM45A in epidermal keratinization (25).

TMEM16A (also termed anoctamin 1) is activated in hepatocytes and increased in the liver tissues of mice and patients with non-alcoholic fatty liver disease. Hepatocyte-specific TMEM16A deletion protects mice against hepatic glucose metabolic disorder, whereas hepatocyte-specific TMEM16A transgenic mice show the opposite phenotype. By binding vesicle-associated membrane protein 3 (VAMP3), hepatocyte TMEM16A disrupts the formation of VAMP3/syntaxin 4 and VAMP3/synaptosome-associated protein 23 complexes, impairing glucose transporter 2 translocation to the plasma membrane and glucose uptake. Thus, TMEM16A regulates hepatic glucose metabolism through a vesicle-trafficking mechanism, and hepatic TMEM16A may represent a therapeutic target in non-alcoholic fatty liver disease (79).

TMEM176A and TMEM176B are cation channels that accumulate in post-Golgi vesicles associated with the late endo-lysosomal system. Experiments using knockout mice demonstrated that these channels are required in dendritic cells for antigen processing and presentation to CD4⁺ T cells. TMEM176A/B therefore act in the major histocompatibility complex class II compartment of dendritic cells to regulate antigen presentation and the priming of naive CD4⁺ T cells and may serve as targets for therapeutic interventions in immune-mediated diseases (26).

Dendritic cells play important roles in promoting recovery and protective autoimmunity after central nervous system injury as well as in inducing neuroprotection and neurogenesis in patients with stroke (80). Microarray screening of peripheral blood mononuclear cells, including dendritic cells, monocytes and macrophages, from patients with chronic spinal cord injury revealed upregulation of TMEM176A and TMEM176B, and high expression of TMEM176A and TMEM176B hindered the maturation and activity of dendritic cells. These findings suggest that altered TMEM176A and TMEM176B expression impedes the maturation and function of protective dendritic cells after spinal cord injury (80), although causality remains unresolved.

TMEM39A was identified as a susceptibility locus for autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus, through genome-wide association (GWA) studies. A large-scale multiracial replication study of systemic lupus erythematosus identified TMEM39A, together with IRF8 and IKZF3-ZPBP2, as a susceptibility locus (81). TMEM39A interacts with seven immune-related molecules, including tumor necrosis factor ligand superfamily member 13B, butyrophilin-like protein 8, 5-hydroxytryptamine receptor 3C and the IL-9 receptor, suggesting its involvement in immune processes such as inflammation, dysregulated type 1 interferon responses and autoantibody production, as summarized in a review of human GWA and protein-interaction studies (44).

Male mice lacking TMEM160 showed delayed establishment of tactile hypersensitivity and decreased pain-associated self-grooming behavior after nerve injury. In cultured dorsal root ganglia, male mice with global TMEM160 knockout showed reduced neuroimmune signaling and transient receptor potential ankyrin 1 (TRPA1)-mediated activity, whereas female mice did not exhibit these changes. These findings suggest that TMEM160 acts as a sexually dimorphic neuroimmune factor influencing specific pain behaviors induced by nerve injury in male mice (82).

TMEM120A (TACAN) is postulated to function as a mechanically activated molecule. TMEM-120, the sole C. elegans ortholog of TMEM120A/B, is expressed throughout development, with notable expression in the germline, embryos and spermatheca. Deletion of the full-length TMEM-120 gene (TMEM-120Δ) leads to abnormal germline development, maternal sterility, reduced brood size and impaired spermathecal contraction, indicating that TMEM120 regulates reproductive physiology in C. elegans (46). The relevance of these findings to human reproductive disease remains to be established.

TMEM16A senses noxious heat and mediates both acute and chronic pain in somatosensory neurons, as summarized in a review of cellular and animal studies (83). Spared nerve injury activates TMEM16A, MEK/ERK and neurokinin-1 receptor (NK-1) in rat dorsal root ganglia, where TMEM16A colocalizes with phosphorylated ERK and NK-1. Additionally, an ERK inhibitor and a TMEM16A antagonist prevent spared nerve injury-induced allodynia, indicating that ERK and NK-1 act downstream of TMEM16A activation (84). The number of TMEM16A-positive neurons and the TMEM16A expression levels are increased in the L4-6 dorsal root ganglia of rats with chronic constriction injury-induced neuropathic pain, and these effects can be reversed by the TMEM16A antagonist T16Ainh-A01 (85). TMEM16A also physically interacts with transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion neurons, where Ca²⁺ influx through TRPV1 activates TMEM16A and the resulting Cl⁻ efflux further depolarizes the neurons, thereby enhancing action potentials and capsaicin-evoked pain-related behaviors (86). 4-isopropylcyclohexanol relieves pain by inhibiting both TRPV1 and TMEM16A, suggesting its potential as an analgesic agent, as summarized in a review (87). In addition, TMEM16A and protease-activated receptor 2 (PAR2) are co-expressed in the dorsal root ganglion neurons of rats with chronic constriction injury and increased inositol 1,4,5-trisphosphate (IP3) levels, supporting a role for TMEM16A, PAR2 and IP3 in the development of neuropathic pain (88). Several molecules modulate TMEM16A activity, as shown in in vitro and animal studies, including liquiritigenin, phosphatidylinositol 4,5-bisphosphate, cholesterol regulators, Eact, N-aroylaminothiazole and capsaicin (89-92). Overall, TMEM16A is a potential therapeutic target for neuropathic pain, as proposed in previous reviews (93,94), although clinical validation is lacking.

TMEM16A also mediates itch signals of Mas-related G protein-coupled receptor (Mrgpr)-dependent pathways. Genetic deficiency of TMEM16A in mouse dorsal root ganglion neurons reduces scratching behaviors in response to dry skin-induced epidermal hyperplasia and in acute and chronic Mrgpr-dependent itch models, whereas TMEM16A overexpression alters itch responses in the dorsal root ganglion neurons of TMEM16A-deficient mice. Therefore, TMEM16A mediates Mrgpr-dependent itch signaling (95).

TMEM48, also termed NDC1, is situated within the nuclear pore wall. Knockdown of TMEM48 disrupts the assembly of nuclear pore complexes in human HeLa cells. In C. elegans, loss of TMEM48 function results in defective nuclear pore complex formation and elevated larval and embryonic mortality. These findings underscore the essential role of TMEM48 in nuclear pore complex assembly (40).

TMEM201, also termed Samp1, localizes to the nuclear poles in normal human myoblasts and myotubes, where the nuclear envelope serves as a microtubule-organizing center. Farnesylated prelamin A is essential for muscle cell differentiation and regulates the localization of TMEM201 at the nuclear poles of myotubes (96). Emery-Dreifuss muscular dystrophy type 2 (EDMD2) is associated with mutations in the Lamin A gene, and in patients with EDMD2 and reduced levels of prelamin A in muscle cell nuclei, TMEM201 is absent from the nuclear poles of myotubes (in vitro studies of patient-derived muscle cells). Consequently, TMEM201 may regulate microtubule nucleation from the myotube nuclear envelope and may contribute to the pathogenesis of EDMD2 (96), possibly as a modifier rather than a primary causal factor.

Members of the TMEM132 family have been implicated in neurological and neuropsychiatric disorders, as discussed below. Through in situ hybridization, TMEM132 family RNAs were detected in whole-mount mouse embryos and tissue sections, with expression of different family members in both the central and peripheral nervous systems, including the early nervous system, trigeminal ganglia, caudal forebrain, cerebral cortex, hippocampus and cerebellar granule layer. These findings suggest that TMEM132 family members have overlapping functions during mouse nervous system development (97).

TMEM132 in C. elegans, the ortholog of human TMEM132D, has been implicated in panic disorder, anxiety and major depressive disorder. Loss-of-function mutations in TMEM132 result in abnormal morphology of dopaminergic posterior deirid neurons in C. elegans. NAP1, a component of the WAVE regulatory complex that regulates F-actin dynamics, directly interacts with TMEM132D, and overexpression of TMEM132D in mammalian cells reduces components of the WAVE regulatory complex and weakens actin nucleation and cell motility. These findings suggest that TMEM132 family proteins play evolutionarily conserved roles in regulating neuronal morphogenesis through the WAVE regulatory complex (98). In addition, three single-nucleotide polymorphisms in TMEM132E (rs887231, rs887230 and rs4795942) were shown to be associated with panic disorder in a case-control association study, primarily in a Danish cohort (among cohorts from the Faroe Islands, Denmark and Germany), suggesting that TMEM132E may contribute to panic disorder risk (99). This association is based on limited genetic evidence, and a TMEM132E-specific mechanism has not been established.

Several TMEMs modulate intracellular signaling pathways, including transforming growth factor-β (TGF-β)/Smad, β-catenin, protein kinase B (Akt), AMP-activated protein kinase (AMPK)/mTOR complex 1 (mTORC1) and inflammatory kinase cascades, or regulate gene expression at the RNA level. Through these pathways, TMEMs influence cell proliferation, fibrosis, survival, senescence and behavior.

TMEM11 overexpression impairs neonatal cardiomyocyte proliferation and regeneration in mice. TMEM11 directly interacts with the methyltransferase METTL1, increasing the N7-methylguanosine methylation of activating transcription factor 5 (ATF5) mRNA. The resulting increase in ATF5 expression upregulates the cyclin-dependent kinase inhibitor INCA1, ultimately inhibiting cardiomyocyte proliferation. Thus, targeting the TMEM11/METTL1/ATF5 axis may enhance heart regeneration after cardiac injury (100).

TMEM88 regulates fibrogenesis in pleural fibrosis, a condition associated with various lung diseases. TMEM88 expression is decreased in tissues affected by pleural fibrosis, and overexpression of TMEM88 inhibits the TGF-β1-induced proliferation of human pleural mesothelial Met-5A cells. TMEM88 overexpression also prevents TGF-β1-induced accumulation of extracellular matrix (ECM) molecules, such as collagen I and fibronectin, reverses changes in the epithelial-mesenchymal transition marker E-cadherin, reduces the fibrosis markers vimentin and α-smooth muscle actin, and downregulates TGF-β receptors I/II and phosphorylated Smad2 and Smad3. Thus, TMEM88 inhibits pleural fibrosis by suppressing TGF-β1/Smad signaling in vitro (101).

TMEM88 expression is low in human keloid tissues and in keloid-derived fibroblasts stimulated by TGF-β1. Increased TMEM88 suppresses cyclin D1, c-Myc and β-catenin protein levels, as well as the migration, proliferation and ECM expression of these fibroblasts, suggesting that TMEM88 acts as an inhibitor of TGF-β1-stimulated fibroblast activation and represents a potential therapeutic target for keloids (102).

Angiotensin II stimulation upregulates TMEM63C expression in cultured human podocytes, which are pivotal in the development of renal diseases. Knockdown of TMEM63C reduces cell viability and Akt signaling and enhances apoptosis in angiotensin II-activated human podocytes, suggesting that TMEM63C serves as a pro-survival factor in human podocytes (103).

TMEM16A Cl⁻ channel activity is augmented by chloride channel accessory 1 (CLCA1), a protein increased in the kidneys of aged mice. Overexpression of human CLCA1 in kidney cells in vitro induces the senescence-associated secretory phenotype by inhibiting AMPK and stimulating mTORC1 signaling. Inhibition of TMEM16A reverses these signaling changes and prevents senescence-associated secretory phenotype alterations. Therefore, TMEM16A contributes to age-related kidney injury through AMPK/mTORC1 signaling (104).

TMEM16A expression and activity are promoted under inflammatory conditions, such as bacterial and viral infections, and inflammatory mediators, including cytokines, bradykinin, histamine and ATP/UTP, affect TMEM16A expression and/or activity. In turn, TMEM16A activates inflammatory signaling pathways, including ERK signaling, NF-κB signaling and IP3 receptor-mediated Ca²⁺ signaling, thereby contributing to the pathogenesis of several inflammatory diseases, as summarized in a review of cellular and animal studies (105).

Adeno-associated virus-mediated TMEM168 overexpression in the mouse nucleus accumbens (NAc) was shown to raise accumbal TMEM168 mRNA approximately seven-fold and induce anxiety-like behavior, reducing open-arm entries and time in the elevated plus-maze and time in the light compartment of the light/dark box, without affecting locomotion, cognition, social interaction or depression-like behavior; the anxiety was reversed by diazepam. TMEM168 overexpression also lowered basal extracellular GABA and blunted the high-K⁺-evoked GABA increase in the NAc, while total NAc GABA content was unchanged (106).

Upon repeated methamphetamine administration, TMEM168 is upregulated in the nucleus accumbens of mice, triggering adaptive changes associated with dependence. Mice with adeno-associated virus-mediated overexpression of TMEM168 in the nucleus accumbens show attenuated methamphetamine-induced hyperlocomotion, conditioned place preference and dopamine elevation, suggesting that TMEM168 inhibits methamphetamine-induced behavioral changes by regulating dopaminergic function in the nucleus accumbens and may be a therapeutic target for methamphetamine dependence (106,107).

TMEM59, also termed DCF1, regulates neural stem cell differentiation. Overexpression of TMEM59 maintains neural stem cells in an undifferentiated state in the C17.2 mouse neural stem cell line (108), whereas knockdown of TMEM59 induces the differentiation of neural stem cells into neurons and astrocytes. Furthermore, miR-351 targets TMEM59 in both C17.2 cells and primary neural stem cells to regulate neural stem cell differentiation in vitro. These findings underscore the importance of TMEM59 in neural differentiation and migration during development and in related diseases (109).

Whole-exome and whole-genome sequencing cohort analyses have identified variants in TMEM230, TMEM59 and TMEM108 in patients with Parkinson's disease. In total, three rare damaging missense variants of TMEM230 (S174F, Y165C and V9L) were found in four patients with sporadic Parkinson's disease but not in controls. Additionally, TMEM59 harbored 11 rare damaging missense variants in sporadic early-onset or familial cases, and TMEM108 harbored 24 rare missense variants in sporadic late-onset cases. These findings suggest genetic associations of these three TMEMs with various forms of Parkinson's disease (48), which require independent replication and functional validation.

A mutation in TMEM187, located in Xq28 (c.708G>T; p.Gln236His), was detected by whole-exome sequencing in a patient diagnosed with high-functioning ASD (a single-patient case report). In silico STRING protein-protein interaction analysis indicated that TMEM187, which is expressed in the brain, interacts with four established ASD-related genes: i) Host cell factor 1; ii) trimethyl lysine dioxygenase; iii) methyl-CpG-binding protein 2 (MECP2); and iv) gephyrin. Among these, MECP2 is notable for its role in determining brain structure and its association with autism. Consequently, TMEM187 has emerged as a potential candidate gene for ASD (110). However, this evidence remains preliminary, as it is based primarily on a single candidate variant and predicted protein interactions, and does not establish TMEM187 as a causal autism gene. TMEM187 is therefore described here as a possible susceptibility candidate requiring replication in larger cohorts and validation through targeted functional studies.

The Xq28 locus containing TMEM187 has been associated with polymorphisms linked to rheumatoid arthritis risk. In a study of 100 Egyptian patients and 100 age- and sex-matched healthy controls, TMEM187 (rs13397) polymorphisms were genotyped using quantitative PCR TaqMan allelic discrimination assays, and the major allele G of TMEM187 rs13397 was suggested to be a genetic risk factor for rheumatoid arthritis in this population (111).

An earlier GWA study identified an association between the TMEM57 locus and total cholesterol concentrations. Analysis of the rs873308 SNP near TMEM57 in a population-based association study revealed that T-allele carriers in the Han Chinese population had lower levels of serum total cholesterol, apolipoprotein B and high-density lipoprotein cholesterol, as well as lower levels of triacylglycerol, low-density lipoprotein cholesterol and apolipoprotein A1 and a lower apolipoprotein A1/apolipoprotein B ratio, whereas higher high-density lipoprotein cholesterol levels were recorded in T-allele carriers of the Mulao ethnic group. These findings suggest that the TMEM57 rs873308 SNP may influence serum lipid levels (112), although the causal gene and mechanism at this locus remain unresolved.

TMEM26 is a marker of the browning of white adipose tissue. Brown adipose tissue counteracts obesity, and activating brown fat and browning white adipocytes are emerging strategies against obesity and its complications. Treatment with flavan-3-ols induces adipose tissue browning and increases TMEM26 expression in the brown adipose tissue of mice (113). Whether TMEM26 contributes causally to browning or serves only as a marker remains unresolved.

In summary, TMEMs contribute to non-cancerous diseases through a limited number of shared cellular mechanisms, and apparently unrelated conditions can reflect disruption of the same process; for example, immunodeficiency and anhidrosis both result from loss of ORAI1-mediated SOCE, whereas SCA21 and FTLD-TDP both involve TMEM-dependent lysosomal dysfunction. A disease-oriented overview of these TMEMs is shown in Fig. 2, and the mechanistic grouping and evidence strength for each association are summarized in Table SII.