Alternative titles; symbols
HGNC Approved Gene Symbol: TRPV3
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38) : 17:3,510,502-3,557,812 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.2 | ?Palmoplantar keratoderma, nonepidermolytic, focal 2 | 616400 | Autosomal dominant | 3 |
| Olmsted syndrome 1 | 614594 | Autosomal dominant | 3 |
TRPV3 belongs to a large family of nonselective cation channels that function in a variety of processes, including temperature sensation (Peier et al., 2002; Xu et al., 2002; Smith et al., 2002).
Peier et al. (2002) cloned mouse Trpv3 from newborn skin cDNA. The deduced 791-amino acid protein contains 2 coiled-coil domains, 4 ankyrin domains, and 6 transmembrane domains. It shares 20 to 43% sequence identity with other Trpv family members. Northern blot analysis detected a 6.5-kb transcript in mouse and rat skin. TRPV3 was also expressed in human adult and fetal skin. Immunolocalization of Trpv3 in newborn mouse revealed protein in most keratinocytes at the epidermal layer and in hair follicles. A marker protein for temperature-sensitive nerve terminals colocalized with Trpv3 at epidermal endings.
By screening a brain cDNA library, Xu et al. (2002) obtained a human cDNA encoding TRPV3. TRPV3 expression was detected in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord, and brain. The deduced 790-amino acid TRPV3 protein contains 6 transmembrane domains and 3 putative N-terminal ankyrin repeats.
Smith et al. (2002) independently cloned the human TRPV3 gene, which they called VRL3. The predicted TRPV3 protein is structurally homologous to TRPV1 (602076) and contains cytoplasmic termini, 4 ankyrin repeats, 6 transmembrane segments, a pore reentrant loop, and several putative phosphorylation sites. Smith et al. (2002) also identified several splice variants.
Peier et al. (2002) determined that the TRPV3 gene spans about 40 kb and is separated from the TRPV1 gene by about 12 kb.
By genomic sequence analysis, Smith et al. (2002) determined that the TRPV3 gene has 17 coding exons and 1 noncoding exon and spans 48 kb. TRPV3 is separated from the TRPV1 gene by about 7.5 kb, and both genes are in the same transcriptional orientation.
Peier et al. (2002) localized the TRPV3 gene to a BAC clone mapped to chromosome 17p13. They mapped the mouse gene to chromosome 11B4.
Peier et al. (2002) stably expressed mouse Trpv3 in Chinese hamster ovary cells and assayed electrophysiologic activity by whole cell voltage-clamp techniques. They determined that Trpv3 is a cation-permeable channel activated by warm and hot temperatures.
Xu et al. (2002) showed that increasing temperature from approximately 22 to 40 degrees Celsius in mammalian cells transfected with human TRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temperature, sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling. On the basis of these properties, Xu et al. (2002) proposed that TRPV3 is thermosensitive in the physiologic range of temperatures between TRPM8 (606678) and TRPV1.
Smith et al. (2002) determined that TRPV3 is heat-sensitive but capsaicin-insensitive. TRPV3 responded to noxious heat with a threshold of about 39 degrees Celsius and was coexpressed in dorsal root ganglion neurons with TRPV1. When heterologously expressed, TRPV3 was able to associate with TRPV1, and the authors suggested that TRPV3 may modulate its responses. Smith et al. (2002) concluded that not only is TRPV3 a thermosensitive ion channel, but it may represent an additional vanilloid receptor subunit involved in the formation of heteromeric vanilloid receptor channels.
Using coimmunoprecipitation analysis, Cheng et al. (2010) found that mouse Trpv3 interacted directly with Egfr (131550). Activation of Egfr with Tgf-alpha (TGFA; 190170) in cultured mouse keratinocytes resulted in tyrosine phosphorylation of Trpv3.
Olmsted Syndrome 1
In 6 Chinese patients with Olmsted syndrome (OLMS1; 614594), or mutilating palmoplantar keratoderma with periorificial keratotic plaques, Lin et al. (2012) identified heterozygosity for de novo missense mutations in the TRPV3 gene (607066.0001-607066.0003). Patch-clamp studies indicated that mutant TRPV3 channels are constitutively active and act in a gain-of-function manner.
In a girl with Olmsted syndrome and erythermalgia, Duchatelet et al. (2014) identified a de novo heterozygous missense mutation in the TRPV3 gene (L673F; 607066.0004).
Focal Nonepidermolytic Palmoplantar Keratoderma 2
In a Chinese father and son with focal palmoplantar keratoderma with no other abnormalities (FNEPPK2; 616400), He et al. (2015) identified heterozygosity for a missense mutation in the TRPV3 gene (Q580P; 607066.0005) that was de novo in the father. Functional analysis suggested that the mutation is a gain-of-function change that disrupts the balance of the keratinocyte proliferation and differentiation processes.
Moqrich et al. (2005) generated mice deficient in Trpv3 by targeted disruption. The Trpv3 null mice had strong deficits in responses to innocuous and noxious heat but not in other sensory modalities; hence, Trpv3 has a specific role in thermosensation. The natural compound camphor, which modulates sensations of warmth in humans, proved to be a specific activator of Trpv3. Camphor activated cultured primary keratinocytes but not sensory neurons, and this activity was abolished in Trpv3 null mice. Moqrich et al. (2005) concluded that heat-activated receptors in keratinocytes are important for mammalian thermosensation.
Asakawa et al. (2006) studied DS-Nh mice and WBN/Kob-Ht rats, which are both spontaneous hairless mutant rodent strains with autosomal dominant inheritance that develop spontaneous dermatitis (hyperkeratosis) under normal conditions. Breeding studies had indicated that the genes involved in dermatitis and hairlessness were very tightly linked and segregated together, and genetic analysis revealed a G573S mutation in the Trpv3 gene (607066.0001) of DS-Nh mice that was not found in 6 other strains of mice examined. A different TRPV3 mutation at the same position, G573C (607066.0002), was identified in the WBN/Kob-Ht rats.
Imura et al. (2007) reported that DNA microarray data from the skin of 3-day-old DS and DS-Nh mice showed that levels of keratin-associated protein genes 16-1, 16-3, and 16-9 in the anagen phase were decreased in the skins of DS-Nh mice compared to DS mice. Histologic analysis demonstrated that the anagen phase persisted in the DS-Nh mice and that the telogen phase was seen in DS but not DS-Nh mice at 21 days of age. Imura et al. (2007) concluded that regulation of TRPV3 appears to be important for appropriate hair development in rodents.
Cheng et al. (2010) obtained Trpv3 -/- mice at the expected mendelian ratio and at a normal weight. Newborn Trvp3 -/- mice could be identified by their curly whiskers, erythroderma, and dry, scaly skin. Curling of whiskers in Trpv3 -/- animals increased with age, and fur was wavy. Individual hair follicles of Trpv3 -/- skin were curved and pointed in different directions, resulting in a deranged organization compared with wildtype follicles. Trpv3 -/- epidermis showed increased thickness in the keratin-1 (139350)-positive layer, and day-17 Trpv3 -/- embryos exhibited compromised epidermal barrier function. Similar phenotypic changes were observed in mice with conditional Trpv3 knockout in keratinocytes. The phenotype resembled those of mice with defective signaling through Tgf-alpha and/or Egfr. Trpv3 -/- keratinocytes had a similar intracellular calcium concentration as wildtype keratinocytes, but they lacked Trvp3-mediated calcium responses and showed defective Tgf-alpha/Egfr signaling. Cheng et al. (2010) concluded that TRPV3 is involved in a signaling pathway that promotes late terminal differentiation of the epidermis.
In 4 Chinese female patients with mutilating palmoplantar keratoderma with periorificial keratotic plaques (OLMS1; 614594), Lin et al. (2012) identified heterozygosity for a de novo 1717G-A transition in the TRPV3 gene, resulting in a gly573-to-ser (G573S) substitution at a highly conserved residue in the linker region between S4 and S5. Patch-clamp studies in HEK293 cells expressing G573S demonstrated that the mutant channel is constitutively active and acts in a gain-of-function manner. Mutant HEK293 cells were also found to have a significantly higher cell death rate at 24 hours after transfection compared to controls, and the cell death could be partly rescued by a TRP channel inhibitor. In addition, apoptotic cell rates in keratinocytes from patients' keratotic lesions were significantly higher compared to controls. The mutation was not detected in the 3 sets of parents from whom DNA was available, nor was it found in 216 ethnically matched controls. The palmoplantar keratoderma ranged from mild to severe; 3 of the 4 patients had constricting digital bands, and 2 had spontaneous digit amputation, with loss of all digits in 1 patient. Periorificial keratosis was mild in 1 patient, moderate in 1, and severe in 2, and alopecia ranged from minimally present (dry curly hair) to severe.
In a 14-year-old Chinese girl with mutilating palmoplantar keratoderma with periorificial keratotic plaques (OLMS1; 614594), Lin et al. (2012) identified heterozygosity for a de novo 1717G-T transversion in the TRPV3 gene, resulting in a gly573-to-cys (G573C) substitution at a highly conserved residue in the linker region between S4 and S5. Patch-clamp studies in HEK293 cells expressing G573C demonstrated that the mutant channel is constitutively active and acts in a gain-of-function manner. Mutant HEK293 cells were also found to have a significantly higher cell death rate at 24 hours after transfection compared to controls, and the cell death could be partly rescued by a TRP channel inhibitor. In addition, apoptotic cell rates in keratinocytes from the patient's keratotic lesions were significantly higher compared to controls. Her unaffected parents did not carry the mutation, which was also not found in 216 ethnically matched controls. The patient had mild palmoplantar and periorificial keratosis and moderate alopecia.
In a 23-year-old Chinese man with mutilating palmoplantar keratoderma with periorificial keratotic plaques (OLMS1; 614594), Lin et al. (2012) identified heterozygosity for a de novo 2074T-G transversion in the TRPV3 gene, resulting in a trp692-to-gly (W692G) substitution at a highly conserved residue in the TRP box of the TRP domain. Patch-clamp studies in HEK293 cells expressing W692G demonstrated that the mutant channel is constitutively active and acts in a gain-of-function manner. Mutant HEK293 cells were also found to have a significantly higher cell death rate at 24 hours after transfection compared to controls, and the cell death could be partly rescued by a TRP channel inhibitor. His unaffected parents did not carry the mutation, which was also not found in 216 ethnically matched controls. The patient had moderate palmoplantar keratosis with constricting digital bands, moderate periorificial keratosis, and mild alopecia.
In a 5-year-old girl with mutilating palmoplantar keratoderma with periorificial keratotic plaques (OLMS1; 614594) who also exhibited severe erythermalgia, Duchatelet et al. (2014) identified heterozygosity for a de novo c.2017C-T transition (c.2017C-T, NM_001258025.1) in exon 15 of the TRPV3 gene, resulting in a leu673-to-phe (L673F) substitution at a highly conserved residue. The mutation was not found in her parents or in 100 controls, 253 in-house exomes, or 6,503 individuals from the NHLBI Exome Sequencing Project. TRPV3 homology modeling of an assembled channel revealed that L673 is situated immediately above the predicted activation gate residue (M677) on the preceding helical turn, suggesting that the mutation may affect channel gating.
In a Chinese father and son with focal palmoplantar keratoderma (FNEPPK2; 616400), He et al. (2015) identified heterozygosity for a T-G transversion (chr17.3,427,496, GRCh37) in exon 13 of the TRPV3 gene, resulting in a gln580-to-pro (Q580P) substitution at a highly conserved residue within a cytosolic region linking the fourth and fifth transmembrane domains. The mutation occurred de novo in the father; it was not detected in the unaffected paternal grandparents, an unaffected paternal uncle, or an unaffected sister. Transfection studies in HEK293T cells demonstrated an increased intracellular Ca(2+) concentration with the mutant compared to wildtype, suggesting that Q580P is a gain-of-function change. Transcriptome and proteome profiling showed that genes/proteins known to be highly expressed in the stratum granulosum and spinosum layers, such as KRT10 (148080), transglutaminases (see TGM1, 190195), and filaggrins (see FLG, 135940) were decreased in the involved skin compared to uninvolved areas. Immunohistochemical analysis showed weaker signals and no clear stratum granulosum layer staining with TGM1 and FLG in patient skin compared to control. In addition, expression levels of proteins involved in gap junctions, tight junctions, and desmosomes were decreased in affected skin, consistent with the disadhesion of cells in the suprabasal layers of the epidermis observed on histopathologic examination. Transcriptomic profiling also revealed changes in the levels of several keratinocyte proliferation- and differentiation-related transcription factors, and immunohistochemistry showed a broader layer of KRT14 (148066)-positive cells in the basal layer and weaker KRT10-positive cells in the spinosum layer of affected individuals. Based on these results, He et al. (2015) suggested that the Q580P mutation disrupts the balance of the keratinocyte proliferation and differentiation process.
Asakawa, M., Yoshioka, T., Matsutani, T., Hikita, I., Suzuki, M., Oshima, I., Tsukahara, K., Arimura, A., Horikawa, T., Hirasawa, T., Sakata, T. Association of a mutation in TRPV3 with defective hair growth in rodents. J. Invest. Derm. 126: 2664-2672, 2006. [PubMed: 16858425] [Full Text: https://doi.org/10.1038/sj.jid.5700468]
Cheng, X., Jin, J., Hu, L., Shen, D., Dong, X., Samie, M. A., Knoff, J., Eisinger, B., Liu, M., Huang, S. M., Caterina, M. J., Dempsey, P., Michael, L. E., Dlugosz, A. A., Andrews, N. C., Clapham, D. E., Xu, H. TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell 141: 331-343, 2010. [PubMed: 20403327] [Full Text: https://doi.org/10.1016/j.cell.2010.03.013]
Duchatelet, S., Pruvost, S., de Veer, S., Fraitag, S., Nitschke, P., Bole-Feysot, C., Bodemer, C., Hovnanian, A. A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia. JAMA Derm. 150: 303-306, 2014. [PubMed: 24452206] [Full Text: https://doi.org/10.1001/jamadermatol.2013.8709]
He, Y., Zeng, K., Zhang, X., Chen, Q., Wu, J., Li, H., Zhou, Y., Glusman, G., Roach, J., Etheridge, A., Qing, S., Tian, Q., Lee, I., Tian, X., Wang, X., Wu, Z., Hood, L., Ding, Y., Wang, K. A gain-of-function mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family. (Letter) J. Invest. Derm. 135: 907-909, 2015. [PubMed: 25285920] [Full Text: https://doi.org/10.1038/jid.2014.429]
Imura, K., Yoshioka, T., Hikita, I., Tsukahara, K., Hirasawa, T., Higashino, K., Gahara, Y., Arimura, A., Sakata, T. Influence of TRPV3 mutation on hair growth cycle in mice. Biochem. Biophys. Res. Commun. 363: 479-483, 2007. [PubMed: 17888882] [Full Text: https://doi.org/10.1016/j.bbrc.2007.08.170]
Lin, Z., Chen, Q., Lee, M., Cao, X., Zhang, J., Ma, D., Chen, L., Hu, X., Wang, H., Wang, X., Zhang, P., Liu, X., and 9 others. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am. J. Hum. Genet. 90: 558-564, 2012. [PubMed: 22405088] [Full Text: https://doi.org/10.1016/j.ajhg.2012.02.006]
Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., Spencer, K. S. R., Andahazy, M., Story, G. M., Patapoutian, A. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307: 1468-1472, 2005. [PubMed: 15746429] [Full Text: https://doi.org/10.1126/science.1108609]
Peier, A. M., Reeve, A. J., Andersson, D. A., Moqrich, A., Earley, T. J., Hergarden, A. C., Story, G. M., Colley, S., Hogenesch, J. B., McIntyre, P., Bevan, S., Patapoutian, A. A heat-sensitive TRP channel expressed in keratinocytes. Science 296: 2046-2049, 2002. [PubMed: 12016205] [Full Text: https://doi.org/10.1126/science.1073140]
Smith, G. D., Gunthorpe, M. J., Kelsell, R. E., Hayes, P. D., Reilly, P., Facer, P., Wright, J. E., Jerman, J. C., Walhin, J.-P., Ooi, L., Egerton, J., Charles, K. J., Smart, D., Randall, A. D., Anand, P., Davis, J. B. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418: 186-190, 2002. [PubMed: 12077606] [Full Text: https://doi.org/10.1038/nature00894]
Xu, H., Ramsey, I. S., Kotecha, S. A., Moran, M. M., Chong, J. A., Lawson, D., Ge, P., Lilly, J., Silos-Santiago, I., Xie, Y., DiStefano, P. S., Curtis, R., Clapham, D. E. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418: 181-186, 2002. [PubMed: 12077604] [Full Text: https://doi.org/10.1038/nature00882]