Alternative titles; symbols
HGNC Approved Gene Symbol: TRPM1
Cytogenetic location: 15q13.3 Genomic coordinates (GRCh38): 15:31,001,065-31,161,160 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q13.3 | Night blindness, congenital stationary (complete), 1C, autosomal recessive | 613216 | Autosomal recessive | 3 |
TRPM1 is the founding member of the melastatin-related transient receptor (TRPM) channel family. TRPMs are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N and C termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in some TRPM channels, an enzymatic domain (review by Farooqi et al., 2011).
Duncan et al. (1998) used differential display PCR to identify an RNA sequence that was downregulated in highly metastatic mouse melanoma cells compared with poorly metastatic cells. They cloned the corresponding mouse cDNA, termed melastatin. Northern blot analysis of mouse tissues and cell lines revealed that melastatin was expressed as a 2.8-kb mRNA in normal eye and in 4 melanoma cell lines; its expression in each of the 4 cell lines was inversely proportional to metastatic potential. In 45 human melanocytic primary neoplasms examined by in situ hybridization, the loss of melastatin expression correlated with the thickness of the melanomas.
Hunter et al. (1998) cloned the human melastatin cDNA from a retina cDNA library. The gene encodes a 1,533-amino acid polypeptide with homology to members of the TRP family of calcium channels (see TRPC1; 602343).
Using differential display analysis, Fang and Setaluri (2000) identified TRPM1 among genes overexpressed in pigmented metastatic human melanoma cells treated with the differentiation inducer hexamethylene bisacetamide (HMBA). Multiple short transcripts, from both the 5-prime and 3-prime ends of TRPM1, were present in melanocytes and pigmented metastatic melanoma cell lines. The full-length 5.4-kb transcript was only found in melanocytes.
By RT-PCR of cDNA libraries derived from normal human melanocytes, retina, brain, and melanoma cell lines, Oancea et al. (2009) cloned 5 variants of TRPM1 that differ in their use of 5-prime exons and start codons. The deduced proteins contain 1,516 to 1,643 amino acids and differ only in the lengths of their N termini. The TRPM1 exons involved in alternative splicing are conserved across several mammalian species.
Koike et al. (2010) cloned a long form of mouse Trpm1, which they designated Trpm1l. The deduced 1,622-amino acid protein contains 6 transmembrane domains, a pore region, and a TRP domain. Northern blot analysis detected both Trpm1l and the short form of Trpm1, Trpm1s, in retina, but only Trpm1s was detected in skin. Trpm1 expression was not detected in other mouse tissues examined. Immunohistochemical analysis of mouse retina at postnatal day 14 revealed diffuse Trpm1l expression in bipolar cells. At 1 month of age, Trpm1l localized to dendritic tips in the outer plexiform layer. Trpm1l colocalized with Go-alpha (GNAO1; 139311) and Mglur6 (GRM6; 604096) in ON bipolar cells, but it did not colocalize with OFF bipolar cell markers.
Oancea et al. (2009) determined that the TRPM1 gene contains 29 exons, including the alternatively spliced exons 0 and 1-prime.
Hunter et al. (1998) cloned the mouse melastatin genomic region and found that the promoter contains 4 consensus binding sites for the microphthalmia-associated transcription factor (MITF; 156845). One of these binding sites is an M box, a motif shared by the tyrosinase pigmentation genes (see TYRP1; 115501).
Hunter et al. (1998) used a radiation hybrid panel to map the human MLSN1 gene to chromosome 15q13-q14. They used interspecific backcrosses to map the mouse gene to chromosome 7.
Xu et al. (2001) found that TRPM1 mediated Ca(2+) entry when expressed in HEK293 cells. They found that a short form of TRPM1 interacted directly with and suppressed the activity of full-length TRPM1, possibly by inhibiting translocation of the full-length form to the plasma membrane.
Using Northern blot and RT-PCR analyses, Fang and Setaluri (2000) demonstrated that HMBA treatment upregulated expression of full-length TRPM1 and a 5-prime short form of TRPM1.
Oancea et al. (2009) showed that a nonselective, outwardly rectifying current measured in mouse melanoma cells was reduced by introducing a microRNA targeting Trpm1. The current was also blocked by lanthanum, a nonspecific blocker of many TRP channels. By transfection into melanoma cells, Oancea et al. (2009) showed that TRPM1 isoforms containing 1,625 or 1,643 amino acids functioned as nonselective ion channels with a slight preference for Na+ over Ca(2+). TRPM1 mRNA abundance in human epidermal melanocytes correlated with melanin content. Melanocytes from dark-pigmented skin showed higher TRPM1 content than melanocytes obtained from light-pigmented skin. The complement of TRPM1 splice variants also differed between melanocytes from dark- and light-pigmented skin and between normal melanocytes and melanoma cell lines.
Van Genderen et al. (2009) reacted transverse sections of normal human retina with antibodies to TRPM1 and presynaptic and cone terminal markers and observed dense TRPM1 puncta closely aligned with cone photoreceptor terminals, with weaker TRPM1 staining in the inner nuclear layer, associated with bipolar cell bodies. Staining for TRPM1 was closely associated with but did not overlap presynaptic labeling in large cone and small rod terminals. Van Genderen et al. (2009) concluded that, like nyctalopin (NYX; 300278), TRPM1 is localized on rod ON bipolar cell dendrites in the outer plexiform layer of the retina, and suggested that in humans, TRPM1 is the cation channel gated by the GRM6 (604096) signaling cascade, which results in the light-evoked response of ON bipolar cells.
Koike et al. (2010) found that expression of the mouse Trpm1l isoform in Chinese hamster ovary cells resulted in constitutively active inward currents. Coexpression of Trpm1l with Go-alpha resulted in currents that were inhibited by Go-alpha activation, and expression of Mglur6 in addition to Trpm1l and Go-alpha resulted in channels that were inhibited by glutamate. Currents were recorded with all extracellular cations examined, suggesting that Trpm1l is a constitutively active nonselective cation channel.
In a consanguineous family of South Asian ethnicity with complete congenital stationary night blindness (CSNB1C; 613216), Li et al. (2009) analyzed the candidate gene TRPM1 (603576) and identified homozygosity for a splice site mutation (603576.0001) in the affected mother; the father was heterozygous for the mutation. Li et al. (2009) screened the TRPM1 gene in 9 families that were negative for mutation in the NYX and GRM6 genes and identified compound heterozygosity for a 1-bp deletion and a nonsense mutation and 2 missense mutations, respectively, in 2 families of Caucasian European descent (see, e.g., 603576.0002-603576.0003). None of the mutations were found in 192 control individuals.
Audo et al. (2009) analyzed the TRPM1 gene in 38 clinically diagnosed CSNB patients and identified homozygosity or compound heterozygosity for 14 causative mutations in 10 unrelated patients, including missense, splice site, deletion, and nonsense mutations (see, e.g., 603576.0004-603576.0005). Audo et al. (2009) proposed that the complete CSNB phenotype in these patients was due to the absence of functional TRPM1 in retinal ON bipolar cells.
In 6 of 8 female probands of European ancestry with complete CSNB, who were negative for mutation in GRM6 and NYX, van Genderen et al. (2009) identified mutations in TRPM1. Five probands carried either homozygous or compound heterozygous mutations (see, e.g., 603576.0005-603576.0007), and in 1 proband, only a single heterozygous mutation was found.
In 3 unrelated Japanese patients with CSNB, Nakamura et al. (2010) identified compound heterozygosity for 5 different mutations (see, e.g., 603576.0008-603576.0010).
The appaloosa coat spotting pattern in horses is caused by a single incomplete dominant gene, designated 'LP,' homozygosity for which is directly associated with CSNB in Appaloosa horses. Bellone et al. (2008) analyzed the relative expression of 5 candidate genes located in the 6-cM LP region on horse chromosome 1 and found markedly reduced expression of TRPM1 in the retina and pigmented and unpigmented skin of homozygous LP/LP Appaloosa horses compared to non-Appaloosa lp/lp horses (p = 0.001 for all). Bellone et al. (2008) concluded that decreased expression of TRPM1 in the eye and skin might alter bipolar cell signaling as well as melanocyte function, thus causing both CSNB and LP in horses.
Koike et al. (2010) found that Trpm1 -/- mice were indistinguishable from wildtype littermates in appearance, including coat color. However, whole-cell recording of retinal bipolar cells in retinal slices showed that light stimulated an inward current in wildtype rod and cone ON bipolar cells, but not in Trpm1 -/- ON bipolar cells.
In the affected mother of 2 affected daughters from a consanguineous family of South Asian ethnicity with complete congenital stationary night blindness (CSNB1C; 613216), Li et al. (2009) identified homozygosity for a +2T-C transition at the splice donor site of intron 16 of the TRPM1 gene, predicted to abrogate the canonical donor sequence and affect efficient splicing of intron 16 of the gene. The unaffected father was heterozygous for the mutation, which was not found in 192 control individuals.
In a 36-year-old woman of Caucasian European descent with complete congenital stationary night blindness (CSNB1C; 613216), Li et al. (2009) identified compound heterozygosity for a 1-bp deletion (412delG) and a 3105T-A transversion, resulting in a tyr1035-to-ter (Y1035X; 603576.0003) substitution in the TRPM1 gene, both causing premature termination codons predicted to result in nonsense-mediated decay of mRNA. Analysis of her unaffected mother, who had an entirely normal ERG, showed that the variants were in trans; the mutations were not found in 192 unrelated controls.
For discussion of the tyr1035-to-ter (Y1035X) mutation in the TRPM1 gene that was found in compound heterozygous state in a patient with complete congenital stationary night blindness (CSNB1C; 613216) by Li et al. (2009), see 603576.0002.
In a German proband with complete congenital stationary night blindness (CSNB1C; 613216), nystagmus, and myopia, Audo et al. (2009) identified compound heterozygosity for a 31C-T transition in exon 3 of the TRPM1 gene, resulting in a gln11-to-ter (Q11X) substitution, and a 296T-C transition in exon 4, resulting in a leu99-to-pro (L99P; 603576.0005) substitution. The unaffected mother and 2 unaffected sibs were heterozygous for the nonsense mutation, which was not found in 352 control alleles, and the unaffected father was heterozygous for the missense mutation, which was not found in 224 control alleles.
For discussion of the leu99-to-pro (L99P) mutation in the TRPM1 gene that was found in compound heterozygous state in a patient with complete congenital stationary night blindness (CSNB1C; 613216) by Audo et al. (2009), see 603576.0004.
For discussion of the L99P mutation in the TRPM1 gene that was found in compound heterozygous state in a patient with complete congenital stationary night blindness by van Genderen et al. (2009), see 603576.0006.
In a female patient with complete congenital stationary night blindness (CSNB1C; 613216), van Genderen et al. (2009) identified compound heterozygosity for the L99P mutation in the TRPM1 gene (603576.0005) and a 1832C-A transversion in exon 16, resulting in a pro611-to-his (P611H) substitution at a highly conserved residue. DNA from the parents was unavailable, but her unaffected sister and brother were each heterozygous for 1 of the mutations, respectively; neither mutation was detected in 210 control chromosomes.
In a female patient with complete congenital stationary night blindness (CSNB1C; 613216), van Genderen et al. (2009) identified homozygosity for a 36,445-bp deletion involving exons 2 to 7 of the TRPM1 gene. The unaffected parents were heterozygous for the deletion, which was not found in her unaffected sister or in 210 control chromosomes. Van Genderen et al. (2009) noted that the deletion removes exons used in 4 isoforms described by Oancea et al. (2009).
In a 19-year-old Japanese man with congenital stationary night blindness (CSNB1C; 613216), Nakamura et al. (2010) identified compound heterozygous mutations in the TRPM1 gene: a 1870C-T transition in exon 16, resulting in an arg624-to-cys (R624C) substitution at a well-conserved residue in the N-terminal region, and a 2645C-A transversion in exon 21, resulting in a ser882-to-ter (S882X; 603576.0009) substitution. The R624C mutation was not found in 100 Japanese controls or in any SNP database, and functional analyses suggested that mutant R624C protein may be mislocalized in bipolar cells. An unrelated 27-year-old Japanese man with CSNB1C also carried the R624C mutation, in compound heterozygosity with a 4-bp deletion in intron 8 (IVS8+3delAAGT; 603576.0010) of the TRPM1 gene. Transfection studies in HEK293T cells showed that the splice site mutation leads to abnormal protein production, suggesting that IVS8+3delAAGT is a loss-of-function allele.
For discussion of the ser882-to-ter (S882X) mutation in the TRPM1 gene that was found in compound heterozygous state in a patient with congenital stationary night blindness (CSNB1C; 613216) by Nakamura et al. (2010), see 603576.0008.
For discussion of the splice site mutation in the TRPM1 gene (IVS8+3delAAGT) that was found in compound heterozygous state in a patient with congenital stationary night blindness (CSNB1C; 613216) by Nakamura et al. (2010), see 603576.0008.
Audo, I., Kohl, S., Leroy, B. P., Munier, F. L., Guillonneau, X., Mohand-Said, S., Bujakowska, K., Nandrot, E. F., Lorenz, B., Preising, M., Kellner, U., Renner, A. G., and 18 others. TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness. Am. J. Hum. Genet. 85: 720-729, 2009. [PubMed: 19896113] [Full Text: https://doi.org/10.1016/j.ajhg.2009.10.013]
Bellone, R. R., Brooks, S. A., Sandmeyer, L., Murphy, B. A., Forsyth, G., Archer, S., Bailey, E., Grahn, B. Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus). Genetics 179: 1861-1870, 2008. [PubMed: 18660533] [Full Text: https://doi.org/10.1534/genetics.108.088807]
Duncan, L. M., Deeds, J., Hunter, J., Shao, J., Holmgren, L. M., Woolf, E. A., Tepper, R. I., Shyjan, A. W. Down-regulation of the novel gene melastatin correlates with potential for melanoma metastasis. Cancer Res. 58: 1515-1520, 1998. [PubMed: 9537257]
Fang, D., Setaluri, V. Expression and up-regulation of alternatively spliced transcripts of melastatin, a melanoma metastasis-related gene, in human melanoma cells. Biochem. Biophys. Res. Commun. 279: 53-61, 2000. [PubMed: 11112417] [Full Text: https://doi.org/10.1006/bbrc.2000.3894]
Farooqi, A. A., Javeed, M. K., Javed, Z., Riaz, A. M., Mukhtar, S., Minhaj, S., Abbas, S., Bhatti, S. TRPM channels: same ballpark, different players, and different rules in immunogenetics. Immunogenetics 63: 773-787, 2011. [PubMed: 21932052] [Full Text: https://doi.org/10.1007/s00251-011-0570-4]
Hunter, J. J., Shao, J., Smutko, J. S., Dussault, B. J., Nagle, D. L., Woolf, E. A., Holmgren, L. M., Moore, K. J., Shyjan, A. W. Chromosomal localization and genomic characterization of the mouse melastatin gene (Mlsn1). Genomics 54: 116-123, 1998. [PubMed: 9806836] [Full Text: https://doi.org/10.1006/geno.1998.5549]
Koike, C., Obara, T., Uriu, Y., Numata, T., Sanuki, R., Miyata, K., Koyasu, T., Ueno, S., Funabiki, K., Tani, A., Ueda, H., Kondo, M., Mori, Y., Tachibana, M., Furukawa, T. TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. Proc. Nat. Acad. Sci. 107: 332-337, 2010. [PubMed: 19966281] [Full Text: https://doi.org/10.1073/pnas.0912730107]
Li, Z., Sergouniotis, P. I., Michaelides, M., Mackay, D. S., Wright, G. A., Devery, S., Moore, A. T., Holder, G. E., Robson, A. G., Webster, A. R. Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans. Am. J. Hum. Genet. 85: 711-719, 2009. [PubMed: 19878917] [Full Text: https://doi.org/10.1016/j.ajhg.2009.10.003]
Nakamura, M., Sanuki, R., Yasuma, T. R., Onishi, A., Nishiguchi, K. M., Koike, C., Kadowaki, M., Kondo, M., Miyake, Y., Furukawa, T. TRPM1 mutations are associated with the complete form of congenital stationary night blindness. Molec. Vision 16: 425-437, 2010. [PubMed: 20300565]
Oancea, E., Vriens, J., Brauchi, S., Jun, J., Splawski, I., Clapham, D. E. TRPM1 forms ion channels associated with melanin content in melanocytes. Sci. Signal. 2: ra21, 2009. Note: Electronic Article. [PubMed: 19436059] [Full Text: https://doi.org/10.1126/scisignal.2000146]
van Genderen, M. M., Bijveld, M. M. C., Claassen, Y. B., Florijn, R. J., Pearring, J. N., Meire, F. M., McCall, M. A., Riemslag, F. C. C., Gregg, R. G., Bergen, A. A. B., Kamermans, M. Mutations in TRPM1 are a common cause of complete congenital stationary night blindness. Am. J. Hum. Genet. 85: 730-736, 2009. [PubMed: 19896109] [Full Text: https://doi.org/10.1016/j.ajhg.2009.10.012]
Xu, X.-Z. S., Moebius, F., Gill, D. L., Montell, C. Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform. Proc. Nat. Acad. Sci. 98: 10692-10697, 2001. [PubMed: 11535825] [Full Text: https://doi.org/10.1073/pnas.191360198]