Alternative titles; symbols
HGNC Approved Gene Symbol: PMEL
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38): 12:55,954,105-55,966,709 (from NCBI)
Melanocytes preferentially express an mRNA species, PMEL17, whose protein product crossreacts with antityrosinase antibodies and whose expression correlates with the melanin content. Kwon et al. (1991) isolated a cDNA clone corresponding to the human PMEL17 gene from a human melanocyte cDNA library. The deduced 668-amino acid protein has a molecular mass of approximately 70.9 kD. It contains a putative leader sequence and a potential membrane anchor segment, suggesting it is a membrane-associated protein in melanocytes. Removal of the signal peptide results in a 645-amino acid protein with a molecular mass of 68.6 kD. The deduced protein has 5 potential N-glycosylation sites and relatively high levels of serine and threonine. The PMEL17 protein shares amino acid similarity with tyrosinase (606933) and the CAS2 protein (115501).
Maresh et al. (1994) cloned the gene encoding ME20, a melanoma-associated antigen. The cDNA encodes a 661-amino acid precursor with a 23-residue signal peptide and a 26-residue N-terminal transmembrane domain. The transmembrane domain is followed by a C-terminal 45-amino acid putative intracellular domain rich in serine residues. Signal peptide cleavage results in a 637-residue membrane-associated protein, designated ME20-M. ME20-M is derived from a 3.3- to 3.4-kb transcript expressed at varying levels in melanoma cell lines. The ME20-M protein has a deletion of 7 amino acids compared with the human PMEL17 gene product.
Maresh et al. (1994) reported that the calculated molecular masses for ME20-M and soluble ME20 (ME20-S) are 67.8 and 47 kD, respectively. However, the apparent masses were 105 and 76 kD, respectively, indicating utilization of several N-linked glycosylation sites. Maresh et al. (1994) determined that signal peptide cleavage and proteolytic processing of the 661-residue ME20 precursor at val467 yields ME20-S (residues 25 to 467).
Adema et al. (1994) determined that the nucleotide sequence of a melanocyte lineage-specific antigen, GP100, is highly homologous to that of PMEL17 except for an in-frame deletion of 21 bp in GP100 that results in a 7-amino acid deletion. Further analysis showed that GP100 and PMEL17 are alternatively spliced variants of a single gene.
Berson et al. (2001) provided a schematic diagram of PMEL17 and its posttranslational processing. The gene encodes 2 type I integral membrane proteins of 668 and 661 amino acids that differ by the presence or absence of 7 amino acids in the membrane-proximal region of the luminal domain. PMEL17 is synthesized as a 97-kD precursor protein, designated P1. P1 is posttranslationally modified to yield a transient 128-kD protein, designated P2. P2 is then proteolytically cleaved in a post-Golgi, prelysosomal compartment into 2 disulfide-linked mature subunits: a large luminal 443-residue fragment, M-alpha (85 kD), which was originally termed ME20-S, and a transmembrane domain-containing fragment, M-beta (28 kD). Despite cleavage, only a small fraction of M-alpha is secreted, whereas most M-alpha and M-beta remain associated with each other intracellularly.
Theos et al. (2005) reviewed the structure of human SILV, which they called PMEL. The PMEL gene encodes at least 4 splice variants. The long and intermediate variants encode the 668- and 661-amino acid proteins that differ only in the presence or absence of a 7-amino acid sequence. An additional splice removes a 126-bp exon encoding 42 amino acids in the luminal domain and occurs independently of the first splice, yielding 2 short isoforms of 626 and 619 amino acids.
Dean and Lee (2020) noted that multiple PMEL17 isoforms are produced. The most abundant isoform contains an amyloid-forming repeat (RPT) domain with 10 imperfect repeats of 13 amino acids each. Excision of a cryptic intron leads to a minor PMEL17 isoform with 7 imperfect repeats within the RPT domain. Dean and Lee (2020) found that the short RPT isoform enhanced amyloid aggregation of the long RPT isoform. Bioinformatic analysis showed that both long and short RPT isoforms of PMEL17 are conserved in mammals, suggesting a conserved modulation mechanism of amyloid formation through PMEL17 isoforms.
Bailin et al. (1996) determined the DNA sequence and genomic organization of the PMEL17 gene. The gene contains 11 exons.
Kwon et al. (1991) mapped the human PMEL17 gene, which they designated D12S53E, to chromosome 12pter-q21 by Southern analysis of Chinese hamster/human somatic cell hybrids. The murine homolog, designated D12S53Eh, was mapped to chromosome 10 by Southern analysis of mouse/hamster somatic cell hybrids and analysis of interspecies backcrosses. The data indicated the possible location of D12S53Eh near the silver ('si') locus, which affects coat color in the mouse. The information added to the known homology of synteny between human chromosome 12 and mouse chromosome 10.
By fluorescence in situ hybridization, Kubota et al. (1995) mapped the PMEL17 gene to chromosome 12q13-q14.
Berson et al. (2001) showed that PMEL17 associated with the intraluminal membrane vesicles of multivesicular bodies in transfected nonpigmented cells, similar to its association with premelanosomes in pigmented cells. Cells overexpressing PMEL17 displayed structures resembling premelanosomal striations within these compartments. Berson et al. (2001) concluded that PMEL17 is sufficient to drive the formation of striations within multivesicular bodies and is thus directly involved in the biogenesis of premelanosomes.
CD8 T lymphocytes recognize peptides of 8 to 10 amino acids presented by class I molecules of the major histocompatibility complex. Vigneron et al. (2004) found that CD8 T lymphocytes were able to recognize a nonameric peptide on melanoma cells that comprises 2 noncontiguous segments of melanocytic glycoprotein gp100(PMEL17). The production of this peptide involves the excision of 4 amino acids and splicing of the fragments. This process was reproduced in vitro by incubating a precursor peptide of 13 amino acids with highly purified proteasomes. Splicing appears to occur by transpeptidation involving an acyl-enzyme intermediate. Vigneron et al. (2004) concluded that their results reveal an unanticipated aspect of the proteasome function of producing antigenic peptides.
Hoashi et al. (2005) used a multidisciplinary approach, including immunofluorescence, studies of pigmented and nonpigmented human melanoma cell lines, and small interfering RNAs (siRNA), to show that MART1 (MLANA; 605513) interacts with PMEL17 in melanogenesis. MART1 regulated the expression, stability, trafficking, and processing of PMEL17. MART1 colocalized and formed a complex with the P100 form of PMEL17 within early subcellular compartments in melanocytic cells. MART1 siRNA reduced PMEL17 expression, abrogated the processing of PMEL17 in post-Golgi compartments, and interrupted trafficking of PMEL17 to early melanosomes. Hoashi et al. (2005) concluded that MART1 is indispensable for PMEL17 function and plays an important role in regulating mammalian pigmentation.
Fowler et al. (2006) found that fibers in isolated mammalian melanosomes consisted of PMEL17 M-alpha fibers, which have a beta-sheet folded amyloid structure. In vitro, recombinant M-alpha fibers rapidly and spontaneously self-assembled into amyloid sheets. M-alpha amyloidogenesis was at least 4 orders of magnitude faster than that of the beta-amyloid protein (APP; 104760) or alpha-synuclein (SNCA; 163890), suggesting an evolutionary function. M-alpha amyloid fibers hastened melanin formation in vitro by serving as a template for melanin subunit polymerization. Fowler et al. (2006) noted that full-length PMEL17 is synthesized as a transmembrane protein incapable of self-assembly. The amyloidogenic fragment, M-alpha, is released by proteolysis only when sequestered in the early melanosome compartment. This regulated and rapid self-assembly of M-alpha likely protects the cell from the toxicity associated with amyloidogenesis. In addition, M-alpha amyloid sequesters highly reactive and toxic melanin precursor compounds, preventing further cellular toxicity. Fowler et al. (2006) suggested that the amyloid fold is a fundamental protein structural motif with unique properties capable of performing a wide variety of normal functions in a subset of cells.
Theos et al. (2005) reviewed PMEL function and the role of PMEL in melanosome biogenesis.
Associations Pending Confirmation
Lahola-Chomiak et al. (2019) performed whole-exome sequencing (WES) in a large 3-generation family (family 1) segregating autosomal dominant pigment dispersion syndrome (PDS) with or without the development of pigmentary glaucoma (PG), and identified a heterozygous missense mutation (G175S) in the PMEL gene in 7 affected individuals. The variant was also present in an unaffected family member, and there was 1 affected individual who did not carry the variant. The variant was not found in the gnomAD database. Functional analysis showed that the variant was processed normally and did not cause trafficking or fibrillogenesis defects. In affected first cousins from a Canadian Mennonite kindred (family 2), the authors identified heterozygosity for an A340V substitution in the PMEL gene, but noted that modifiers in other genes could not be ruled out. Targeted screening of PMEL in 3 independent cohorts totaling 394 patients with PDS and/or PG yielded an additional 7 PDS/PG-associated variants, all of which were found in heterozygosity in the gnomAD database, and 2 of which were observed in a control population of 1,799 exomes from ophthalmologically examined individuals. Analysis of transfected HeLa cells showed that 5 of the 9 variants exhibited defective processing of the PMEL protein, and 5 of the 9 showed structural changes to pseudomelanosomes. The authors concluded that further study would be required to elucidate how the variants contribute to the pathogenesis of PDS/PG.
Van der Heide et al. (2021) analyzed WES data in a cohort of 198 PDS patients and 359 controls but did not confirm a link between PMEL and PDS. A total of 7 instances of 5 unique PMEL mutations were detected, which were not statistically more common in PDS patients than controls. Moreover, those PMEL variants predicted to be damaging to protein function were found exclusively in the control individuals.
Kwon et al. (1995) found that the si/si mouse has a 1-bp insertion (1806insA) in the Pmel17 gene. The mutation alters the last 24 amino acids at the C terminus and creates a new termination codon that extends the protein by 12 amino acids.
The merle coat pattern in domestic dogs is characterized by patches of diluted pigment and is inherited in an autosomal, incompletely dominant fashion. Dogs heterozygous or homozygous for the merle locus exhibit a wide range of auditory and ophthalmologic abnormalities similar to those observed in human Waardenburg syndrome (see 193500). Clark et al. (2006) identified Silv as a candidate gene for merle patterning based on linkage disequilibrium for a microsatellite marker and the merle phenotype in Shetland sheepdogs. They identified a short interspersed element (SINE) insertion at the boundary of intron 10 and exon 11 in the Silv gene that segregated with the merle phenotype in multiple breeds. Clark et al. (2006) also found deletions within the oligo(dA)-rich tail of the SINE that permitted normal pigmentation. They concluded that SINE insertion in Silv is responsible for merle patterning and is associated with impaired function of the auditory and ophthalmologic systems.
Using CRISPR/Cas9 to disrupt pmel in zebrafish, Lahola-Chomiak et al. (2019) observed a 20-fold reduction in mutant protein compared to wildtype. Zebrafish larvae homozygous for the mutation had reduced global pigmentation. In addition, by 8 days of development, the homozygous mutants showed enlarged anterior segments, microphthalmia, and eyes that were more spherical in shape, consistent with high intraocular pressure.
Adema, G. J., de Boer, A. J., Vogel, A. M., Loenen, W. A. M., Figdor, C. G. Molecular characterization of the melanocyte lineage-specific antigen gp100. J. Biol. Chem. 269: 20126-20133, 1994. [PubMed: 7519602]
Bailin, T., Lee, S.-T., Spritz, R. A. Genomic organization and sequence of D12S53E (Pmel 17), the human homologue of the mouse silver (si) locus. J. Invest. Derm. 106: 24-27, 1996. [PubMed: 8592076] [Full Text: https://doi.org/10.1111/1523-1747.ep12326976]
Berson, J. F., Harper, D. C., Tenza, D., Raposo, G., Marks, M. S. Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Molec. Biol. Cell 12: 3451-3464, 2001. [PubMed: 11694580] [Full Text: https://doi.org/10.1091/mbc.12.11.3451]
Clark, L. A., Wahl, J. M., Rees, C. A., Murphy, K. E. Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc. Nat. Acad. Sci. 103: 1376-1381, 2006. [PubMed: 16407134] [Full Text: https://doi.org/10.1073/pnas.0506940103]
Dean, D. N., Lee, J. C. Modulating functional amyloid formation via alternative splicing of the premelanosomal protein PMEL17. J. Biol. Chem. 295: 7544-7553, 2020. [PubMed: 32277052] [Full Text: https://doi.org/10.1074/jbc.RA120.013012]
Fowler, D. M., Koulov, A. V., Alory-Jost, C., Marks, M. S., Balch, W. E., Kelly, J. W. Functional amyloid formation within mammalian tissue. PLoS Biol. 4: e6, 2006. Note: Electronic Article. [PubMed: 16300414] [Full Text: https://doi.org/10.1371/journal.pbio.0040006]
Hoashi, T., Watabe, H., Muller, J., Yamaguchi, Y., Vieira, W. D., Hearing, V. J. MART-1 is required for the function of the melanosomal matrix protein PMEL17/GP100 and the maturation of melanosomes. J. Biol. Chem. 280: 14006-14016, 2005. [PubMed: 15695812] [Full Text: https://doi.org/10.1074/jbc.M413692200]
Kubota, R., Wang, Y., Minoshima, S., Kudoh, J., Mashima, Y., Oguchi, Y., Shimizu, N. Mapping of the human gene for a melanocyte protein panel Pmel 17 (D12S53E) to chromosome 12q13-q14. Genomics 26: 430-431, 1995. [PubMed: 7601481] [Full Text: https://doi.org/10.1016/0888-7543(95)80239-i]
Kwon, B. S., Chintamaneni, C., Kozak, C. A., Copeland, N. G., Gilbert, D. J., Jenkins, N., Barton, D., Francke, U., Kobayashi, Y., Kim, K. K. A melanocyte-specific gene, Pmel 17, maps near the silver coat color locus on mouse chromosome 10 and is in a syntenic region on human chromosome 12. Proc. Nat. Acad. Sci. 88: 9228-9232, 1991. [PubMed: 1924386] [Full Text: https://doi.org/10.1073/pnas.88.20.9228]
Kwon, B. S., Halaban, R., Ponnazhagan, S., Kim, K., Chintamaneni, C., Bennett, D., Pickard, R. T. Mouse silver mutation is caused by a single base insertion in the putative cytoplasmic domain of Pmel 17. Nucleic Acids Res. 23: 154-158, 1995. [PubMed: 7870580] [Full Text: https://doi.org/10.1093/nar/23.1.154]
Lahola-Chomiak, A. A., Footz, T., Nguyen-Phuoc, K., Neil, G. J., Fan, B., Allen, K. F., Greenfield, D. S., Parrish, R. K., Linkroum, K., Pasquale, L. R., Leonhardt, R. M., Ritch, R., Javadiyan, S., Craig, J. E., Allison, W. T., Lehmann, O. J., Walter, M. A., Wiggs, J. L. Non-synonymous variants in premelanosome protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma. Hum. Molec. Genet. 28: 1298-1311, 2019. [PubMed: 30561643] [Full Text: https://doi.org/10.1093/hmg/ddy429]
Maresh, G. A., Marken, J. S., Neubauer, M., Aruffo, A., Hellstrom, I., Hellstrom, K. E., Marquardt, H. Cloning and expression of the gene for the melanoma-associated ME20 antigen. DNA Cell Biol. 13: 87-95, 1994. [PubMed: 8179825] [Full Text: https://doi.org/10.1089/dna.1994.13.87]
Maresh, G. A., Wang, W.-C., Beam, K. S., Malacko, A. R., Hellstrom, I., Hellstrom, K. E., Marquardt, H. Differential processing and secretion of the melanoma-associated ME20 antigen. Arch. Biochem. Biophys. 311: 95-102, 1994. [PubMed: 8185325] [Full Text: https://doi.org/10.1006/abbi.1994.1213]
Theos, A. C., Truschel, S. T., Raposo, G., Marks, M. S. The Silver locus product Pmel17/gp100/Silv/ME20: controversial in name and in function. Pigment Cell Res. 18: 322-336, 2005. [PubMed: 16162173] [Full Text: https://doi.org/10.1111/j.1600-0749.2005.00269.x]
van der Heide, C., Goar, W., Meyer, K. J., Alward, W. L. M., Boese, E. A., Sears, N. C., Roos, B. R., Kwon, Y. H., DeLuca, A. P., Siggs, O. M., Gonzaga-Jauregui, C., Sheffield, V. C., and 10 others. Exome-based investigation of the genetic basis of human pigmentary glaucoma. BMC Genomics 22: 477, 2021. [PubMed: 34174832] [Full Text: https://doi.org/10.1186/s12864-021-07782-0]
Vigneron, N., Stroobant, V., Chapiro, J., Ooms, A., Degiovanni, G., Morel, S., van der Bruggen, P., Boon, T., Van den Eynde, B. J. An antigenic peptide produced by peptide splicing in the proteasome. Science 304: 587-590, 2004. [PubMed: 15001714] [Full Text: https://doi.org/10.1126/science.1095522]