PMEL gene

The PMEL gene (PMEL stands for Premelanosome Protein) is a protein-coding gene located on chromosome 12q13.2. The expression of the PMEL gene is regulated by the microphthalmia-associated transcription factor (see MITF gene below). Alternative splicing leads to several transcript variants. An important paralog of this gene is GPNMB.

The PMEL gene encodes a melanocyte-specific type I transmembrane glycoprotein(GP100). The encoded protein is enriched in melanosomes and plays an essential role in the structural organization of premelanosomes. PMEL is involved in melanosome maturation, including melanogenesis, melanosome biogenesis and melanin polymerization.

Thus, the protein encoded by the PMEL gene (GP100/also called HMB45) is involved in the formation of internal matrix fibers that define the transition from stage I to stage II melanosomes. The transmembrane form of PMEL/GP100 is modified in the secretory pathway by the formation of N-linked oligosaccharides and the addition and modification of O-linked oligosaccharides. It is then transported to precursors of the pigment organelle, the melanosome, where it is proteolytically processed into several small fragments. Some of these fragments form a non-pathological amyloid that organizes into sheets, forming striped patterns that underlie the melanosomal ultrastructure. PMEL cleavage is mediated by several proteases, including a proprotein convertase of the furin family, a "sheddase", as well as other proteases in melanosomes or their precursors. After cleavage of the amyloidogenic region, the small remaining integral membrane fragment is digested by a gamma-secretase. The expression of the PMEL gene is regulated by the microphthalmia-associated transcription factor (MITF- see MITF gene below).

A secreted form of PMEL/GP100 can be used as a melanoma-specific serum marker (HMB45).

Diseases associated with the PMEL gene include:

• Vitiligo-Associated Multiple Autoimmune Disease Susceptibility 1, an autoimmune-driven predisposition characterized by the association of vitiligo with various autoimmune and autoinflammatory diseases, including autoimmune thyroid disease, rheumatoid arthritis and systemic lupus erythematosus
• and
• gallbladder melanoma.

The encoded PMEL protein GP100 forms physiological amyloids, which play a central role in melanosome morphogenesis and pigmentation. The maturation of unpigmented stage I to II premelanosomes is characterized by the aggregation of processed amyloidogenic fragments into parallel fibrillar sheets that elongate the vesicle into a striated ellipsoidal shape. In pigmented melanosomes of stages III and IV, the amyloid matrix serves as a platform on which eumelanin precursors accumulate in high local concentrations for pigment formation.

The encoded PMEL protein GP100 can prevent the toxicity associated with pigmentation by sequestering toxic reaction intermediates of the eumelanin biosynthetic pathway.

GP100 is a potent melanoma-specific antigen. Among the non-mutated melanoma autoantigens, G9-154 , G9-209 and G9-280 appear to act as immunodominant common epitopes that stimulate an anti-tumor immune response mediated by cytotoxic T cells.

Note: Short fragments of GP100 were used to develop the GP100 cancer vaccine. Hydrophilic recombinant GP100 protein (HR-gp100) was applied topically to intact human skin in vitro and used as a vaccine in a mouse model. HR-GP100 was shown to penetrate human skin and to be processed and presented by human dendritic cells. In the mouse model, an HR-GP100-based vaccine elicited antigen-specific T cell responses as shown by proliferation assays, ELISA and intracellular staining for IFN-γ.

The GPR143 protein in melanocytes and cells of the retinal pigment epithelium belongs to a comparable signaling pathway.

1. Bharti N et al. (2024) Estimation of genetic variation in vitiligo associated genes: Population genomics perspective. BMC Genome Data 25:72.
2. Bojar P et al. (2023) Melanoma of the gallbladder. Folia Med Cracov 63:77-92.
3. Nath SK et al. (2001) Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am J Hum Genet 69:1401-1406.
4. Salgaller ML et al. (1995) Recognition of multiple epitopes in the human melanoma antigen gp100 by peripheral blood lymphocytes stimulated in vitro with synthetic peptides. Cancer Res 55:4972-4979.