TYRP1
TYRP1, also known as tyrosinase-related protein 1, is a human gene that encodes a melanosomal protein belonging to the tyrosinase family, playing a critical role in the melanin biosynthetic pathway.[1] Located on chromosome 9p23, the gene consists of 8 exons and produces a 537-amino-acid protein that contributes to eumelanin production, the dark pigment responsible for skin, hair, and eye coloration, primarily through structural roles rather than direct enzymatic activity on 5,6-dihydroxyindole-2-carboxylic acid (DHICA).[1] Expressed primarily in melanocytes of the skin, hair follicles, and retinal pigment epithelium, TYRP1 also stabilizes the enzyme tyrosinase—the rate-limiting step in melanin synthesis—and influences melanosome maturation and structure.[2][1] Mutations in TYRP1 are associated with oculocutaneous albinism type 3 (OCA3), a form of albinism characterized by reduced pigmentation, often resulting in reddish-brown skin, ginger-red hair, and hazel or brown irises in affected individuals, particularly prevalent among dark-skinned populations in southern Africa.[2] Common mutations include the Ser166Ter nonsense mutation and the 368delA frameshift deletion, both of which lead to a nonfunctional protein and impaired melanin production.[2] Beyond pigmentation disorders, TYRP1 has been implicated in melanoma progression, where it acts as a tumor antigen (gp75) targeted by immunotherapy, including recent CAR-T cell approaches as of 2024, highlighting its dual role in normal physiology and cancer.[2][3] Research continues to explore its regulatory mechanisms, including interactions with transcription factors like MITF, underscoring its importance in melanocyte differentiation and overall pigmentary system integrity.[4]Genetics
Gene location and organization
The TYRP1 gene in humans is located on the short arm of chromosome 9 at position 9p23, with genomic coordinates spanning 12,693,385 to 12,710,285 in the GRCh38.p14 assembly, encompassing approximately 17 kb.[1] In mice, the orthologous Tyrp1 gene resides on chromosome 4 at coordinates 80,752,360 to 80,769,973 in the GRCm39 assembly, covering about 18 kb.[5] These positions highlight the syntenic conservation between human chromosome 9 and mouse chromosome 4, facilitating comparative genetic studies.[6] The TYRP1 gene consists of 8 exons and 7 introns, organized over its genomic span to encode a protein involved in melanogenesis.[1] The promoter region upstream of the first exon includes binding sites for the microphthalmia-associated transcription factor (MITF), which is essential for melanocyte-specific expression.[7] In the mouse model, the Tyrp1 gene corresponds to the classic brown (b) locus, where the Tyrp1^b mutation disrupts normal pigmentation and serves as a key animal model for studying gene function.[5] TYRP1 exhibits high sequence conservation across mammalian species, reflecting its fundamental role in pigmentation. A 2023 comparative analysis of TYRP1 orthologs in diverse mammals revealed strong evolutionary preservation of functional domains, underscoring its contributions to pigmentation evolution and modulation of oxidative stress as an adaptive mechanism.[8]Sequence variants
The TYRP1 gene harbors several common single nucleotide polymorphisms (SNPs) that influence pigmentation traits and disease susceptibility. One prominent example is rs1408799, an intronic variant (c.1099-354T>C) associated with reduced risk of cutaneous melanoma, with an odds ratio of 0.77 (95% CI: 0.68-0.87) in genome-wide association studies of European populations.[9] The minor allele (C) has a frequency of approximately 0.167 in Northern and Western European populations, such as those in the HapMap CEU panel, and shows linkage with variants influencing eye color, including blue irides.[10][11] Another notable common variant is rs61795860 (p.Arg93Cys, R93C), a missense change causing blond hair in Melanesian populations; its allele frequency reaches 0.26 in Solomon Islanders but is absent in 941 individuals across 52 global populations, indicating a population-specific adaptation.[12] Pathogenic mutations in TYRP1 predominantly cause loss-of-function effects leading to oculocutaneous albinism type 3 (OCA3). A frameshift mutation, c.368delA in exon 6, results in a premature stop codon at position 184 [p.(Arg123Glyfs*62)], producing a truncated protein lacking critical catalytic domains and causing complete loss of enzymatic activity; this variant was identified in an African American individual with OCA3.[6] Similarly, the missense mutation c.977G>A (p.Arg326His, R326H) in exon 5 alters a conserved residue on the protein's periphery, disrupting two hydrogen bonds essential for structural stability and reducing DHCA oxidase activity by impairing substrate binding.[13][14] These mutations are more prevalent in African and Asian ancestries, with OCA3 accounting for up to 7% of albinism cases in sub-Saharan Africa.[6] Haplotype analyses reveal structured linkage disequilibrium (LD) patterns in TYRP1, reflecting population-specific selection pressures on pigmentation. The R93C blond hair variant occurs on a distinct haplotype spanning ~100 kb around TYRP1, with high LD (r² > 0.8) to nearby SNPs and evidence of recent positive selection in Oceanic populations, as indicated by extended haplotype homozygosity.[12] In global contexts, TYRP1 haplotypes show elevated LD in non-coding regions, such as introns and the 3' untranslated region (UTR), where variants like rs1834640 form blocks influencing regulatory element accessibility; these patterns differ by ancestry, with stronger LD in East Asians (average r² = 0.6) compared to Africans (r² = 0.3).[15][16] Non-coding variants, particularly in the 3'UTR, modulate TYRP1 expression; for instance, the G allele of rs1834640 disrupts miR-155 binding, stabilizing mRNA and increasing protein output by up to 2-fold in allele-specific assays.[17] Functional assays demonstrate how TYRP1 variants disrupt molecular processes. In vitro luciferase reporter studies of 3'UTR SNPs, such as rs1834640, reveal allele-dependent miR-155 repression, with the G allele enhancing translation efficiency and mRNA half-life (from ~4 hours to 8 hours under miRNA overexpression), thereby elevating TYRP1 protein levels in melanoma cell lines.[17] For pathogenic coding variants, expression of R326H in HEK293 cells shows reduced protein stability, with a 30% decrease in steady-state levels due to accelerated degradation, confirmed by cycloheximide chase assays; similarly, the 368delA frameshift abolishes full-length translation in minigene constructs, yielding only unstable truncated transcripts.[18][19] These assays highlight variants' roles in impairing post-transcriptional regulation without altering splicing per se.| Variant | Type | Location | Molecular Effect | Population Frequency/Example | Reference |
|---|---|---|---|---|---|
| rs1408799 | SNP (intronic) | Intron 7 | Modulates expression; LD with eye color loci | Minor allele (C): 0.167 in Europeans | [10] |
| rs61795860 (R93C) | Missense | Exon 3 (c.277C>T) | Reduces protein stability; blond hair trait | 0.26 in Solomon Islanders | [12] |
| c.368delA | Frameshift | Exon 6 | Truncated protein (p.Arg123Glyfs*62); loss of function | Rare; reported in African ancestry | [6] |
| c.977G>A (R326H) | Missense | Exon 5 | Disrupts H-bonds; decreased stability/activity | Rare; OCA3 in diverse ancestries | [13] |
| rs1834640 | SNP (3'UTR) | 3'UTR | Alters miR-155 binding; affects mRNA stability | Variable; G allele common in Asians (~0.4) | [17] |