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OCA2
Identifiers
AliasesOCA2, BEY, BEY1, BEY2, BOCA, D15S12, EYCL, EYCL2, EYCL3, HCL3, PED, SHEP1, OCA2 melanosomal transmembrane protein, P
External IDsOMIM: 611409; MGI: 97454; HomoloGene: 37281; GeneCards: OCA2; OMA:OCA2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4948

18431

Ensembl

ENSG00000104044
ENSG00000277361

ENSMUSG00000030450

UniProt

Q04671

Q62052

RefSeq (mRNA)

NM_000275
NM_001300984

NM_021879

RefSeq (protein)

NP_000266
NP_001287913

NP_068679

Location (UCSC)Chr 15: 27.75 – 28.1 MbChr 7: 55.89 – 56.19 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

P protein, also known as melanocyte-specific transporter protein or pink-eyed dilution protein homolog, is a protein that in humans is encoded by the oculocutaneous albinism II (OCA2) gene.[5] The P protein is believed to be an integral membrane protein involved in small molecule transport, specifically of tyrosine—a precursor of melanin. Certain mutations in OCA2 result in type 2 oculocutaneous albinism.[5] OCA2 encodes the human homologue of the mouse p (pink-eyed dilution) gene.

In human, the OCA2 gene is located on the long (q) arm of chromosome 15 between positions 12 and 13.1

The human OCA2 gene is located on the long arm (q) of chromosome 15, specifically from base pair 28,000,020 to base pair 28,344,457 on chromosome 15.

Function

[edit]

OCA2 provides instructions for making the protein called P protein which is located in melanocytes which are specialized cells that produce melanin, and in the cells of the retinal pigment epithelium. Melanin is responsible for giving color to the skin, hair, and eyes. Moreover, melanin is found in the light-sensitive tissue of the retina of the eye which plays a role in normal vision.

The exact function of protein P is unknown, but it has been found that it is essential for the normal coloring of skin, eyes, and hair; and likely involved in melanin production. This gene seems to be the main determinant of eye color depending on the amount of melanin production in the iris stroma (large amounts giving rise to brown eyes; little to no melanin giving rise to blue eyes).

This gene is mutated in Astyanax mexicanus, a Mexican fish which is characterized by a chronic albinism in cave-dwelling individuals. It exists as a deletion in fish from the Pachón and Molino caves, which produces albinism.[6]

Clinical significance

[edit]

Mutations in the OCA2 gene cause a disruption in the normal production of melanin; therefore, causing vision problems and reductions in hair, skin, and eye color. Oculocutaneous albinism caused by mutations in the OCA2 gene is called oculocutaneous albinism type 2. The prevalence of OCA type 2 is estimated at 1/38,000-1/40,000 in most populations throughout the world, with a higher prevalence in the African population of 1/3,900–1/1,500.[7] Other diseases associated with the deletion of the OCA2 gene are Angelman syndrome (light-colored hair and fair skin) and Prader–Willi syndrome (unusually light-colored hair and fair skin). With both these syndromes, the deletion often occurs in individuals with either syndrome.[8][9]

A mutation in the HERC2 gene adjacent to OCA2, affecting OCA2's expression in the human iris, is found common to nearly all people with blue eyes. It has been hypothesized that all blue-eyed humans share a single common ancestor with whom the mutation originated.[10][11][12]

The His615Arg allele of OCA2 is involved in the light skin tone and the derived allele is restricted to East Asia with high frequencies, with highest frequencies in Eastern East Asia (49-63%), midrange frequencies in Southeast Asia, and the lowest frequencies in Western China and some Eastern European populations.[13][14]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

P protein

View on Grokipedia
from Grokipedia
The P protein, also known as OCA2 melanosomal , is a protein encoded by the in humans. Located on 15q12-q13, it is an primarily expressed in melanocytes, where it functions in melanosomes to regulate and facilitate biosynthesis, influencing , , and eye pigmentation. Mutations in OCA2 lead to oculocutaneous albinism type 2 (), a form of characterized by reduced production, resulting in very light , , and eye color, along with vision impairments such as and . Certain variants also contribute to normal variation in pigmentation traits, including . The protein's homolog in mice is associated with the pink-eyed dilution phenotype, underscoring its conserved role in pigmentation.

Genetics

OCA2 gene

The OCA2 gene, which encodes the P protein, is located on the long (q) arm of human chromosome 15 at cytogenetic band 15q12-q13.1. This region is part of a complex genomic area prone to deletions associated with imprinting disorders like Prader-Willi and Angelman syndromes. The gene spans approximately 380 kb of genomic DNA, from nucleotide positions 27,719,008 to 28,099,315 on the reverse strand of reference sequence NC_000015.10. It comprises 30 exons, with the majority being coding, though alternative splicing can produce multiple transcript variants. The OCA2 gene was discovered in 1993 through positional cloning efforts that identified it as the human homolog of the mouse pink-eyed dilution (p) locus on chromosome 7, which had been linked to pigmentation defects since the early 20th century. Linkage studies in families affected by oculocutaneous albinism type 2 (OCA2) mapped the human locus to 15q11-q13, enabling the isolation of complementary DNA clones from melanocyte libraries that matched the mouse p gene sequence. This homology confirmed OCA2's role in a conserved pigmentation pathway across mammals, with the human gene sharing over 80% sequence identity in key functional domains with its murine counterpart. Subsequent analyses in 1995 detailed the gene's structure, reporting 25 exons (later refined to 30 in updated annotations) spanning 250-600 kb, with exon 1 being noncoding. Full genomic sequencing and mutation screening were advanced by 2000, solidifying its association with albinism phenotypes. Regulatory elements play a critical role in OCA2 expression, particularly in pigmentation traits. The gene lies adjacent to the gene, and a key regulatory polymorphism, SNP rs12913832, is located in an evolutionarily conserved enhancer within intron 86 of HERC2, approximately 21 kb upstream of the OCA2 promoter. This SNP modulates OCA2 transcription by altering binding sites for s like helicase-like transcription factor (HLTF); the ancestral A permits higher expression associated with brown eyes, while the derived G reduces OCA2 levels, leading to eyes in homozygous individuals. This variant explains up to 74% of the variance in blue-brown in European populations and represents a classic example of a noncoding regulatory influencing .

Expression patterns

The OCA2 gene, encoding the P protein, exhibits primary expression in melanocytes located in the skin, hair follicles, and (RPE), with lower levels observed in other pigmented tissues such as the iris. In human tissues, GTEx data indicate median TPM values of approximately 25-30 in non-sun-exposed (suprapubic), reflecting contributions from resident melanocytes, while expression is detectable but lower in sun-exposed skin (lower ) at around 15-20 TPM; similarly, modest levels occur in mucosal tissues like esophageal mucosa (median ~10 TPM) and vaginal mucosa (~8 TPM), though these are not primarily pigmented. In the eye, OCA2 mRNA is enriched in RPE cells essential for visual pigmentation, with reduced detection in iris melanocytes, correlating with its role in modulating variation. Developmental regulation of OCA2 involves upregulation during differentiation, driven by key transcription factors such as MITF and TFAP2A to activate transcription and promote pigmentation . This process is integral to maturation from progenitors, where MITF coordinates with co-factors like TFAP2A to enhance OCA2 levels, ensuring timely synthesis during terminal differentiation. Alternative splicing of OCA2 pre-mRNA generates multiple isoforms, including a major transcript incorporating all 24 s and a minor isoform resulting from in-frame skipping of 10 (72 bp, encoding 24 , p.349-p.372). This ΔE10 isoform, observed at basal levels of ~3% in normal tissues but elevated by certain variants (e.g., up to 17% with rs1800404), may exert dominant-negative effects through heterodimerization with full-length P protein, potentially reducing overall protein structural stability and impairing melanosomal function. Recent studies (as of 2025) have shown that the variant rs1800404 enhances 10 skipping, contributing to lighter pigmentation phenotypes in European populations. Such splicing variations contribute to phenotypes without complete loss of function. Quantitative expression data reveal high OCA2 mRNA levels associated with stage III-IV melanosomes, where the protein translocates alongside melanogenic enzymes like during maturation to support pH regulation and deposition. In experimental models, OCA2 is readily detectable via RT-PCR in human cell lines, such as those derived from primary or metastatic lesions, with qRT-PCR showing variable but consistent expression (e.g., elevated in brown-eyed strains compared to blue-eyed, reflecting pigmentation status).

Structure and localization

Protein topology

The P protein, encoded by the OCA2 gene, is an 838-amino acid polypeptide with a calculated molecular weight of approximately 93 kDa, although it often appears as ~110 kDa on SDS-PAGE gels due to post-translational modifications. It functions as an integral melanosomal membrane protein, featuring a complex transmembrane architecture predicted to include 12 alpha-helical segments, though advanced modeling reveals a pseudo-inverted repeat topology with broken helices and re-entrant loops rather than a simple bundle of intact helices. This arrangement resembles members of the SLC13 solute carrier family, such as the sodium-coupled citrate transporter (NaCT), rather than a tetraspanin-like fold. The protein's topology positions both the N- and C-termini in the , with the N-terminal region comprising a disordered segment of about 171 residues that may contribute to regulatory interactions. Extracellular (luminal) loops include a prominent 130-residue GOLD domain forming an 8-stranded beta-sandwich structure between certain transmembrane elements, alongside smaller loops; re-entrant loops from the pseudo-repeat face inward to line a predicted central pore potentially involved in anion . A 95-residue cytosolic helical bundle links the repeat domains, supporting the overall scaffold. Structural understanding relies on computational models derived from AlphaFold2 predictions and homology to SLC13 transporters, including cryo-EM structures like that of NaCT (PDB: 6WTW), which informed the dimeric assembly of P protein in both inward- and outward-facing conformations. No experimental atomic-resolution structure of the full P protein exists as of 2023, limiting direct validation of these models. Dimerization is proposed to occur via interfaces in the scaffold domain, enhancing stability and potential transport efficiency. Post-translational N-glycosylation is critical for and stability, occurring at conserved sites within extracellular loops, such as Asn214, Asn218, and Asn273 in the GOLD domain; mutations disrupting these sites impair trafficking and function. These modifications add to the observed molecular weight and are essential for the protein's maturation in the secretory pathway.

Subcellular targeting

The P protein, also known as OCA2, is targeted to melanosomes primarily through dileucine-based sorting signals located in its cytoplasmic N-terminal domain. These acidic dileucine motifs (LL1, LL2, and LL3) enable direct physical interaction with the adaptor protein complexes AP-1 and AP-3, which mediate cargo sorting from early endosomes to the melanosomal pathway. Specifically, the LL1 motif binds both AP-1 and AP-3 hemicomplexes, with sequence variations influencing binding affinity; AP-3 interaction is crucial for efficient delivery and steady-state retention in melanosomes, while AP-1 supports initial endosomal sorting. This process also involves cooperation with the BLOC-1 complex, which coordinates tubule formation from recycling endosomes for cargo transfer to maturing melanosomes. At , the P protein localizes to the limiting of mature melanosomes (stages III and IV), where it integrates into the during pigmentation. It is largely absent from early-stage melanosomes (I and II) and lysosomes in non-melanocytic cells, reflecting cell-type-specific trafficking. Experimental evidence from immunofluorescence microscopy in human melanocytes confirms this localization, showing strong co-localization of endogenous P protein with the melanosomal marker and pigment granules, but mislocalization to the plasma or when sorting signals are disrupted. Pathogenic mutations in the dileucine motifs, such as substitutions (e.g., OCA2-AA123 triple mutant), abolish AP-3 binding and redirect the protein to the cell surface, preventing melanosomal incorporation and abolishing its role in pigmentation. Similarly, disease-associated variants that impair endosomal sorting lead to retention in upstream compartments, underscoring the motifs' necessity for proper subcellular targeting.

Function

Melanosomal pH regulation

The P protein, encoded by the OCA2 gene, functions as a chloride anion channel embedded in the melanosomal membrane, where it mediates Cl⁻ efflux to regulate the and counteract excessive acidification caused by proton pumping via the vacuolar H⁺-ATPase (). This activity elevates the melanosomal from a highly acidic range of approximately 5.1 to a near-neutral 6.7, establishing an optimal luminal environment ( >6) for activity and other melanosomal processes. The channel's role in ion is independent of direct enzymatic interactions but essential for maintaining electrochemical balance within the . The mechanism of regulation by the P protein involves anion conductance that influences the . The pumps H⁺ into the lumen, generating acidity and a positive interior potential; OCA2-mediated Cl⁻ efflux from the lumen reduces activity by altering this potential, limiting proton accumulation and preventing over-acidification. In the absence of P protein activity, efficiency increases, resulting in lower levels (~5.1). Structural features, such as its 12-transmembrane topology with re-entrant loops, enable the formation of a selective pore for anion via an elevator-like mechanism, though detailed gating dynamics remain under investigation. Experimental validation of the P protein's channel properties has been achieved through patch-clamp , including expression studies in oocytes that reveal robust anion currents. These assays demonstrate high selectivity for over other , with a permeability ratio of P_Cl/P_Na exceeding 10, underscoring its specificity as a rather than a non-selective pathway. Reversal potential shifts in response to varying Cl⁻ concentrations further confirm the Nernstian behavior expected of a Cl⁻-selective conductance. In parallel, pH modulation has been directly assessed in OCA2-knockout melanocytes using ratiometric dyes, where loss of the protein leads to a significant drop in melanosomal (ΔpH ≈ 1.55 units) and impaired , while wild-type expression restores neutralization. Critical residues within the protein, particularly Thr444 in the N-terminal re-entrant loop and V443 in the luminal loop between transmembrane domains 5 and 6, are essential for channel gating and anion permeation. These sites contribute to the voltage-sensing apparatus and pore stability; studies show that alterations at these positions, such as the albinism-associated V443I substitution, reduce overall conductance by approximately 85%, severely compromising regulatory capacity. This highlights their role in conformational changes during , consistent with the protein's predicted elevator-like transport mechanism for anion translocation.

Role in melanin biosynthesis

The P protein facilitates melanin biosynthesis primarily by enabling optimal tyrosinase activity through the elevation of melanosomal pH to near-neutral levels (~6.5-6.7), which is crucial for the rate-limiting hydroxylation of tyrosine to L-DOPA. This pH-dependent regulation supports the initial steps of the melanogenic pathway, where tyrosinase catalyzes the formation of DOPAquinone, a key intermediate for both eumelanin and pheomelanin. Earlier hypotheses suggested that the P protein might transport tyrosine as a substrate into melanosomes to fuel this process, but experimental evidence has refuted direct tyrosine transport by the protein. The P protein significantly impacts the balance between eumelanin (dark brown-black pigment) and pheomelanin (red-yellow pigment) production, with elevated P protein activity correlating to increased eumelanin synthesis and darker overall pigmentation through enhanced DOPAquinone availability for eumelanogenic enzymes. In contrast, loss-of-function mutations in the OCA2 gene greatly inhibit eumelanin deposition (>20-fold reduction) in affected tissues while pheomelanin levels remain largely intact, shifting pigmentation toward lighter phenotypes. Within the melanosomal proteome, the P protein works in concert with (product of the OCA3 gene) and SLC45A2 (also known as MATP) to regulate the melanosomal environment, supporting downstream enzymatic activities in production and ensuring efficient maturation and deposition. Studies in model organisms highlight the P protein's indispensable role in . OCA2-null mice exhibit a >20-fold reduction in eumelanin content across skin and , attributable to disrupted maturation and melanosomal dysregulation. In zebrafish bearing orthologous oca2 mutations, granule maturation is blocked at early stages, resulting in hypopigmented cells with underdeveloped melanosomes and minimal accumulation.

Clinical significance

Oculocutaneous albinism type 2

Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive disorder characterized by reduced or absent pigmentation in the skin, hair, and eyes, leading to and associated visual impairments. The global prevalence is approximately 1 in 38,000 individuals, with higher rates in sub-Saharan African populations ranging from 1 in 1,500 to 1 in 3,900 due to founder effects. Affected individuals typically exhibit pale skin that may tan minimally with age, light-colored hair ranging from white to yellow or light brown, and ocular features including , reduced (often 20/60 to 20/400), , , and iris transillumination. These symptoms arise from mutations in the OCA2 gene, which disrupt normal pigmentation processes without affecting activity directly, distinguishing OCA2 from tyrosinase-negative forms. Over 100 loss-of-function variants in the OCA2 gene have been identified as causative for OCA2, with certain mutations recurring in specific populations. A common founder mutation in individuals of African descent is a 2.7-kb deletion encompassing exons 7 through 12 (often referred to as the 2.8-kb deletion in some literature), which accounts for up to 75% of cases in sub-Saharan Africa and leads to a truncated protein lacking key transmembrane domains. In European populations, the missense variant p.Arg305Trp (R305W) is frequently observed, though its pathogenicity is sometimes debated due to its presence in milder phenotypes; the p.Arg305Gln variant has also been reported in some cases. Among Pakistani families, the splice variant c.1045-15T>G is recurrent, contributing to abnormal splicing and reduced protein function. These biallelic mutations result in absent or dysfunctional P protein, confirming the recessive inheritance pattern. The of OCA2 involves defective regulation of melanosomal by the P protein, leading to an acidic environment within melanosomes that destabilizes , the rate-limiting enzyme in synthesis. This instability reduces tyrosinase activity and proper maturation, resulting in the accumulation of immature stage III melanosomes and, in some cases, the formation of giant, irregularly shaped melanosomes due to impaired fission and . Consequently, eumelanin production is severely diminished, while pheomelanin levels may be relatively preserved, contributing to the variable pigmentation observed. Unlike wild-type function, where P protein maintains neutral to support efficient melanogenesis, these defects primarily affect melanocytes in the skin, hair follicles, and , exacerbating visual pathway abnormalities such as foveal and optic nerve decussation defects. Diagnosis of OCA2 relies on clinical evaluation of and ocular signs, supplemented by through targeted sequencing or next-generation sequencing of the OCA2 gene to identify biallelic pathogenic variants, which confirms the subtype and differentiates it from other OCA forms. Management is supportive and multidisciplinary, focusing on photoprotection with broad-spectrum sunscreen, protective clothing, and regular dermatologic screening to mitigate risk, alongside ophthalmologic interventions such as corrective lenses, low-vision aids, and monitoring for or surgery. There is no curative treatment, but preclinical research into using viral vectors to restore OCA2 expression shows promise in animal models, with ongoing investigations as of 2024.

Variants in pigmentation traits

Variants in the OCA2 gene, which encodes the P protein, play a pivotal role in modulating normal human pigmentation traits beyond the severe seen in type 2. These variants, often single nucleotide polymorphisms (SNPs) or haplotypes, influence production and function, contributing to diversity in eye, skin, and hair color across populations. Unlike loss-of-function mutations causing , common OCA2 polymorphisms typically exert subtle effects on eumelanin and pheomelanin levels, with frequencies varying geographically due to evolutionary selection pressures. A landmark example involves variation, primarily driven by a regulatory SNP in the adjacent gene, rs12913832 (c.−5387G>A), which disrupts a for transcription factors and reduces OCA2 expression by approximately 13-fold in melanocytes. This derived A , originating from a single founder event around 6,000–10,000 years ago in the Black Sea region, is nearly fixed (>95%) in northern and central Europeans and accounts for about 74% of the variance between and eyes. Individuals homozygous for the A exhibit significantly lower iris , resulting in eyes, while the ancestral G supports pigmentation; heterozygous states often yield intermediate shades like or . This variant's effect is mediated through P protein's role in melanosomal acidification, essential for activity and synthesis. Coding variants in OCA2 further fine-tune pigmentation. For instance, rs1800407 (p.Ala481Thr) in 10 is associated with lighter eye colors, particularly green/hazel, and interacts epistatically with rs12913832 to enhance blue eye when in cis configuration. In pigmentation, this SNP correlates with reduced index in Europeans, contributing to fairer complexions. Similarly, rs1800414 (p.His615Arg) in East Asian populations decreases skin reflectance (indicating lighter tone) by 0.85–1.3 melanin units, likely by altering P protein's anion transport and melanosome pH, without affecting significantly. This variant's derived allele frequency reaches 80–100% in northern East Asians, reflecting for lighter independent of European adaptations. In hair pigmentation, OCA2 variants influence pheomelanin predominance. A three-SNP in 1 (rs7495174 T/C, rs6497268 G/T, rs11855019 T/C; "TGT" ) associates with lighter color and fair skin in Europeans, occurring at high frequency and contributing to the lighter alongside MC1R variants. Genome-wide studies in Icelandic cohorts identified additional OCA2 SNPs, such as rs10831496 near the , linked to blonde and freckling, underscoring P protein's broad impact on epidermal distribution. Across populations, OCA2 alleles like rs1800404 (synonymous T variant) contribute to lighter in Europeans and some African groups, such as the KhoeSan, highlighting polygenic and population-specific effects on pigmentation traits.

References

  1. https://medlineplus.gov/genetics/gene/oca2/
  2. https://omim.org/entry/611409
  3. https://www.ncbi.nlm.nih.gov/gene/4948
  4. https://pubmed.ncbi.nlm.nih.gov/8421497/
  5. https://pubmed.ncbi.nlm.nih.gov/18252222/
  6. https://www.genecards.org/cgi-bin/carddisp.pl?gene=OCA2
  7. https://www.proteinatlas.org/ENSG00000104044-OCA2/tissue
  8. https://gtexportal.org/home/gene/OCA2
  9. https://elifesciences.org/articles/04543
  10. https://pmc.ncbi.nlm.nih.gov/articles/PMC5939569/
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC12463227/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC11178461/
  13. https://www.sciencedirect.com/science/article/pii/S0022202X15341890
  14. https://pubmed.ncbi.nlm.nih.gov/15712365/
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC10372470/
  16. https://doi.org/10.1091/mbc.e11-06-0509
  17. https://doi.org/10.1091/mbc.e08-07-0710
  18. https://portlandpress.com/bioscirep/article/43/7/BSR20230060/233275/Structural-insights-into-pink-eyed-dilution
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC4270065/
  20. https://pubmed.ncbi.nlm.nih.gov/10998131/
  21. https://pubmed.ncbi.nlm.nih.gov/8789201/
  22. https://pubmed.ncbi.nlm.nih.gov/21232027/
  23. https://www.sciencedirect.com/science/article/pii/S0005273620301498
  24. https://pubmed.ncbi.nlm.nih.gov/24330346/
  25. https://www.orpha.net/en/disease/detail/79432
  26. https://www.ncbi.nlm.nih.gov/books/NBK519018/
  27. https://omim.org/entry/203200
  28. https://www.ncbi.nlm.nih.gov/clinvar/variation/955/
  29. https://researcherslinks.com/current-issues/Mutation-Analysis-Pakistani-Oculocutaneous-Albinism-Family/20/1/4716
  30. https://onlinelibrary.wiley.com/doi/10.1111/pcmr.13165
  31. https://emedicine.medscape.com/article/1200472-overview
  32. https://rarediseases.org/rare-diseases/oculocutaneous-albinism/
  33. https://omim.org/entry/227220
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC3325407/
  35. https://pubmed.ncbi.nlm.nih.gov/18172690/
  36. https://pubmed.ncbi.nlm.nih.gov/19208107/
  37. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1000867
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC2832666/
  39. https://pubmed.ncbi.nlm.nih.gov/17236130/
  40. https://pubmed.ncbi.nlm.nih.gov/17470494/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC8117430/
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