P protein explained

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.^[1] 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.^[1] OCA2 encodes the human homologue of the mouse p (pink-eyed dilution) gene.

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

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's individuals. It exists as a deletion in Pachón and Molino's caves fish that produces the albinism. ^[2]

Clinical significance

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.^[3] 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.^{[4] [5]}

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.^{[6] [7] [8]}

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.^{[9] [10]}

Further reading

• Oetting WS, King RA . Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism . Human Mutation . 13 . 2 . 99–115 . 1999 . 10094567 . 10.1002/(SICI)1098-1004(1999)13:2<99::AID-HUMU2>3.0.CO;2-C . 27315644 . free.
• Brilliant MH . The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH . Pigment Cell Research . 14 . 2 . 86–93 . April 2001 . 11310796 . 10.1034/j.1600-0749.2001.140203.x . free.
• Ramsay M, Colman MA, Stevens G, Zwane E, Kromberg J, Farrall M, Jenkins T . The tyrosinase-positive oculocutaneous albinism locus maps to chromosome 15q11.2-q12 . American Journal of Human Genetics . 51 . 4 . 879–884 . October 1992 . 1415228 . 1682821.
• Gardner JM, Nakatsu Y, Gondo Y, Lee S, Lyon MF, King RA, Brilliant MH . The mouse pink-eyed dilution gene: association with human Prader-Willi and Angelman syndromes . Science . 257 . 5073 . 1121–1124 . August 1992 . 1509264 . 10.1126/science.257.5073.1121 . 5800811 . 1992Sci...257.1121G.
• Ludowese CJ, Thompson KJ, Sekhon GS, Pauli RM . Absence of predictable phenotypic expression in proximal 15q duplications . Clinical Genetics . 40 . 3 . 194–201 . September 1991 . 1773534 . 10.1111/j.1399-0004.1991.tb03076.x . 28419032.
• Lee ST, Nicholls RD, Jong MT, Fukai K, Spritz RA . Organization and sequence of the human P gene and identification of a new family of transport proteins . Genomics . 26 . 2 . 354–363 . March 1995 . 7601462 . 10.1016/0888-7543(95)80220-G.
• Spritz RA, Fukai K, Holmes SA, Luande J . Frequent intragenic deletion of the P gene in Tanzanian patients with type II oculocutaneous albinism (OCA2) . American Journal of Human Genetics . 56 . 6 . 1320–1323 . June 1995 . 7762554 . 1801108.
• Lee ST, Nicholls RD, Schnur RE, Guida LC, Lu-Kuo J, Spinner NB, Zackai EH, Spritz RA . Diverse mutations of the P gene among African-Americans with type II (tyrosinase-positive) oculocutaneous albinism (OCA2) . Human Molecular Genetics . 3 . 11 . 2047–2051 . November 1994 . 7874125.
• Durham-Pierre D, Gardner JM, Nakatsu Y, King RA, Francke U, Ching A, Aquaron R, del Marmol V, Brilliant MH . African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism . Nature Genetics . 7 . 2 . 176–179 . June 1994 . 7920637 . 10.1038/ng0694-176 . 6185436.
• Lee ST, Nicholls RD, Bundey S, Laxova R, Musarella M, Spritz RA . Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism . The New England Journal of Medicine . 330 . 8 . 529–534 . February 1994 . 8302318 . 10.1056/NEJM199402243300803 . free.
• Rinchik EM, Bultman SJ, Horsthemke B, Lee ST, Strunk KM, Spritz RA, Avidano KM, Jong MT, Nicholls RD . A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism . Nature . 361 . 6407 . 72–76 . January 1993 . 8421497 . 10.1038/361072a0 . 21794972 . 1993Natur.361...72R.
• Spritz RA, Lee ST, Fukai K, Brondum-Nielsen K, Chitayat D, Lipson MH, Musarella MA, Rosenmann A, Weleber RG . Novel mutations of the P gene in type II oculocutaneous albinism (OCA2) . Human Mutation . 10 . 2 . 175–177 . 1997 . 9259203 . 10.1002/(SICI)1098-1004(1997)10:2<175::AID-HUMU12>3.0.CO;2-X . 5762140 . free.
• Kerr R, Stevens G, Manga P, Salm S, John P, Haw T, Ramsay M . Identification of P gene mutations in individuals with oculocutaneous albinism in sub-Saharan Africa . Human Mutation . 15 . 2 . 166–172 . 2000 . 10649493 . 10.1002/(SICI)1098-1004(200002)15:2<166::AID-HUMU5>3.0.CO;2-Z . 1306686 . free.
• Oetting WS, Gardner JM, Fryer JP, Ching A, Durham-Pierre D, King RA, Brilliant MH . Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Mutations in brief no. 205. Online . Human Mutation . 12 . 6 . 434 . 1998 . 10671067 . 10.1002/(SICI)1098-1004(1998)12:6<434::AID-HUMU16>3.0.CO;2-7 . 34505863 . free.
• Passmore LA, Kaesmann-Kellner B, Weber BH . Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population . Human Genetics . 105 . 3 . 200–210 . September 1999 . 10987646 . 10.1007/s004390051090. 2024-04-08 .
• Manga P, Kromberg J, Turner A, Jenkins T, Ramsay M . In Southern Africa, brown oculocutaneous albinism (BOCA) maps to the OCA2 locus on chromosome 15q: P-gene mutations identified . American Journal of Human Genetics . 68 . 3 . 782–787 . March 2001 . 11179026 . 1274491 . 10.1086/318800.
• Manga P, Orlow SJ . Inverse correlation between pink-eyed dilution protein expression and induction of melanogenesis by bafilomycin A1 . Pigment Cell Research . 14 . 5 . 362–367 . October 2001 . 11601658 . 10.1034/j.1600-0749.2001.140508.x.
• Toyofuku K, Valencia JC, Kushimoto T, Costin GE, Virador VM, Vieira WD, Ferrans VJ, Hearing VJ . The etiology of oculocutaneous albinism (OCA) type II: the pink protein modulates the processing and transport of tyrosinase . Pigment Cell Research . 15 . 3 . 217–224 . June 2002 . 12028586 . 10.1034/j.1600-0749.2002.02007.x.

External links

• GeneReviews/NCBI/NIH/UW entry on Oculocutaneous Albinism Type 2

Notes and References

1. Web site: Entrez Gene: OCA2 oculocutaneous albinism II (pink-eye dilution homolog, mouse). 2015-03-12.
2. Warren WC, Boggs TE, Borowsky R, Carlson BM, Ferrufino E, Gross JB, Hillier L, Hu Z, Keene AC, Kenzior A, Kowalko JE, Tomlinson C, Kremitzki M, Lemieux ME, Graves-Lindsay T, McGaugh SE, Miller JT, Mommersteeg MT, Moran RL, Peuß R, Rice ES, Riddle MR, Sifuentes-Romero I, Stanhope BA, Tabin CJ, Thakur S, Yamamoto Y, Rohner N . A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution . Nature Communications . 12 . 1 . 1447 . March 2021 . 33664263 . 7933363 . 10.1038/s41467-021-21733-z . 2021NatCo..12.1447W.
3. Web site: Oculocutaneous albinism type 2 . Hayashi . Masahiro . Suzuki . Tamio . April 2013 . . 2014-11-09.
4. Web site: OCA2 - oculocutaneous albinism II. Genetics Home Reference - Your guide to understanding genetic conditions. U.S. National Library of Medicine. 30 March 2013.
5. Web site: Don't it make your brown eyes blue?. Understanding Genetics. 30 March 2013. 12 May 2018. https://web.archive.org/web/20180512181520/http://genetics.thetech.org/original_news/news39. dead.
6. Web site: Here's what made those brown eyes blue . Bryner J . 2008-01-31 . Health News . NBC News . 2008-11-06 .

   Web site: One Common Ancestor Behind Blue Eyes . Bryner J . 2008-01-31 . LiveScience . Imaginova Corp. . 2008-11-06 . ; Web site: Blue-eyed humans have a single, common ancestor . 2008-01-30 . News . University of Copenhagen . 2008-11-06 . 2013-07-02 . https://web.archive.org/web/20130702085032/http://news.ku.dk/all_news/2008/blue-eyes . dead .

7. Eiberg H, Troelsen J, Nielsen M, Mikkelsen A, Mengel-From J, Kjaer KW, Hansen L . Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression . Human Genetics . 123 . 2 . 177–187 . March 2008 . 18172690 . 10.1007/s00439-007-0460-x . 9886658.
8. Sturm RA, Duffy DL, Zhao ZZ, Leite FP, Stark MS, Hayward NK, Martin NG, Montgomery GW . A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color . American Journal of Human Genetics . 82 . 2 . 424–431 . February 2008 . 18252222 . 2427173 . 10.1016/j.ajhg.2007.11.005.
9. Donnelly MP, Paschou P, Grigorenko E, Gurwitz D, Barta C, Lu RB, Zhukova OV, Kim JJ, Siniscalco M, New M, Li H, Kajuna SL, Manolopoulos VG, Speed WC, Pakstis AJ, Kidd JR, Kidd KK . A global view of the OCA2-HERC2 region and pigmentation . Human Genetics . 131 . 5 . 683–696 . May 2012 . 22065085 . 3325407 . 10.1007/s00439-011-1110-x.
10. Edwards M, Bigham A, Tan J, Li S, Gozdzik A, Ross K, Jin L, Parra EJ . Association of the OCA2 polymorphism His615Arg with melanin content in east Asian populations: further evidence of convergent evolution of skin pigmentation . PLOS Genetics . 6 . 3 . e1000867 . March 2010 . 20221248 . 2832666 . 10.1371/journal.pgen.1000867 . free .