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OCA2
OCA2 melanosomal transmembrane protein
The OCA2 gene provides instructions for producing the P protein, which is essential for melanin synthesis and pigmentation of the skin, hair, and eyes. OCA2, also known as the P gene, plays a crucial role in determining an individual's pigmentation.
OCA2 is located on the long (q) arm of chromosome 15, at band 15q12-q13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The OCA2 gene, previously referred to as the P gene, carries the genetic blueprint for a protein known as the P protein. This protein is primarily found within melanocytes, which are specialised cells responsible for manufacturing melanin, the pigment that gives colour to our skin, hair, and eyes. Melanin is also present in the retina, where it contributes to normal visual function.
While the exact mechanism of the P protein is still under investigation, it is understood to be critical for typical pigmentation. It is thought to be involved in the transportation of molecules into and out of melanosomes, which are the organelles within melanocytes where melanin is produced. Additionally, the P protein may help regulate the pH balance within melanosomes, a crucial factor for many biological processes.
What the gene does
The OCA2 gene is responsible for generating the P protein, a melanosomal transmembrane protein located within melanocytes. These cells are the body's primary producers of melanin, a pigment vital for skin, hair, and eye colouration, as well as contributing to proper vision within the retina. Although the full functional details of the P protein are yet to be elucidated, its presence is indispensable for normal pigmentation.
Research indicates that the P protein may act as a transporter, facilitating the movement of specific molecules into and out of melanosomes - the cellular compartments where melanin synthesis occurs. There is also a hypothesis that it participates in maintaining the optimal pH level within melanosomes, a factor critical for the efficient operation of the enzymatic pathways involved in melanin production.
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Chromosome location
The OCA2 gene is situated on chromosome 15, specifically within the 15q12-q13.1 region. This particular chromosomal location has broader clinical relevance, as deletions in this area can also be associated with other genetic conditions.
Protein structure
The P protein, encoded by the OCA2 gene, is composed of 838 amino acids. Its structural characteristics include two disordered regions, one spanning amino acids 38-60 and another from amino acids 74-94. These disordered regions suggest a degree of flexibility in the protein's structure, which may be important for its functional interactions.
Key variants
Genetic variations within the OCA2 gene can affect the function of the P protein, leading to altered melanin production. More than 80 different variations have been identified that are associated with inherited conditions. These variants can include single nucleotide changes, insertions, deletions, or larger rearrangements within the gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1079C>T | p.Ser360Phe | Pathogenic | ★★☆☆ | Oculocutaneous albinism |
c.1091del | p.Leu364fs | Pathogenic/Likely pathogenic | ★★☆☆ | OCA2-related disorder |
c.1456del | p.Asp486fs | Pathogenic/Likely pathogenic | ★★☆☆ | SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES |
c.1841dup | p.His615fs | Pathogenic | ★★☆☆ | Tyrosinase-positive oculocutaneous albinism |
c.1982T>A | p.Leu661Ter | Pathogenic/Likely pathogenic | ★★☆☆ | OCA2-related disorder |
c.2195C>G | p.Ser732Ter | Pathogenic | ★★☆☆ | Tyrosinase-positive oculocutaneous albinism |
c.2378G>T | p.Cys793Phe | Pathogenic | ★★☆☆ | OCA2-related disorder |
c.2433-22889T>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Tyrosinase-positive oculocutaneous albinism |
c.2491G>C | p.Ala831Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Oculocutaneous albinism |
c.408_409del | p.Arg137fs | Pathogenic | ★★☆☆ | Tyrosinase-positive oculocutaneous albinism |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variations in the OCA2 gene are primarily linked to oculocutaneous albinism type 2, an inherited condition characterised by reduced melanin synthesis affecting the skin, hair, and eyes. Individuals with this condition typically have light-coloured hair, pale skin, and light-coloured eyes, often accompanied by vision problems. Additionally, individuals with specific chromosomal deletions encompassing the OCA2 gene, such as those seen in Angelman syndrome or Prader-Willi syndrome, may present with lighter hair and skin colour.
Inheritance pattern
Conditions caused by pathogenic OCA2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The OCA2 gene is included in several NHS Genomic Medicine Service national test directories, indicating its clinical relevance in the UK. It is assessed under panels such as 'Albinism or congenital nystagmus (R39)', 'Infantile nystagmus', 'Ocular and oculo-cutaneous albinism', and 'Pigmentary skin disorders (R236)'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the OCA2 gene?
The OCA2 gene provides instructions for making the P protein, which is crucial for the production of melanin, the pigment responsible for the colour of our skin, hair, and eyes.
What condition is most commonly associated with changes in the OCA2 gene?
Changes in the OCA2 gene are most commonly associated with oculocutaneous albinism type 2, a condition that results in reduced pigmentation of the skin, hair, and eyes, along with visual impairments.
Can variants in OCA2 affect anything other than pigmentation?
Yes, aside from affecting pigmentation, the P protein (encoded by OCA2) plays a role in vision due to melanin's presence in the retina. Therefore, OCA2 variants can also lead to vision problems.
References
- Duffy DL, Montgomery GW, Chen W. A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. American journal of human genetics. 2007. PMID: 17236130
- Bittel DC, Kibiryeva N, Talebizadeh Z. Microarray analysis of gene/transcript expression in Angelman syndrome: deletion versus UPD. Genomics. 2005. PMID: 15607424
- Oetting WS, Garrett SS, Brott M. P gene mutations associated with oculocutaneous albinism type II (OCA2). Human mutation. 2005. PMID: 15712365
- Suzuki T, Miyamura Y, Matsunaga J. Six novel P gene mutations and oculocutaneous albinism type 2 frequency in Japanese albino patients. The Journal of investigative dermatology. 2003. PMID: 12713581
- Fridman C, Hosomi N, Varela MC. Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene. American journal of medical genetics. Part A. 2003. PMID: 12749060
- Bittel DC, Kibiryeva N, Talebizadeh Z. Microarray analysis of gene/transcript expression in Prader-Willi syndrome: deletion versus UPD. Journal of medical genetics. 2003. PMID: 12920063
- Toyofuku K, Valencia JC, Kushimoto T. The etiology of oculocutaneous albinism (OCA) type II: the pink protein modulates the processing and transport of tyrosinase. Pigment cell research. 2002. PMID: 12028586
- Brilliant MH. The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment cell research. 2001. PMID: 11310796
- Kerr R, Stevens G, Manga P. Identification of P gene mutations in individuals with oculocutaneous albinism in sub-Saharan Africa. Human mutation. 2000. PMID: 10649493
- Saitoh S, Oiso N, Wada T. Oculocutaneous albinism type 2 with a P gene missense mutation in a patient with Angelman syndrome. Journal of medical genetics. 2000. PMID: 10905897
- Spritz RA, Bailin T, Nicholls RD. Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele. American journal of medical genetics. 1997. PMID: 9215770
- Adam MP, Bick S, Mirzaa GM. Oculocutaneous Albinism Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 1993. PMID: 20301410