OCA2

Official Full Name

OCA2 melanosomal transmembrane protein

Organism

Homo sapiens

GeneID

4948

Background

This gene encodes the human homolog of the mouse p (pink-eyed dilution) gene. The encoded protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine, which is a precursor to melanin synthesis. It is involved in mammalian pigmentation, where it may control skin color variation and act as a determinant of brown or blue eye color. Mutations in this gene result in type 2 oculocutaneous albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Synonyms

P; BEY; PED; BEY1; BEY2; BOCA; EYCL; HCL3; EYCL2; EYCL3; SHEP1; D15S12; SLC13B1;

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Detailed Information

Oculocutaneous albinism (OCA) is the most common inherited disorder of skin pigmentation and affects 1 in every 18,000 people in the United States. Oculocutaneous albinism type 2 (OCA2) is the most common OCA type that is caused by mutations of the OCA2 gene. The human OCA2 gene (previously called the P gene), located at chromosome 15q11.2-q12, is the homolog of the mouse pink-eyed dilution gene (p). The OCA2 gene consists of 24 exons, the first representing a noncoding 50'UTR. Although its function is not precisely characterized, the P-protein, the OCA2 gene product, contains 12 transmembrane spanning regions and is an integral component of the melanosomal membrane (Figure 1). It appears to have multiple functions in the biosynthesis of melanin including a key role in the maturation and transport of tyrosinase into the melanosome. To date, 117 OCA2 mutations have been reported, including 71 missense/nonsense, 14 splicing, 18 small deletions, 7 gross deletions, 5 small insertions, and 2 small indels.

Figure 1. Schematic of the P proteins.

Individuals affected by OCA2 as well as other types of albinism are at a dramatically increased risk for sun-induced skin-cancers, including malignant melanoma (MM). However, compared to other OCA types, the low rates of MM seen in patients with OCA2 can in part be explained by the high-frequency OCA2 variants in individuals of African descent. While the increased rates of MM among individuals with OCA2 may be entirely accounted for by the reduction of melanin, some published reports suggest that OCA2 variants, which in and of themselves do not cause albinism, could represent an inherited biomarker of MM susceptibility independent of its role in human pigmentation. Nevertheless, other similar genome wide association studies (GWAS) have failed to demonstrate this association. The identification of a new OCA2 variant within a melanoma-prone pedigree provides an opportunity to study the connection between OCA2 variants and the risk of MM. The discovery of the novel OCA2 variant increases the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma.

In a recent study, researchers analyzed the pathogenic effect of 95 non-synonymous single nucleotide polymorphisms reported in OCA2 gene using computational methods. They found R305W mutation as the most deleterious and disease associated. In order to understand the atomic arrangement in 3D space, the native and mutant (R305W) structures were modeled. Molecular dynamics simulation was conducted to study the structural significance of computationally prioritized disease-associated mutation (R305W). Root-mean-square deviation, root-meansquare fluctuation, the radius of gyration, solvent accessibility surface area, hydrogen bond (NH bond), eigenvector projection analysis, the trace of covariance matrix, and density analysis results showed prominent loss of stability and rise in mutant flexibility values in 3D space. This study presents a well-designed computational method to examine the albinism-associated SNPs.

References:

Kamaraj B, Purohit R. Computational screening of disease-associated mutations in OCA2 gene. Cell Biochemistry & Biophysics, 2014, 68(1):97-109.
Kondo T, et al. Oculocutaneous albinism: Developing novel antibodies targeting the proteins associated with OCA2 and OCA4. Journal of Dermatological Science, 2015, 77(1):21-27.
Hawkes J E, et al. Report of a Novel OCA2 Gene Mutation and an Investigation of Two OCA2 Variants on Melanoma Predisposition in a Familial Melanoma Pedigree. Journal of Dermatological Science, 2013, 69(1):30-37.
Duffy D L, et al. Multiple Pigmentation Gene Polymorphisms Account for a Substantial Proportion of Risk of Cutaneous Malignant Melanoma. Journal of Investigative Dermatology, 2010, 130(2):520-528.

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