Alternative titles; symbols
HGNC Approved Gene Symbol: OCA2
SNOMEDCT: 11160000, 26336006; ICD10CM: E70.321;
Cytogenetic location: 15q12-q13.1 Genomic coordinates (GRCh38) : 15:27,719,008-28,099,315 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q12-q13.1 | [Skin/hair/eye pigmentation 1, blond/brown hair] | 227220 | Autosomal recessive | 3 |
| [Skin/hair/eye pigmentation 1, blue/nonblue eyes] | 227220 | Autosomal recessive | 3 | |
| Albinism, brown oculocutaneous | 203200 | Autosomal recessive | 3 | |
| Albinism, oculocutaneous, type II | 203200 | Autosomal recessive | 3 |
The OCA2 gene encodes a protein that corresponds to the 'pink-eyed dilution' (p) mouse mutant. The gene product plays a role in regulating the pH of melanosomes (Yuasa et al., 2007).
Gardner et al. (1992) isolated mouse cDNA clones from the p locus from murine melanoma and melanocyte libraries. The deduced 833-residue protein has a molecular mass of 92 kD. Gardner et al. (1992) obtained the human counterpart of the murine p cDNA by screening a human melanoma cDNA library with a fragment of mouse genomic DNA. The predicted amino acid sequence of the human gene product showed 84% identity from amino acids 283 to 414 of the predicted mouse protein.
Rinchik et al. (1993) demonstrated that the human cDNA DN10, linked to the p locus in mice, identifies the human homolog (P) of the mouse p gene, and appears to encode an integral membrane transporter protein. The human P protein is an 838-amino acid polypeptide that contains 12 putative transmembrane domains and exhibits structural homology to transporters of small organic molecules.
Lee et al. (1995) noted that the 838-residue P protein contains 12 transmembrane domains arranged similarly to various transporters and appears to be an integral membrane protein of melanosomes. Sequence comparisons suggested to Lee et al. (1995) that the P protein is a member of a family of transporters that includes an E. coli Na+/H+ antiporter and that it may be a tyrosine transporter.
Lee et al. (1995) reported that the human OCA2 gene contains 25 exons spanning between 250 and 600 kb; exon 1 is noncoding.
Using pulsed field gel electrophoresis, Gardner et al. (1992) found that probes derived from the mouse p gene showed identical patterns of hybridization to those observed with the human D15S12 locus on human chromosome 15q, suggesting that the 2 were homologs. The D15S12 locus had been mapped to human chromosome 15q11.2-q12 (Donlon et al., 1986; Knoll et al., 1990; Robinson et al., 1991), the region of abnormality associated with Prader-Willi syndrome (PWS; 176270) and Angelman syndrome (AS; 105830).
Using immunoblot analysis to examine murine melanocytes, Rosemblat et al. (1994) demonstrated that the p gene encodes a 110-kD hydrophobic integral melanosomal membrane protein. The protein was absent from melanosomes cultured from 2 strains of mutant mice in which the p gene transcript was not expressed. Subcellular fractionation of cultured melanocytes showed that the protein was present in melanosomes, but absent from the vesicle-rich small granule fraction of melanocytes.
Lee et al. (1995) reported several polymorphisms in the P gene.
Oculocutaneous Albinism Type II
In a patient with tyrosinase-positive oculocutaneous albinism, or OCA2 (203200), Rinchik et al. (1993) demonstrated deletion of the poly(A) tail and part of the last exon of the OCA2 gene, inherited from his mother, and deletion of the entire locus inherited from his father. The patient also had Prader-Willi syndrome. The authors noted that the prevalence of type II OCA among patients with Prader-Willi syndrome and Angelman syndrome, perhaps 1%, is consistent with the expected frequency of carriers of type II OCA, given a frequency of the disease of approximately 1 per 36,000 in Caucasians.
In affected members of a consanguineous kindred with OCA2, Durham-Pierre et al. (1994) identified a homozygous 2.7-kb deletion encompassing an exon of the P gene (611409.0001). The kindred was of African, Caucasian, and American Indian descent. The same deletion allele was identified in unrelated African Americans, Haitian, and Africans with OCA2, suggesting a founder effect.
Brown oculocutaneous albinism (see 203200) is also linked to the P locus, and the occurrence of both OCA2 and BOCA within the same family suggested that these disorders are allelic. Manga (1997) found that a large proportion (9/10) of BOCA subjects were compound heterozygotes with the 2.7-kb deletion of the OCA2 gene on one allele.
Lee et al. (1994) identified homozygous or compound heterozygous mutations in the OCA2 gene (see, e.g., 611409.0003-611409.0006) in individuals with oculocutaneous albinism. Lee et al. (1994) studied 7 unrelated African American patients with OCA2 and identified different abnormalities of the P gene in all 7.
Kawai et al. (2005) noted that over 50 different mutations in the OCA2 gene have been reported.
Rooryck et al. (2011) identified a 184-kb deletion in the OCA2 gene (611409.0015) as a founder mutation in 3 unrelated patients of Polish ancestry with OCA2. Sequence analysis indicated that the 2 breakpoints were located in repeat-rich regions containing numerous Alu and L1 repeats, suggesting nonhomologous end joining (NHEJ) as the molecular mechanism. The authors noted that they had found rearrangements of the OCA2 gene in more than 20% of their OCA2 patients and recommended high-resolution array CGH analysis for adequate molecular diagnosis in candidate patients.
In a mother and 3 of her children with oculocutaneous or ocular albinism, Jedlickova et al. (2023) identified biallelic mutations in the OCA2 gene, involving homozygosity or compound heterozygosity for the previously reported V443I substitution (611409.0004). Other members of the family had autosomal dominant retinal dystrophy with coloboma (see 616722).
Normal Pigment Variation
Akey et al. (2001) studied the contribution of the P and MC1R (155555) genes to interindividual variation in skin pigmentation in a Tibetan population. They genotyped 3 single-nucleotide polymorphisms (SNPs) in the MC1R gene and 2 SNPs in the P gene in 184 randomly ascertained Tibetan subjects, whose skin color was measured as a quantitative trait by reflective spectroscopy. Single-locus analyses failed to demonstrate an association between any of the 5 SNPs and skin pigmentation. However, when an epistatic model was applied to the data, a significant gene-gene interaction was identified between val92 to met (155555.0002) in the MC1R gene and the IVS13-15T-C polymorphism in the P gene identified by Lee et al. (1995).
A genomewide linkage scan for eye color by Zhu et al. (2004) suggested that 74% of variation in eye color in Europeans can be attributed to a QTL linked to the OCA2 region of 15q.
Duffy et al. (2007) conducted additional genotyping to clarify the role of OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. The highest association for blue/nonblue eye color (227220) was found with 3 OCA2 SNPs in intron 1, rs7495174 (T/C), rs4778241 (G/T), and rs4778138 (T/C). These 3 SNPs are in 1 major haplotype block (611409.0013), with TGT representing 78.4% of alleles. The minor population impact of the nonsynonymous coding region polymorphisms arg305-to-trp (611409.0011) and arg419-to-gln (611409.0012) associated with nonblue eyes (Rebbeck et al., 2002; Jannot et al., 2005) and the tight linkage of the major TGT haplotype within intron 1 of OCA2 with blue eye color and lighter hair and skin tones suggested that differences within the 5-prime proximal regulatory region of the OCA2 gene alter expression or mRNA transcript levels and may be responsible for these associations.
Frudakis et al. (2007) developed an iris color score for quantifying iris melanin content ('C') in silico and analyzed the OCA2 locus in 1,317 individuals, confirming 6 previously described associations and identifying another 27 SNPs strongly associated with 'C.' Using 4 discontinuous and nonoverlapping SNP sets across blocks of linkage disequilibrium, the authors examined 82 samples and found that those with matching diplotypes composed of nonoverlapping OCA2 SNPs exhibited a rate of 'C' concordance of 96.3%, which was significantly greater than that for randomly selected samples (62.6%; p less than 0.0001). Frudakis et al. (2007) concluded that OCA2 is the major human iris color gene and suggested that by using an empirical database-driven system, genotypes from a modest number of SNPs within this gene can be used to accurately predict iris melanin content from DNA.
See HERC2 (605837) for information on noncoding variants in the HERC2 gene that affect OCA2 expression and are associated with eye color.
By examining 1,570 ethnically diverse African genomes from individuals with quantified pigmentation levels, Crawford et al. (2017) identified 10 SNPs in the OCA2/HERC2 region that were highly associated with pigmentation. The SNP with the highest probability of being causal in OCA2 was rs1800404 (p = 1.6 x 10(-8)), a synonymous variant within exon 10. The ancestral rs1800404C allele, associated with dark pigmentation, is common in most Africans as well as southern and eastern Asians and Australo-Melanesians, whereas the derived T allele, associated with light pigmentation, is most common (greater than 70%) in Europeans and San. The rs1800404C variant, associated with dark pigmentation, is identical by descent in South Asian and Australo-Melanesian populations. Crawford et al. (2017) noted the extensive linkage disequilibrium among SNPs in the OCA2/HERC2 region.
Melanoma
Jannot et al. (2005) genotyped 113 patients with cutaneous malignant melanoma (see 155600) and 105 controls for SNPs in the OCA2 gene. Analysis of allelic distribution showed an association between melanoma and OCA2 (p = 0.030); combination testing revealed that a combination formed by 2 SNPs, IVS13+112 and A776A (rs1800419), was most strongly associated with melanoma (nominal p = 0.001). Jannot et al. (2005) concluded that OCA2 genotype influences melanoma risk.
The pink-eye (or pink-eyed dilution) locus in the mouse is of historic significance because the linkage of this locus with a locus for albinism by Haldane et al. (1915) was the first mammalian linkage to be discovered. The gene was subsequently demonstrated to be on mouse chromosome 7 and the molecular nature of the mutation identified (Lyon et al., 1992; Gardner et al., 1992).
The 'pink-eyed dilution' (p) mouse has reduced pigmentation of the coat and eyes inherited as an autosomal recessive trait. Gardner et al. (1992) found that the murine transcript for the p gene was missing or altered in 6 independent mutant alleles of the p locus derived from hypopigmented mice, suggesting that disruption of this gene is responsible for the disorder. The authors noted that although hypopigmentation characterizes both Prader-Willi and Angelman syndromes, other features of these disorders are not found in the p mouse. Mice heterozygous for mutant p alleles are fully pigmented regardless of the parental origin of the mutant allele, suggesting that the mouse gene is not affected by imprinting.
Gondo et al. (1993) studied the mouse pink-eyed unstable mutation, p(un), affecting coat color, which exhibits one of the highest reported reversion frequencies of any mammalian mutation and is associated with a duplication of genomic DNA at the p locus. They showed that DNA from p(un) was distinguished from wildtype and revertant DNA by a head-to-tail tandem duplication of approximately 70 kb. No differences were detected between revertant and wildtype DNAs. Thus, the reversion in phenotype was coupled with a loss of one copy of the 70-kb duplicated segment. They commented that the mouse p locus has a human homolog in D15S12 and that duplications of this gene occur in about 6% of Prader-Willi syndrome patients (Hamabe et al., 1991).
Hagiwara et al. (2000) characterized a radiation-induced mutant allele of the mouse p locus that was associated with failure-to-thrive syndrome and diminished pigmentation. Homozygous mice showed delayed growth and died within 2 weeks of birth. They developed progressive atrioventricular heart block and significant ultrastructural changes in both cardiac and skeletal muscle cells. Hagiwara et al. (2000) determined that the mutation was associated with a chromosome 7 inversion that disrupted both the p gene and the Sox6 gene (607257).
Protas et al. (2006) generated a genomewide linkage map to allow quantitative trait analysis of evolutionarily derived morphologies in the Mexican cave tetra, a species that has, in a series of independent caves, repeatedly evolved specialized characteristics adapted to a unique and well-studied ecologic environment. They focused on the trait of albinism and discovered that it is linked to the Oca2 gene in 2 cave populations. They found different deletions in Oca2 in each population, and, using a cell-based assay, showed that both caused loss of function of the corresponding protein. Thus, the 2 cave populations evolved albinism independently, through similar mutational events.
In affected members of a consanguineous kindred with oculocutaneous albinism type II (OCA2; 203200), Durham-Pierre et al. (1994) identified a homozygous 2.7-kb deletion encompassing an exon of the P gene. The kindred was of African, Caucasian, and American Indian descent. The same deletion allele was identified in unrelated African Americans, Haitian, and Africans with OCA2, suggesting a founder effect.
Brown oculocutaneous albinism (BOCA) is also linked to the P locus, and the occurrence of both OCA2 and BOCA within the same family suggested that these disorders are allelic. Manga (1997) found that a large proportion (9/10) of BOCA subjects were compound heterozygotes with the 2.7-kb deletion of the OCA2 gene on one allele. Manga et al. (2001) demonstrated that 10 persons with brown oculocutaneous albinism in southern Africa were heterozygous for the 2.7-kb deletion. They did not succeed in defining the second mutation but presumed that it was a milder mutation, possibly in the promoter region (downregulating expression) or in other regions of the P gene they did not screen.
By analyzing a 5-SNP haplotype of the OCA2 gene in 53 unrelated Cameroonian OCA2 patients homozygous for the 2.7-kb deletion and 48 ethnically matched controls, Aquaron et al. (2007) estimated that the mutation originated 4,100 to 5,645 years ago.
In a 7-year-old girl of northern European ancestry with a mild form of oculocutaneous albinism type II (OCA2; 203200), Lee et al. (1994) identified compound heterozygosity for 2 mutations in the OCA2 gene: a G-to-T transversion in the first nucleotide of the donor splice junction of IVS17 gene, and A481T (611409.0003). The patient's skin was fair but tanned normally, and her hair was reddish brown. Her irides were blue and showed transillumination, and the fundi appeared nonpigmented, with hypoplastic maculae. She had nystagmus and severe myopia, with corrected visual acuity of 20/200. Her parents were unrelated and had normal pigmentation, and there was no family history of albinism. Hair-bulb tyrosinase activity was normal.
In a girl with a mild form of oculocutaneous albinism type II (OCA2; 203200), Lee et al. (1994) identified compound heterozygosity for 2 substitutions in the OCA2 gene: an ala481-to-thr (A481T) change and a splice site mutation (611409.0002). Lee et al. (1994) estimated the frequency of the A481T substitution to be 0.01 in normal Caucasian individuals.
In a cellular transfection study, Sviderskaya et al. (1997) showed that the thr481 allele had approximately 70% residual function.
Suzuki et al. (2003) found that the allele frequency of thr481 was 0.12 in normally pigmented Japanese individuals. Two individuals who were homozygous were entirely normal with respect to pigmentation of the eyes, skin, and hair. The findings suggested that the thr481 only results in the OCA2 phenotype when combined with a null or almost null mutant OCA2 allele.
Yuasa et al. (2007) stated that the A481T substitution results from a 1559G-A transition in exon 14 of the OCA2 gene. Among more than 2,615 healthy individuals from 20 African and Eurasian populations, Yuasa et al. (2007) found that the thr481 allele prevailed almost exclusively in a northeastern part of Asia. The allele frequency was highest in Buryat (0.24) in Mongolia and showed a north-south gradient. The findings suggested that thr481 allele arose in a region of low ultraviolet radiation and thereafter spread to neighboring populations.
In a 4-year-old boy of northern European ancestry with typical type II oculocutaneous albinism (OCA2; 203200), Lee et al. (1994) identified compound heterozygosity for 2 mutations in the OCA2 gene: a G-to-A transition, resulting in a val443-to-ile (V443I) substitution inherited from the mother, and a C-to-T transition in exon 22 resulting in a pro743-to-leu (P743L; 611409.0005) substitution inherited from the father. The patient's skin was very lightly pigmented with no apparent tanning ability, and his hair was pale golden yellow. His irides were blue and showed transillumination, and the fundi appeared nonpigmented, with hypoplastic maculae. His corrected visual acuity was 20/100, and he had nystagmus and strabismus. Chromosomal analysis demonstrated mosaicism for 46,XY and 46,XY,dup(15)(q12). The duplication, which occurred in 25% of stimulated peripheral-blood leukocytes, was interpreted as a nonpathologic chromosomal variant (Ludowese et al., 1991). Lee et al. (1994) found the same V443I substitution on the maternally derived chromosome 15 in a 7-year-old boy with typical type II oculocutaneous albinism and Prader-Willi syndrome (PWS; 176270), the latter being due to deletion of 15q11.2-q13.1 derived from the father. The paternal OCA2 gene was deleted in this child.
In a mother and 3 of her children in a Czech family with oculocutaneous or ocular albinism, Jedlickova et al. (2023) identified homozygosity or compound heterozygosity for the V443I mutation in the OCA2 gene. The mother and a daughter, who both had oculocutaneous albinism, were compound heterozygous for V443I and a large complex rearrangement in the OCA2 gene, whereas the 2 sons, who had ocular albinism, were homozygous for the V443I substitution. The authors noted that the sons had normal visual acuity with discrete fundus hypopigmentation and foveal hypoplasia, which was only revealed due to the familial investigation; they suggested that these findings supported the notion of V443I as a hypomorphic allele causing only a partial loss of function, thus accounting for the 4 homozygous individuals present in the gnomAD database (v2.1.1).
For discussion of the pro743-to-val (P743V) mutation in the OCA2 gene that was found in compound heterozygous state in a patient with oculocutaneous albinism type II (OCA2; 203200) by Lee et al. (1994), see 611409.0004.
In an 8-year-old Pakistani girl with severe type II oculocutaneous albinism (OCA2; 203200), Lee et al. (1994) identified a homozygous 1-bp deletion of the first base in codon 654 of the OCA2 gene, resulting in a frameshift and premature termination of the protein at codon 662. The patient was a member of a large and highly consanguineous kindred. Her skin was virtually white, with no apparent tanning ability, and her hair was pale golden yellow. Her irides were pale blue and showed transillumination, and the optic fundi appeared nonpigmented with hypoplastic maculae.
In a study of southern African blacks with oculocutaneous albinism type II (OCA2; 203200) who had at least 1 allele of the OCA2 gene that was not the common 2.7-kb deletion (611409.0001), Kerr et al. (2000) found 4 mutations in the OCA2 gene, 1 of which was an ala334-to-val (A334V) substitution in the second transmembrane domain of the OCA2 protein.
Yi et al. (2003) found a LINE-mediated 122.5-kb deletion of the OCA2 gene as the cause of frequently occurring oculocutaneous albinism type II (OCA2; 203200) among Navajo of northeastern Arizona. The deletion removed exons 10 through 20. Although it did not disrupt the reading frame of the gene, it removed 345 of the total 838 amino acids. The 12 transmembrane domains of the wildtype protein were reduced to 5. Sequence analysis of the breakpoints and the flanking sequences showed that both breakpoints were exactly end-joined and both were found within long interspersed nucleotide elements (LINEs). However, the breakpoint LINEs were oppositely oriented, and no sequence homology between them was found at the breakpoint juncture.
In a patient with oculocutaneous albinism type II (OCA2; 203200), King et al. (2003) found compound heterozygosity for 2 mutations in the OCA2 gene: trp679-to-cys (W679C) on the maternal allele and asn489-to-asp (N489D; 611409.0010) on the paternal allele. This patient represented an unusual pigmentation phenotype that involved red rather than yellow hair. Indeed, King et al. (2003) found a mutation in the MC1R gene (155555.0004) to be responsible for the red hair in this patient and in 5 others with OCA2 who continued to have red hair after birth.
For discussion of the asn489-to-asp (N489D) mutation in the OCA2 gene that was found in compound heterozygous state in a patient with oculocutaneous albinism type II (OCA2; 203200) by King et al. (2003), see 611409.0009.
Using a sample of 629 normally pigmented individuals, Rebbeck et al. (2002) found that individuals carrying the OCA2 variants arg305-to-trp (R305W) or arg419-to-gln (R419Q) (611409.0012) or both were more likely to have nonblue eyes (see 227220) (P = 0.002, 0.001, and 0.003, respectively). The R305W variant was associated with brown eyes. These results suggested that the OCA2 gene may, in part, determine normal phenotypic variation in human eye color and may therefore represent an inherited biomarker of cutaneous cancer risk.
Jannot et al. (2005) replicated the association of the R305W variant in OCA2 with nonblue eye color in a French population.
For discussion of the arg419-to-gln (R419Q) mutation in the OCA2 gene that was found in individuals with nonblue eyes (see 227220) by Rebbeck et al. (2002), see 611409.0011. Rebbeck et al. (2002) found that the R419Q variant was associated with green/hazel eyes (see 227220).
Jannot et al. (2005) were unable to replicate the association of the R419Q variant of OCA2 with nonblue eye color in a French population.
Sturm et al. (2008) demonstrated that the OCA2 coding SNP R419Q (rs1800407) acts as a penetrance modifier of HERC2 rs12913832 (605837.0003).
To clarify the role of OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations, Duffy et al. (2007) genotyped 3,839 adolescent twins, sibs, and parents for 58 synonymous and nonsynonymous exonic SNPs and tagging SNPs at the OCA2 locus. The authors found that the highest association for blue/nonblue eye color (227220) was found with 3 OCA2 SNPs in intron 1: rs7495174, T/C; rs4778241 (formerly rs6497268), G/T; and rs4778138 (formerly 11855019), T/C. These 3 SNPs are in 1 major haplotype block, with TGT representing 78.4% of alleles. The TGT/TGT diplotype found in 62.2% of samples was the major genotype seen to modify eye color, with a frequency of 0.905 in blue or green compared with only 0.095 in brown eye color. This genotype was also at highest frequency in subjects with light brown hair and was more frequent in fair and medium skin types, consistent with the TGT haplotype acting as a recessive modifier of lighter pigmentary phenotypes. Homozygotes for rs4778138 C/C were predominantly without freckles and had lower mole counts.
In an association study of pigmentation variants using Icelandic and Dutch population samples, Sulem et al. (2007) found association of the rs7495174, rs4778241, and rs4778138 identified by Duffy et al. (2007) with blue eye color and blond hair. The A allele of rs7495174 was strongly associated with blue versus brown eyes (OR = 6.90, p = 3.0 x 10(-24)).
In a 21-year-old Japanese man with subclinical oculocutaneous albinism type II (OCA2; 203200), Kawai et al. (2005) identified compound heterozygosity for 2 mutations in the OCA2 gene: a G-to-A transition, resulting in a met394-to-ile (M394I) substitution, and A481T (611409.0003). The man presented with a severe blistering sunburn on the back and upper arms after bathing in the sea for about 1 hour. He had a superficial dermal burn over 18% of the body surface and was admitted to the hospital for treatment. He was noted to have pale skin, but dark brown hair and irides. Kawai et al. (2005) noted that this patient had a subclinical form of OCA2 with pale skin and little resistance to the stress of sunburn.
In 3 unrelated patients of Polish ancestry with oculocutaneous albinism type II (OCA2; 203200), Rooryck et al. (2011) identified a 184-kB deletion in the OCA2 gene (chr15:25,793,533-25,977,380, NCBI36.1) encompassing exons 3 to 20. One patient was homozygous for the deletion, and another was compound heterozygous for the deletion and another pathogenic OCA2 mutation. A second mutation could not be identified in the third patient. Haplotype analysis indicated a founder effect. Sequence analysis showed that the 2 breakpoints were located in repeat-rich regions containing numerous Alu and L1 repeats, suggesting nonhomologous end joining as the molecular mechanism.
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