Albinism, Oculocutaneous, Type Ii

A number sign (#) is used with this entry because oculocutaneous albinism type II (OCA2) is caused by homozygous or compound heterozygous mutation in the OCA2 gene (611409) on chromosome 15q.

For a discussion of genetic heterogeneity of OCA, see OCA1A (203100).

Description

Tyrosinase-positive oculocutaneous albinism (OCA, type II) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Although affected infants may appear at birth to have OCA type I, or complete absence of melanin pigment, most patients with OCA type II acquire small amounts of pigment with age. Individuals with OCA type II have the characteristic visual anomalies associated with albinism, including decreased acuity and nystagmus, which are usually less severe than in OCA type I (Lee et al., 1994; King et al., 2001).

OCA type II has a highly variable phenotype. The hair of affected individuals may turn darker with age, and pigmented nevi or freckles may be seen. African and African American individuals may have yellow hair and blue-gray or hazel irides. One phenotypic variant, 'brown OCA,' has been described in African and African American populations and is characterized by light brown hair and skin color and gray to tan irides. The hair and irides may turn darker with time and the skin may tan with sun exposure; the ocular features of albinism are present in all variants (King et al., 2001). In addition, previous reports of so-called 'autosomal recessive ocular albinism,' (see, e.g., Witkop et al., 1978 and O'Donnell et al., 1978) with little or no obvious skin involvement, are now considered most likely to be part of the phenotypic spectrum of OCA1 or OCA2 (Lee et al., 1994; King et al., 2001).

Clinical Features

Trevor-Roper (1952, 1963) reported 2 albino parents who had 4 normally pigmented children. Inheritance was most likely autosomal recessive. X-linked albinism could be excluded because the obligate heterozygous daughters of the father did not have mosaic pigmentary patterns in the ocular fundus. Trevor-Roper (1963) suggested that the parents had different forms of albinism. Applying the chemical method of Kugelman and Van Scott (1961), Witkop (1966) examined the family reported by Trevor-Roper (1952, 1963) and found that whereas the mother did not show pigmentation in the Kugelman-Van Scott test, the father did show pigment. Witkop (1966) asserted that it is difficult to distinguish tyrosinase-positive from tyrosinase-negative albinism clinically, especially in Caucasians. Pigmented nevi in tyrosine-positive cases may be the only clue. In blacks with this form of albinism, the hair is yellow and many pigmented spots develop in the skin. In such cases, Witkop (1966) hypothesized a block in the formation of eumelanin with a continuing formation of pheomelanin.

Witkop et al. (1978) referred to 4 families in which males and females were equally severely affected with a form of ocular albinism without apparent skin involvement. Affected females had ocular changes similar to those of hemizygous sales with X-linked ocular albinism (OA1; 300500). Some of the parents had diaphanous irides. None of the mothers had affected male relatives, and 2 of the families were Amish with consanguineous parents, suggesting autosomal recessive inheritance. The authors noted that ocular albinism had been reported in a female by Scialfa (1972). O'Donnell et al. (1978) observed 7 females and 2 males from unrelated Caucasian kindreds with ocular albinism. Affected individuals showed impaired vision, translucent irides, congenital nystagmus, photophobia, albinotic fundi with hyperplasia of the fovea, and strabismus. Unlike the X-linked form of ocular albinism, females were as severely affected as males, obligatory heterozygotes lacked the mosaic pattern, and skin and hairbulbs did not show giant pigment granules. Autosomal recessive inheritance was suggested.

Castle et al. (1988) could demonstrate no asymmetry on monocular testing of visual evoked potentials to suggest an abnormality of decussation in heterozygotes.

Witkop et al. (1989) stated that tyrosinase-positive albinism was the form present in the Hopi and Zuni Indians studied by Woolf (1965) and Woolf and Dukepoo (1969). This form was also found in the Brandywine triracial isolate (Witkop et al., 1972).

In southern Africa, negroids with tyrosinase-positive ocular cutaneous albinism present with 2 distinctly different phenotypes, with or without darkly pigmented patches (ephelides, or dendritic freckles) on exposed areas of the skin. These phenotypes were concordant within families. Among 111 albinos from southern Africa, Kromberg et al. (1989) found a correlation between the presence of ephelides and a lower risk of developing skin cancer, possibly as the result of the presence of some melanin pigment offering photoprotection.

Brown oculocutaneous albinism (BOCA) in humans is linked to the P locus, where mutations causing OCA2 are located. The occurrence of both OCA2 and BOCA within the same family suggested that these disorders are allelic (Manga, 1997).

Using MRI, Schmitz et al. (2003) found that the size and configuration of the optic chiasm in humans with albinism are distinctly different from the chiasms of normal control subjects. These chiasmal changes reflect the atypical crossing of the optic fibers, irrespective of the causative gene mutation. Eight patients had tyrosinase gene-related OCA1, 4 patients had P gene-related OCA2, and 1 had ocular albinism (OA1); the albinism-causing mutation had not been identified in 4 other patients.

Clinical Variability

Chiang et al. (2008) noted that heterozygous carriers of the common 2.7-kb deletion in the OCA2 gene (611409.0001) from sub-Saharan Africa are not hypopigmented. However, Caucasian individuals with Prader-Willi syndrome (PWS; 176270) or Angelman syndrome (AS; 105830), who are haploinsufficient for the OCA2 gene, often show hypopigmentation. The authors concluded that the phenotype of haploinsufficiency for the OCA2 gene depends upon the genetic pigmentary background of the individual. Chiang et al. (2008) presented a Hispanic family in which the proband with OCA2 was compound heterozygous for the 2.7-kb deletion and another pathogenic mutation in the OCA2 gene. Family members carrying the heterozygous 2.7-kb deletion had mild skin hypopigmentation without ocular defects. The findings suggested that haploinsufficiency of the OCA2 gene can contribute to skin hypopigmentation that may be more obvious in Caucasian or Hispanic populations compared to Africans, who have color above the threshold of distinction. The report of Chiang et al. (2008) was in agreement with the findings of Sulem et al. (2007), who found a role for variations in the OCA2 gene in skin/hair/eye pigmentation (SHEP1; 227220).

Mapping

Studying Bantu subjects in South Africa, Ramsay et al. (1992) demonstrated linkage of the OCA2 locus to 2 DNA markers, D15S10 and D15S13, in the region 15q11.2-q12. Since the pink-eyed dilution locus, p, on mouse chromosome 7, maps to a region of homology of synteny with human 15q, Ramsay et al. (1992) postulated that the OCA2 and p loci are homologous.

Kedda et al. (1994) analyzed for linkage with markers on 15q11-q13 in 41 southern African negroid families, each containing at least 1 affected tyrosinase-positive albino. Analysis showed no obligatory crossovers between the alleles at D15S12 and a tyrosinase-positive OCA, suggesting that the D15S12 locus is very close to or part of the disease locus, P. The affected persons in 13 of the families had ephelides; those in 23 families did not have ephelides; and those in 5 families were of unknown ephelis status, with 100% concordance with respect to ephelis status in all 36 families.

Manga et al. (2001) showed by linkage analysis in 5 families that the BOCA phenotype maps to the same region as the OCA2 locus on 15q.

Molecular Genetics

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.

In 4 unrelated patients with OCA2, Lee et al. (1994) identified mutations in the OCA2 gene (see, e.g., 611409.0002-611409.0006).

Lee et al. (1994) studied 7 unrelated African American patients with OCA2 and identified different abnormalities of the P gene in all 7. In addition to the single exon deletion found by Durham-Pierre et al. (1994), they observed 2 large deletions, 2 small in-frame deletions, and 6 different point mutations.

Stevens et al. (1995) also found that the 2.7-kb intragenic deletion first identified by Durham-Pierre et al. (1994) is a frequent cause of OCA2 in South African negroids, being found in 114 of 146 (78%) of OCA2 chromosomes. A common haplotype was found in 43 of 55 (78%) OCA2 chromosomes studied, confirming the African origin of this allele. On the basis of haplotype data, it appeared that at least 7 additional, less-frequent OCA2 mutations had occurred in this population. Spritz et al. (1995) found that the same 2.7-kb deletion allele accounted for most of the mutant P alleles in Tanzania. The 2.7-kb deletion includes exon 7 and results in a frameshift and premature termination of the predicted polypeptide product.

In a screening of filter blood spots from 470 newborn African Americans in Michigan, Durham-Pierre et al. (1996) found that 2 were heterozygous for the 2.7-kb deletion.

Kerr et al. (2000) screened the coding region of the P gene for mutations in the non-2.7-kb deletion alleles of OCA2 patients who did not carry the deletion allele in either 1 or both of their P genes. In a group of 39 unrelated black OCA2 patients with a total of 52 non-2.7-kb deletion OCA2 genes, they identified 4 mutations, including A334V (611409.0007).

Manga (1997) found that a large proportion (9/10) of BOCA subjects are compound heterozygotes for the common 2.7-kb deletion and another pathogenic mutation in the OCA2 gene. Mutation analysis of the P gene in 10 unrelated individuals with BOCA in southern Africa revealed that 9 had 1 copy of the 2.7-kb deletion. Manga et al. (2001) suggested that the second mutation in the subjects with BOCA may be a milder mutation, possibly in the promoter region (downregulating expression) or in other regions of the P gene they did not screen.

Rooryck et al. (2011) stated that rearrangements of the OCA2 gene may be present in about 20% of OCA2 patients, indicating that high-resolution array CGH analysis is important for adequate molecular diagnosis in candidate patients.

Modifier Genes

Chiang et al. (2008) reported a Hispanic girl with OCA2 caused by compound heterozygous mutations in the OCA2 gene. She had pale skin, blue irides, and visual defects, including horizontal nystagmus, irides that transilluminated light, absence of foveal reflexes, albinotic fundi, and decreased visual acuity. However, she also had curly reddish-blonde hair, which was unusual for OCA2. The unaffected mother was of Puerto Rican and Cuban descent, and the unaffected father was of Dominican and Ecuadorian descent. Each parent was heterozygous for an OCA2 mutation. Further genetic analysis identified a heterozygous mutation in the TYRP1 gene (S166X; 115501.0002) in the girl and her father. The father, who had haploinsufficiency at the OCA2 and TYRP1 loci together, did not have a noticeable phenotype. Variations in the MC1R gene (155555) associated with red hair (SHEP2; 266300) were not identified. Chiang et al. (2008) concluded that haploinsufficiency of TYRP1 can modify the OCA2 phenotype, resulting in red hair in the absence of MC1R red alleles.

Population Genetics

Lee et al. (1994) gave the overall frequency of OCA2 in the United States as approximately 1:36,000; however, the incidence is about 1:10,000 among African Americans and is said to have a prevalence of 1:1,100 in the Ibo of Nigeria (Okoro, 1975) and a rate of about 1:3,900 in negroids of South Africa (Kromberg and Jenkins (1982, 1984)) where it is the most common recessive genetic disorder of this group. Throughout sub-Saharan Africa, OCA2 is responsible for a great deal of morbidity, with skin cancer and gross visual impairment being important sequelae.

Kagore and Lund (1995) found that the prevalence of OCA2 in school children in Harare, the capital city of Zimbabwe, was 1:2,833. On the basis of this prevalence, the gene frequency for OCA2 was estimated to be 0.0188, with a carrier frequency of 1:27. Most of the school children with albinism belonged to the majority Shoney ethnic group. As consanguineous marriages were discouraged in the Shoney culture, this high rate was probably the result of genetic drift in a relatively small population showing limited mobility.

Stevens et al. (1997) found the common 2.7-kb P gene deletion (611409.0001) in 10 (1.3%) of 780 OCA2 chromosomes in a normally pigmented southern African population, and at a lower frequency in normally pigmented individuals from central Africa, 2 (0.2%) of 834 OCA2 chromosomes. Among OCA2-affected individuals, the deletion was found in 131 (77%) of 170 OCA2 chromosomes in southern Africa, 11 (79%) of 14 OCA2 chromosomes in Zambia, and 4 (33%) of 12 OCA2 chromosomes in the Central African Republic. The study confirmed the African origin of the deletion allele. Haplotype analysis suggested that the deletion mutation occurred only once and that it arose before the divergence of these African populations, which was estimated to be about 2,000 to 3,000 years ago. The unusually high frequency of OCA2 mutations, in particular the 2.7-kb deletion, suggested selection or genetic drift.

A high frequency of albinism has been found among several Native American populations, varying in frequency from 1:140 in the Jemez to 1:3,750 in the Navajo (Woolf, 1965; Woolf and Dukepoo, 1969). Yi et al. (2003) studied albinism among the Navajos, who live predominantly in northeastern Arizona. The phenotype of albinism in the Navajos overlaps those for OCA2 and for OCA4 (606574), which are caused by mutations in the P and MATP (SLC45A2; 606202) genes, respectively. Consequently, Yi et al. (2003) did a mutation screen of these 2 genes. Although no mutations were found in the MATP gene, all Navajos with albinism were found to have a homozygous deletion of 122.5 kb of genomic DNA, including exons 10 through 20 of the P gene (611409.0008). The deletion allele was not found in 34 other individuals with albinism who had other Native American origins, and had not been reported in any other ethnic group. The molecular characterization of the deletion allele allowed Yi et al. (2003) to design a 3-primer PCR system to estimate the carrier frequency in the Navajo population, an estimated 4.5%. The estimated prevalence of OCA2 in Navajos is between 1:1,500 and 1:2,000. They estimated that this mutation originated from a single founder 400 to 1,000 years ago.

Suzuki et al. (2003) performed mutation analysis on 40 OCA1-negative Japanese albino patients and identified 6 different novel mutations in 6 unrelated patients. They estimated the frequency of OCA2 in the Japanese albino population to be 8%, indicating that OCA2 was not as common as OCA1. Thirty-four patients remained as unclassified OCA, supporting the idea that a third locus might be a major contributor to OCA.

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.

Animal Model

Autosomal recessive ocular albinism is known in rabbits (Magnussen, 1952).

History

The male and his sister reported by McKusick (1964) as having 'albinoidism' in fact had autosomal recessive ocular albinism.

In a study of 20 informative families, Heim et al. (1988) excluded linkage between the tyrosinase-positive oculocutaneous albinism locus and the beta-globin locus (HBB; 141900); the maximum lod score was -9.85 at theta = 0.05.

Walpole and Mulcahy (1991) reported a family with a balanced translocation, 46,XY,t(2;4)(q31.2;q31.22). One child with the translocation also had tyrosinase-positive albinism. The authors postulated that the OCA2 gene resides at either 2q31.1 or 4q31.22 and was disrupted by the translocation, but did not lead to albinism until it was paired up with a mutant gene at that locus through mating of a translocation carrier with a carrier of the mutant gene.

Rose et al. (1992) reported ocular albinism in a male with deletion of the q13-q15 region of chromosome 6. The deletion was secondary to a recombination of a maternal intrachromosomal inverted insertion of this region. The facial features were described as 'coarse,' with upslanting palpebral fissures, thin vermilion border of the upper lip, and elongated philtrum. Rose et al. (1992) postulated that the ocular albinism was due to hemizygosity for a paternally derived gene located in the region 6q13-q15. The father, an African American, had dark brown skin, hair, and eyes, with normal visual acuity and no abnormal iris transillumination.

In linkage studies in negroid peoples of South Africa, Colman et al. (1993) excluded the tyrosinase locus (606933) on chromosome 11 and the CAS2/TRP1 locus (115501) on chromosome 9 as the site of the mutation in tyrosinase-positive oculocutaneous albinism.