Albinism, Oculocutaneous, Type Vi

A number sign (#) is used with this entry because of evidence that oculocutaneous albinism-6 (OCA6) is caused by homozygous or compound heterozygous mutation in the SLC24A5 gene (609802) on chromosome 15q21.

Variation in the SLC24A5 gene has also been found to influence skin, hair, and eye pigmentation (SHEP4).

Description

Oculocutaneous albinism (OCA) is a heterogeneous autosomal recessive disorder, with a worldwide prevalence of approximately 1:17,000. It manifests as a reduction or complete loss of melanin in the skin, hair, and eyes, often accompanied by eye symptoms such as photophobia, strabismus, moderate to severe visual impairment, and nystagmus (summary by Wei et al., 2013).

For a discussion of genetic heterogeneity of oculocutaneous albinism, see OCA1 (203100).

For a general phenotypic description and a discussion of genetic heterogeneity of variation in skin, hair, and eye pigmentation, see SHEP1 (227220).

Clinical Features

Wei et al. (2013) studied a Chinese family in which the proband was a girl who had clinically been diagnosed at 3 years of age with oculocutaneous albinism. Her hair at birth was blond but darkened with age. Her skin was white and her irides were transparent and brownish. She had mild nystagmus and photophobia, with visual acuity of 20/100. Color fundus photography showed hypopigmentation and underdeveloped macula; optical coherence tomography showed disappearance of the central fovea of the macula, compared to her unaffected brother. The patient had no other apparent malformation on physical or radiologic examination, and no neurologic symptoms or bleeding tendency. Complete blood counts, coagulation tests, immunoglobulins, trace metals, and levels of serum and urine metabolites were all within normal limits in the proband. Electron microscopy of patient epidermal melanocytes showed fewer mature melanosomes (stage IV) and more immature melanosomes (stages I, II, and III) in both the cell body and dendrites extending to keratinocytes compared to control melanocytes. Hair eumelanin content in the proband was significantly lower than that of her unaffected brother and parents, suggesting that her brown hair color was likely due to the loss of eumelanin rather than the production of more pheomelanin.

Morice-Picard et al. (2014) described 7 patients from 5 unrelated families of French, Portuguese, Syrian, and Belgian ethnicity with OCA6. All of the patients had reduced visual acuity, nystagmus, iris transillumination, foveal hypoplasia, and retinal hypopigmentation. Hair color ranged from platinum blond to light brown and eye color was green or blue. Four had a tendency to tan and 4 had pigmented nevi.

Bertolotti et al. (2015) described 2 Bushinengue women in French Guiana with OCA6. Both women had brown irides, photophobia, reduced visual acuity, and nystagmus. Their hair was blonde at birth but darkened with age. Both patients had light brown skin and tanned with sun exposure. One patient had significant pachydermia on face, neck, arms, and legs and some actinic keratosis, but she did not have any melanoma, squamous cell papilloma, or basal cell carcinoma. The other patient had no pachydermia or skin tumors.

Skin/Hair/Eye Pigmentation 4

Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of the melanocytes. Lamason et al. (2005) showed that zebrafish 'golden' (slc24a5) mutants share these melanosomal changes. To evaluate the potential impact of SLC24A5 (609802) on the evolution of human skin pigmentation, Lamason et al. (2005) looked for polymorphisms within the gene. They noted that the G and A alleles of the single-nucleotide polymorphism (SNP) rs1426654 encoded an alanine or threonine, respectively, at amino acid 111 in the third exon of SLC24A5 (609802.0001). The allele frequency for the thr111 variant ranged from 98.7% to 100% among several European-American population samples, whereas the ancestral alanine allele had a frequency of 93 to 100% in African, indigenous American, and East Asian population samples. The difference in allele frequencies between the African and European populations at rs1426654 was consistent with the possibility that this SNP has been a target of natural or sexual selection.

Based on the average pigmentation difference between European-Americans and African Americans of about 30 melanin units, the results of Lamason et al. (2005) suggested that variation in SLC24A5 explains between 25% and 38% of the European-African difference in skin melanin index. Because Africans and East Asians share the ancestral ala111 allele of rs1426654 (609802.0001), this polymorphism cannot be responsible for the marked difference in skin pigmentation between these groups.

Molecular Genetics

In a Chinese family with nonsyndromic oculocutaneous albinism in which the proband was known to be negative for mutation in 6 OCA-associated genes, Wei et al. (2013) performed exome sequencing and identified compound heterozygosity for a nonsense and a frameshift mutation in the SLC24A5 gene (609802.0003 and 609802.0004) in the proband. Her unaffected father was heterozygous for the frameshift mutation, whereas her unaffected mother, brother, and a maternal aunt were heterozygous for the nonsense mutation. Neither mutation was found in 120 controls. Screening in 10 additional OCA patients who were negative for mutation in OCA-associated genes did not reveal any further SLC24A5 mutations.

In 7 patients from 5 unrelated families of French, Portuguese, Syrian, and Belgian ethnicity with oculocutaneous albinism, Morice-Picard et al. (2014) identified 7 different mutations in homozygous or compound heterozygous state in the SLC24A5 gene (see, e.g., 609802.0005). The mutations segregated with the phenotype in all families and were not found in the HapMap or 1000 Genomes Project database.

In 2 Bushinengue women in French Guiana with oculocutaneous albinism who were negative for mutation in 11 known albinism genes, Bertolotti et al. (2015) identified homozygosity for a missense mutation (R174K; 609802.0006) in the SLC24A5 gene. The parents were not available for study, but the mutation was not found in the dbSNP, ESP or ExAC databases.

Skin/Hair/Eye Pigmentation 4

Stokowski et al. (2007) demonstrated an association between the SNP rs1426654 (A111T; 609802.0001) and skin pigmentation variation in individuals of South Asian descent.

In a man from eastern India who had extreme hypopigmentation resulting in pinkish-white skin, but with dark brown hair and brown irides, Mondal et al. (2012) identified homozygosity for a 4-bp insertion in the SLC24A5 gene (609802.0002). Detailed clinical information regarding the proband's eye phenotype was unavailable. His parents both had dark-pigmented skin, but his brother had similar hypopigmentation; however, his parents and brother declined to participate in the study.

In a study of 1,570 genotyped ethnically diverse African individuals with quantified pigmentation levels, Crawford et al. (2017) found that the SLC24A5 SNP rs1426654 (609802.0001) was significantly associated with skin color (p = 5.5 x 10(-62)). They found that the rs1426654A variant, associated with light pigmentation, was common (28 to 50% frequency) in populations from Ethiopia and Tanzania with high Afro-Asiatic ancestry and was at moderate frequency (5 to 11%) in San and Bantu-speaking populations from Botswana with low levels of East African ancestry and recent European admixture. Haplotype analysis indicated that the A variant in Africans is on the same haplotype background as in Europeans, likely reflecting gene flow from western Eurasia over at least the past 3 to 9 thousand years.

Animal Model

Lamason et al. (2005) stated that the zebrafish 'golden' phenotype causes hypopigmentation of skin melanophores and retinal pigment epithelium (RPE). The golden phenotype is characterized by delayed and reduced development of melanin pigmentation. At approximately 48 hours postfertilization, melanin pigmentation is evident in the melanophores and RPE of wildtype embryos but is not apparent in golden embryos. By 72 hours postfertilization, golden melanophores and RPE begin to develop pigmentation that is lighter than that of wildtype. In adult zebrafish, the melanophore-rich dark stripes are considerably lighter in golden compared with wildtype animals. The melanophores of golden zebrafish are thinner and contain fewer melanosomes, and melanosomes are smaller than wildtype, less electron dense, and irregularly shaped. Unlike mouse models of Hermansky-Pudlak syndrome (203300), in which defects in platelet-dense granules and lysosomes as well as melanosomes occur, the golden phenotype is not associated with any changes of thrombocyte number or function. Lamason et al. (2005) determined that the golden gene contains a tyrosine-to-stop mutation at amino acid 208.

In Puerto Rican Paso Fino horses, 'tiger eye' or 'goat eye' is recessively inherited yellow, amber, or bright orange iris coloration. Using a genomewide association study (GWAS) followed by Sanger sequencing, Mack et al. (2017) identified a homozygous nonsynonymous change in exon 2 of the Slc24a5 gene in 20 of 32 tiger-eyed horses. This mutation (c.271A-T), called Tiger-eye 1, was predicted to change a conserved phe91 to tyr91 (F91Y) in the intraluminal loop just prior to transmembrane domain 1. The 12 remaining horses were heterozygous for the Tiger-eye 1 allele; 8 of these were compound heterozygous for a deletion of exon 7 in the Slc24a5 transcript (c.875-340_1081+82del), called Tiger-eye 2. Tiger-eye 2 was predicted to cause in-frame deletion of residues 292 through 360, removing part of cation exchange domains 1 and 2 and 2 transmembrane domains in Slc24a5. A second mutation in the 4 remaining horses was not found. None of 122 wildtype Paso Fino horses and 196 wildtype horses representing 4 related breeds showed either mutation. Genotyping of 19 additional horses revealed an individual that was homozygous for Tiger-eye 2, providing evidence that this mutation is not homozygous lethal. Neither mutation in the Slc24a5 gene appeared to be related to coat color. No ocular or visual abnormalities were observed in any homozygous tiger-eye 1 or compound heterozygous horse; the homozygous tiger-eye 2 horse was not examined by a veterinary ophthalmologist.