Oculocutaneous Albinism

Albinism, Oculocutaneous Albinism type 1 (OCA1) , Oculocutaneous Albinism type 2 (OCA2) , Oculocutaneous Albinism type 3 (OCA3) , Oculocutaneous Albinism type 4 (OCA4) , Oculocutaneous Albinism type 5 (OCA5) , Oculocutaneous Albinism type 6 (OCA6) , Oculocutaneous Albinism type 7 (OCA7) , Tyrosinase-Negative Albinism , Tyrosinase-Positive Albinism

Oculocutaneous Albinism (OCA) is a group of congenital developmental disorder characterized by complete or partial loss of melanin in skin, hair and eye. OCA is caused due to defects in genes associated with melanin biosynthetic pathway. Depending on the gene mutated, OCA can be classified into Oculocutaneous Albinism type 1 (OCA1), Oculocutaneous Albinism type 2 (OCA2), Oculocutaneous Albinism type 3 (OCA3) and Oculocutaneous Albinism type 4 (OCA4), Oculocutaneous Albinism type 5 (OCA5), Oculocutaneous Albinism type 6 (OCA6) and Oculocutaneous Albinism type 7 (OCA7). OCA1 affects 1 per 40000 individuals in most populations (King et al., 2001) but is very uncommon among African-Americans. The overall prevalence of OCA2 is estimated to be 1:36000 in USA, but it is a lot more common among the African Americans with a prevalence of 1:10000 (Okoro, 1975). In fact, OCA2 affects 1 in 3900 of the population in the southern parts of Africa. OCA3 or Rufous oculocutaneous albinism has been estimated to affect 1:8500 individuals in Africa; however, it is very rare in any other populations as per published literature. OCA4 has been found to be the second largest rare form of albinism after OCA1 in Japan. The 3 other forms of OCA are very rare. There is a single report till date for OCA5 in a consanguineous Pakistani family [Kausar et al., 2013]. A few distinct cases of SLC24A5 mediated OCA6 - one from India, one from China, two patients from France, three from Portugal, one from Belgium and one from Syria, have been reported till date [Mondal et al., 2012; Wei et al., 2013; Fanny et al., 2014]. Nine Faroese patients and one Danish patient of Lithuanian origin harbored mutations in C10ORF11 gene representing OCA7 [ Gronskov et al., 2014]. It is worth mentioning that in countries like India where endogamy prevails, the incidence of OCA would be higher than the world average. In fact, in India, a preponderance of homozygous mutations is found and OCA1 is caused majorly because of founder mutations (Chaki et al., 2005; Chaki et al. 2006).

OCA is inherited in an autosomal recessive mode. However, recently, it has been hypothesized that the clinical spectrum of OCA depends on the pigmentation threshold of the patient. In genotypically darker complexion individuals such as in Africans, two mutations are needed to completely shut off the high pigmentation background; whereas in individuals with lighter complexion such as Caucasians, OCA can be manifested by the presence of one mutation and one hypomorphic allele (Chiang et al., 2008).

203100 , 203200 , 203290 , 605962 , 606574

D016115

55 Oculocutaneous albinism

C0078918

OCA is characterized by partial or total absence of melanin in the skin, hair and eyes at birth. The absence of optimum content of melanin during embryogenesis acts as a cue to trigger defects in eye development that cannot be corrected. A portion of the retinal ganglion cell (RGC) axons, originally destined to the ipsilateral hemisphere of the dorsal lateral geniculate nuclei (dLGN) of the midbrain, misproject to the contralateral side, thereby resulting in the disruption of binocular vision (Lund, 1965; Guillery, 1971; Cooper and Pettigrew, 1979; Drager and Olsen, 1980; Lavado and Montoliu, 2006). The developmental defect concerned with abnormal nerve fibre projection has been discussed in details in a review by Ray et al., 2007 (Ray et al., 2007).

The reduction of melanin in peripheral retina results in a stereoscopic set of developmental defects in neuronal migration in the visual pathways leading to foveal hypoplasia, abnormal routing of the nerve fibers from the eye to brain with consequent low vision (reduced visual acuity usually in the range 20\/60 to 20\/400 and refractive errors), photophobia, iris transillumination, nystagmus and strabismus. An OCA affected person is considered legally blind if he\/she has a visual acuity of 20\/200 (6\/60) or less. The degree of severity of the eye features as well as skin pigmentation varies with the different subtypes of albinism. Due to loss of pigmentation, the iris looks hazel or light blue or in extreme cases as in OCA1, it is translucent to such an extent that it appears pink or red in ambient light. The skin remains white or only become slightly pigmented with time in case of OCA1 whereas the patients suffering from the other 3 types of albinism have residual pigmentation and look pinkish or yellowish. If unprotected from sun rays, hypopigmented skin in the albinistic individuals may develop erythema. Moreover, the reduction in melanin pigment in the skin results in an increased sensitivity to UV induced skin damage and subsequently non-melanotic skin cancers.
It must be stated here that based on the severity of pigment loss, the most severe form of OCA viz. OCA1 can be sub-classified into two categories - (a) OCA1A: when the tyrosinase enzyme activity is completely lacking, and (b) OCA1B: when some residual activity is retained. The visual acuity of the OCA1A patients is greatly reduced; the degree of nystagmus, strabismus, photophobia are usually severe and the translucent iris that appear pink early in life, often become gray-blue with age. In case of OCA1A there is an absence of pigmentation throughout the patients life. In contrast, in OCA1B, although there is little or no apparent melanin at birth, progressive melanization might occur with time. The range of pigmentation in OCA1B varies from little cutaneous pigment to nearly normal skin color and the phenotype is often influenced by ethnicity. OCA1B is called yellow OCA due to the color of the hair, produced by pheomelanin synthesis.

The loss of pigment often leads to non-melanotic skin cancers in form of Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) (Mabula et al., 2012). Melanoma is rare in albino patients (Pehamberger et al., 1984).

No specific treatment is available for OCA. Attention must be paid to avoidance of direct sun exposure.

OCA1B patients although are born with almost no pigmentation, show a progressive melanization with age.

With proper protection from direct exposure from sun and visual aids like dome magnifiers, reading glasses, hand-held and stand magnifiers, patients should be able to lead a normal life.

OCA can be classified into seven major types viz. Oculocutaneous Albinism type 1 (OCA1), Oculocutaneous Albinism type 2 (OCA2), Oculocutaneous Albinism type 3 (OCA3) and Oculocutaneous Albinism type 4 (OCA4), Oculocutaneous Albinism type 5 (OCA5), Oculocutaneous Albinism type 6 (OCA6) and Oculocutaneous Albinism type 7 (OCA7). Each of the classical subtypes is caused due to defects in 7 different genes independently. Table 1 shows the genes involved in OCA:
Table 1: Causal genes and specific symptoms for 7 classical OCA syndromes.

Gene	Syndrome	Specific symptoms
TYR	OCA1 (A and B)	OCA1A: The skin, hair, eyelashes and eyebrows are white, Irises completely translucent. Visual acuity is 1\/10 or less with intense photophobia. OCA1 symptoms do not vary with age or race. Amelanotic nevi may be present.OCA1B: In OCA1B, the hair and skin may develop some pigment with time and the irises may appear to green\/brown. Visual acuity is 2\/10.
OCA2	OCA2	While the degree of cutaneous pigment and iris color may vary, the newborn with OCA2 nearly always have pigmented hair. Nevi and freckles are commonly found in the skin. Visual acuity is better than in OCA1, and can reach 3\/10. Africans with OCA2 appear with light brown hair and skin, and gray irises.
TYRP1	OCA3	Among Africans OCA3 affected individuals have red hair and reddish brown skin (xanthism). Visual anomalies are less severe and often not detectable.
SLC45A2	OCA4	The clinical findings of OCA are very similar to that of OCA2
Locus 4q24(gene not identified)	OCA5	The patients have been reported with golden hair, white skin, nystagmus, photophobia, foveal hypoplasia, and impaired visual acuity
SLC24A5	OCA6	Patients are generally characterized by light hair at birth that darkens with age, white skin, transparent irides, photophobia, nystagmus, foveal hypoplasia and reduced visual acuity. In a man from eastern India who had extreme hypopigmentation resulting in pinkish-white skin, but with dark brown hair and brown irides, homozygosity for a 4-bp insertion in the SLC24A5 gene was observed (Mondal et al,, 2012)
C10ORF11	OCA7	Patients have a light skin pigmentation that is reported as lighter than their relatives. Hair color ranges from light blond to dark brown. Eye findings include nystagmus, iris transillumination, visual acuity ranging from 6\/9 to 3\/60 and very sparse peripheral ocular fundus pigmentation. Alias Monophenol monooxygenase, SHEP3, Tumor rejection antigen AB, LB24-AB, SK29-AB. Note TYR codes for Tyrosinase protein, the rate limiting enzyme of melanin biosynthetic pathway. Description The human tyrosinase gene consists of 5 exons and spans about 65 kb of the genome. Transcription It encodes a 2082 bp transcript (Accession No: NM_000372.4). Pseudogene TYR-like segment (TYRL, 11p11.2, MIM 191270) is a pseudogene of TYR, which contains sequences very similar to exons IV and V of TYR gene. It is hypothesized that duplication of TYR exons IV and V regions followed by 11q:11p translocation has given rise to the TYRL segment. Description TYR (monophenol monoxygenase EC 1.14.18.1) encodes a ~80 kDa glycoprotein (Accession No: NP_000363.1) composed of 529 amino acids. TYR is a melanosomal membrane bound glycoenzyme with a type-3 copper active site. The mature TYR polypeptide includes an 18-amino acid long N-terminal signal peptide, six N-glycosylation sites, two copper binding sites (CuA and CuB) and one transmembrane (TM) domain followed by a relatively short carboxyl tail. Expression TYR is mainly expressed in two cell types: (a) Melanocytes that are derived from neural crest cells colonizing within iris, cochlea, skin and choroids, and (b) Retinal pigment epithelial (RPE) cells that are derived from the optic cup. During mouse embryogenesis, the expression of TYR could be first detected from +16.5 days post coitum onwards in the skin melanocytes and from +10.5 days postcoitum onwards in the RPE cells (Beermann et al., 1992). Localisation TYR is a melanosomal membrane protein and the TM region anchors the bulk of the protein inside the melanosomal lumen. Function TYR catalyzes the rate limiting steps of melanin biosynthesis viz. hydroxylation of L-tyrosine to L-DOPA and oxidation of L-DOPA to DOPAquinone. It also catalyzes the conversion of 5,6 dihydroxyindole to Indole 5,6 Quinone and 5,6,dihydroxyindole carboxylic acid to Indole 5,6 quinone carboxylic acid. Homology TYR, Tyrosinase Related Protein 1 (TYRP1) and Tyrosinase Related Protein 2 (TYRP2\/DCT) represent a family of closely related gene products (with almost 40% amino acid identity) that share a common tertiary structure (Jimenez-Cervantes et al., 1998; Kobayashi et al., 1998). These have been grouped together to form the TYRP family of genes. Germinal TYR mutations are responsible for OCA1. A few OCA2 mutations have been associated with autosomal recessive ocular albinism (AROA). OCA1 is an endoplasmic reticulum retention (ER) disorder and all the missense mutations that have been functionally characterized have yielded ER -retained proteins. Alias P, Pink-eyed dilution protein homolog, D15S12, Melanocyte-specific transporter protein, EYCL, EYCL2, EYCL3, BOCA, BEY, BEY1, BEY2, HCL3, PED, SHEP1, oculocutaneous albinism II (pink-eye dilution (murine) homolog)1 Note OCA2 codes for OCA2 protein, hypothesized to be involved in the transport of tyrosine, the precursor to melanin synthesis, within the melanocyte. Description The human OCA2 gene consists of 24 exons and spans ~344.5 kb of the genome. Transcription It encodes a 3154 bp transcript (Accession No: NM_000275.2). Description OCA2 encodes a ~110 kDa protein (Accession No: NP_000266.2) composed of 838 amino acids. The OCA2 protein is thought to be a melanosomal multipass integral membrane protein (with 12 predicted transmembrane domains) involved in small molecule transport, specifically tyrosine - a precursor of melanin. Expression Due to its localization in the melanosomal membrane, OCA2 is thought to be expressed in the melanocytes. Localisation OCA2 is hypothesized to be present in the melanosomal membrane of the melanocytes. Function The precise function of OCA2 has not been elucidated till date. However, the potential functions include: a) normal biogenesis of melanosomes (Rosemblat et al., 1998; Orlow and Brilliant et al., 1999); b) for normal processing and transport of tyrosinase and other melanosomal proteins (Puri et al., 2000; Manga et al., 2001; Toyofuku et al., 2002; Chen et al., 2002); and c) maintenance of an acidic pH in melanosomes (Ni-Komatsu and Orlow, 2006). Homology Its sequence predicts that OCA2 has a homology to a superfamily of permeases (Rinchik et al., 1993; Lee et al., 1995). Germinal OCA2 mutations are responsible for OCA2. A few OCA2 mutations have been associated with autosomal recessive ocular albinism (AROA) too. Alias RP11-3L8.1, CAS2, CATB, GP75, SHEP11, TRP, TYRP, b-PROTEIN Note TYRP1 codes for TYRP1 protein, hypothesized to be involved in melanin synthesis, stabilization of tyrosinase and modulating its catalytic activity, maintenance of melanosome structure and affects melanocyte proliferation and melanocyte cell death. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III. Description The human TYRP1 gene consists of 8 exons and spans ~24.8 kb of the genome. Transcription It encodes a 2876 bp transcript (Accession No: NM_000550.2). Description TYRP1 encodes a 60.7 kDa protein (Accession No: NP_000541.1) composed of 537 amino acids. The TYRP1 protein is thought to be a melanosomal membrane single-pass type I membrane protein. Expression TYRP1, similar to TYR, is mainly expressed in two cell types: (a) Melanocytes that are derived from neural crest cells colonizing within iris, cochlea, skin and choroids, and (b) Retinal pigment epithelial (RPE) cells that are derived from the optic cup. Localisation TYRP1 is hypothesized to be localized in melanosome membrane. Function Oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into indole-5,6-quinone-2-carboxylic acid. May regulate or influence the type of melanin synthesized. Homology Belongs to the tyrosinase family. Homologous to murine brown locus. Germinal TYRP1 mutations are responsible for OCA3. Alias Membrane associated transporter protein, MATP, MELANOMA ANTIGEN AIM1, AIM1 Note SLC45A2 codes for SLC45A2 protein, hypothesized to be involved in the transport of substances required for melanin biosynthesis within the melanocyte. Description The human SLC45A2 gene consists of 7 exons and spans 40.1 kb of the genome. Transcription It encodes a 1734 bp transcript (Accession No: NM_016180.3). Description SLC45A2 encodes a ~58 kDa protein (Accession No: NP_057264.3) and composed of 530 amino acids. The protein is thought to be a melanosomal multipass membrane protein (contains 12 putative transmembrane domains) involved in small molecule transport. Expression Expressed in most melanoma cell lines and melanocytes. Localisation SLC45A2 is hypothesized to be present in the melanosomal membrane of the melanocytes. Function The precise function of SLC45A2 has not been elucidated till date. Studies on Medaka fish show that the SLC45A2\/MATP plays an important role in pigmentation and probably functions as a membrane transporter in melanosomes (Fukamachi et al., 2001). Homology Belongs to the glycoside-pentoside-hexuronide (GPH) cation symporter transporter (TC 2.A.2) family. Germinal SLC45A2 mutations are responsible for OCA4. Alias Oculocutaneous Albinism 5 (Autosomal Recessive) Note This chromosomal locus harbors 14 genes, none of which are directly responsible for melanin biosynthesis Description 4q24 harbors 14 genes (CENPE, TACR3, CXXC4, TET2, PPA2, INTS12, GSTCD, NPNT, AIMP1, DKK2, PAPSS1, SGMS2, CYP2U1, HADH) with linkage interval of 3.84Mb. Transcription The underlying gene causing OCA5 has not yet been identified. Function 4q24 is a chromosomal locus harbouring about 14 genes in it with a linkage interval of 3.84 Mb. Though none of those 14 genes are known to have any role in melanin synthesis, but studies are being done to ascertain the role of this locus and to identify the underlying gene. Germinal Though inheritance indicates germinal origin of the mutations, the causal gene is yet to be recognized. Alias Solute Carrier Family 24 (Sodium\/Potassium\/Calcium Exchanger), Member 5, JSX, OCA6 Note SLC24A5 codes for a cation exchanger which is probably involved in ion transport in melanosomes. Description The human SLC24A5 gene consists of 5 exons and spans 21.701 kb of the genome Transcription This gene has 4 transcripts (splice variants), three of which either skips an exon or are truncated versions. The actual protein coding transcript is 1617 bp long (NM_205850.2). Description SLC24A5 codes for a cation exchanger which is 500 amino acid long (NP_995322). This protein is an intracellular potassium-dependent sodium\/calcium exchanger with 2 large hydrophilic loops and 2 sets of multiple trans-membrane-spanning segments. Expression Due to its localization in the melanosomal membrane, OCA2 is thought to be expressed in the melanocytes. Localisation SLC24A5 is hypothesized to be present in the trans-Golgi network of melanocytes. Function The precise function of SLC24A5 has not been elucidated till date. However, the potential functions include: (a) transporting 1 Ca2+ and 1 K+ to the melanosome in exchange for 4 cytoplasmic Na+ [Lamason RL et al., 2005]; (b) Influencing natural variation in skin pigmentation via a novel, unknown mechanism affecting cellular sterol levels [Wilson S et al., 2013]. Homology It belongs to Solute Carrier Family 24 (http:\/\/www.guidetopharmacology.org\/GRAC\/FamilyDisplayForward?familyId=202). Germinal SLC24A5 mutations are responsible for OCA6. Alias Chromosome 10 Open Reading Frame, OCA7 Note C10Orf11 codes for a leucine rich repeat containing protein. Description The human C10ORF11 gene consists of 6 exons and spans 959 kb of the genome. Transcription C10ORF11 encodes 16 splice variants of which 4 are protein coding and rest are processed transcripts. Of those 16, transcript variant 2 (Accession No: NM_032024.4) is 909 bp long and codes for a 198 amino acids long peptide. Description C10ORF11 encodes a 22.5 kDa protein (Accession No: NP_114413.1) composed of 198 amino acids. The sub-cellular localization of leucine rich repeat containing protein C10ORF11 is not clear. Expression This protein was found in melanoblast of embryo and melanocytes of fetus, but not in retinal pigment epithelial cells. Localisation C10ORF11 is hypothesized to be present in the melanosome, but not in retinal pigment epithelial cells. Function The precise function of C10ORF11 has not been elucidated till date. However, there is some evidence that it may play some role in melanocyte differentiation (Grønskov K et al., 2013). Germinal C10ORF11 mutations are responsible for OCA7. Article Bibliography Pubmed ID Last Year Title Authors 1557387 1992 Expression of the mouse tyrosinase gene during embryonic development: recapitulation of the temporal regulation in transgenic mice. Beermann F et al 16056219 2005 Higher prevalence of OCA1 in an ethnic group of eastern India is due to a founder mutation in the tyrosinase gene. Chaki M et al 16907708 2006 OCA1 in different ethnic groups of india is primarily due to founder mutations in the tyrosinase gene. Chaki M et al 12058062 2002 Pink-eyed dilution protein controls the processing of tyrosinase. Chen K et al 19533789 2009 Oculocutaneous albinism spectrum. Chiang PW et al 489782 1979 The retinothalamic pathways in Siamese cats. Cooper ML et al 7410600 1980 Origins of crossed and uncrossed retinal projections in pigmented and albino mice. Dräger UC et al 11479596 2001 Mutations in the gene encoding B, a novel transporter protein, reduce melanin content in medaka. Fukamachi S et al 23395477 2013 Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism. Grønskov K et al 5134931 1971 An abnormal retinogeniculate projection in the albino ferret (Mustela furo). Guillery RW et al 9918801 1998 Molecular interactions within the melanogenic complex: formation of heterodimers of tyrosinase and TRP1 from B16 mouse melanoma. Jiménez-Cervantes C et al 23050561 2013 OCA5, a novel locus for non-syndromic oculocutaneous albinism, maps to chromosome 4q24. Kausar T et al 9822646 1998 Tyrosinase stabilization by Tyrp1 (the brown locus protein). Kobayashi T et al 16357253 2005 SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Lamason RL et al 16146766 2006 New animal models to study the role of tyrosinase in normal retinal development. Lavado A et al 7601462 1995 Organization and sequence of the human P gene and identification of a new family of transport proteins. Lee ST et al 17791642 1965 Uncrossed Visual Pathways of Hooded and Albino Rats. Lund RD et al 22681652 2012 Skin cancers among Albinos at a University teaching hospital in Northwestern Tanzania: a retrospective review of 64 cases. Mabula JB et al 11601658 2001 Inverse correlation between pink-eyed dilution protein expression and induction of melanogenesis by bafilomycin A1. Manga P et al 23010199 2012 Molecular basis of albinism in India: evaluation of seven potential candidate genes and some new findings. Mondal M et al 24066960 2014 Increasing the complexity: new genes and new types of albinism. Montoliu L et al 23985994 2014 SLC24A5 mutations are associated with non-syndromic oculocutaneous albinism. Morice-Picard F et al 16199032 2006 Heterologous expression of tyrosinase recapitulates the misprocessing and mistrafficking in oculocutaneous albinism type 2: effects of altering intracellular pH and pink-eyed dilution gene expression. Ni-Komatsu L et al 1174464 1975 Albinism in Nigeria. A clinical and social study. Okoro AN et al 10068480 1999 The pink-eyed dilution locus controls the biogenesis of melanosomes and levels of melanosomal proteins in the eye. Orlow SJ et al 6490997 1984 Dysplastic nevus syndrome with multiple primary amelanotic melanomas in oculocutaneous albinism. Pehamberger H et al 10998131 2000 Aberrant pH of melanosomes in pink-eyed dilution (p) mutant melanocytes. Puri N et al 17355913 2007 Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1. Ray K et al 8421497 1993 A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Rinchik EM et al 9521852 1998 Melanosomal defects in melanocytes from mice lacking expression of the pink-eyed dilution gene: correction by culture in the presence of excess tyrosine. Rosemblat S et al 12028586 2002 The etiology of oculocutaneous albinism (OCA) type II: the pink protein modulates the processing and transport of tyrosinase. Toyofuku K et al 23364476 2013 Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism. Wei AH et al 23224873 2013 NCKX5, a natural regulator of human skin colour variation, regulates the expression of key pigment genes MC1R and alpha-MSH and alters cholesterol homeostasis in normal human melanocytes. Wilson S et al External Links GARD ERN GENTURIS OMIM ORPHANET MeSH Citation Kunal Ray ; Mainak Sengupta ; Kausik Ganguly Oculocutaneous Albinism Atlas Genet Cytogenet Oncol Haematol. 2015-04-01 Online version: http://atlasgeneticsoncology.org/cancer-prone-disease/10022/oculocutaneous-albinism Historical Card 2012-08-01 Oculocutaneous Albinism by  Kunal Ray,Mainak Sengupta  Affiliation Academy of Scientific and Innovative Research (AcSIR), New Delhi # (KR); Department of Genetics, University of Calcutta, Kolkata (MS, KG), India. [email protected]; [email protected]; [email protected] Generate PDF × Please, confirm that you want to generate a PDF file of this page. This may take some seconds once process has started. Then it will be opened automatically. 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