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Medico-Genetics of Oculocutaneous Albinism; An Updated Study with Pakistani Perspective.

Byline: Muzammil Ahmad Khan Muhammad Ayaz Khan Muhammad Akhlaq and Muhammad Zubair

Abstract

Albinism is a rare genetic disease associated with reduced melanin pigment biosynthesis in eyes skin or hair. Clinically it is categorized based on the affected tissue into two types i.e ocular albinism (OA); when hypopigmentation influence the retinal pigment epithelium leaving skin and hair unaffected and oculocutaneous albinism (OCA); when hypopigmentation occur in hair skin and eye. Various genetic studies to date identified six genes (TYR TYRP1 OCA2 SLC45A2 SLC24A5 C10orf11) and a locus (OCA5) for whom the candidate gene is yet to be known. All these reported genes at the molecular level are involved in melanin pigment biosynthesis. Among these reported genes TYR and OCA2 are the most prevalent genetic factors of OCA in Pakistani population. The study will assist in understanding the molecular factors of OCA and melanin synthesis pathway to reduce its prevalence rate.

The review aims to systematically reread and analyze the oculocutaneous albinism and its various types in the context of developed world as well as Pakistani community.

Key words: Oculocutaneous albinism melanin TYR TYRP1 OCA2 SLC45A2 SLC24A5 MC1R.

Introduction

Albinism is a rare genetic disease with reduced melanin pigment biosynthesis in eyes skin or hair. Clinically it is categorized based on the affected tissue into two types i.e ocular abinism (OA); when hypopigmentation influence the retinal pigment epithelium leaving skin and hair unaffected and Oculo cutaneous albinism (OCA); when hypopigmentation occur in hair skin and eye1.

Oculocutaneous albinism

Oculocutaneous albinism (OCA) is a disordered condition of melanin pigment biosynthesis in melanocytes. The persons affected of this disease have reduced or no melanin pigment in the skin hair and eyes along with retinal cell deterioration. The disease segregate mostly in autosomal recessive mode with non syndromic features. The additional clinical features include congenital nystagmus hypopigmentation low pigmentation of retinal epithelium and permanent photophobia. In oculocutaneous albinism (OCA) biosynthesis of melanin pigment is disturbed. Lack of this pigment in dermal tissue leads to severe photosensitivity and high risk of skin cancer while lack of pigment in the eye affects optic neural tracts misrouting and results in photophobia nystagmus and reduced visual acuity2.

Epidemiology of OCA

Epidemiologic survey has estimated that all known forms of albinism affects one in 17000 newborns in western societies specially north America and Europe but this ratio may be high in Asia and Africa due to high rate of consanguineous marriages. Prevalence rate of different genetic forms of OCA among the various world populations has determined OCA1 as the most widespread type of loci mapped among the Caucasian patients followed by OCA2 OCA4 and OCA3 respectively3.

Genetics of oculocutaneous albinism and its clinical analysis

Genetic analysis of families with inherited OCA so far has identified seven loci and six genes including; OCA1 (TYR) OCA2 (OCA2) OCA3 (TYRP1) OCA4 (SLC45A2) OCA5 OCA6 (SLC24A5) and OCA7 (C10orf11). The detailed information of each locus its gene and associated phenotype is explained in Table-1.

OCA1 (MIM# 203100)

OCA1 was the first locus reported to be associated with OCA. This locus was mapped on chromosome 11q14.3 and harbor TYR gene (MIM# 606933) which consist of 5 exons. TYR gene encodes 529 amino acid long tyrosinase enzyme. This enzyme contains tyrosine hydroxylase and DOPA oxidase catalytic domains. This enzyme mediates the initial two steps of melanin pigment synthesis by converting tyrosine to DOPA and then to DOPA quinone.

It is expressed predominantly in melanocytes where it controls the biosynthesis of melanin pigment from tyrosine. Clinically it is sub-categorized into OCA1A characterized by complete loss of tyrosinase activity and OCA1B characterized by reduced enzyme activity4.

The clinical spectrum of OCA1 linked patients showed whitish colour of hair eyelashes and eyebrows and the colour of Iris ranges from light blue to almost pink. In this OCA condition pigment does not develop and amelanotic nevi may also be present. Visual acuity in patients is 1/10 or even less and photophobic condition is severe.

In OCA1B the hair and skin may develop some pigment with the passage of time (after 1 to 3 years). Colour of iris also changes during the life time from blue to green/brown. Being the temperature-sensitive variant manifest the depigmented body hairs and pigmented hairs on hands and feet. Visual acuity in these patients is normally 2/10. This phenotype was previously known as yellow albinism5.

OCA2 (MIM# 203200)

OCA2 locus is located on human chromosome 15q11-q13 and contain OCA2 (previously called as P gene) (MIM# 611409). This gene contains two non- coding and 23 coding exons which encodes a polypeptide of 838 amino acids long (~110 kDa by weight) making 12 putative transmembrane helices. As a member of the Na+/H+ antiporter family the OCA2 protein is thought to play an essential role in maintaining the acid pH of the melanosomes which regulates the tyrosinase activity.

The OCA2 protein also participates in the localization of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1) to the plasma membrane and thus involved in biogenesis of melanosomes.

The phenotypic consequences of OCA2 mutant individuals include varied amount of cutaneous pigment in hair and skin. Nevi and ephelids are common. Iris color in these patients is same as like in OCA1A cases. Visual acuity is usually better than in OCA1 and can reach up to 3/10 6.

OCA3 (MIM# 115501)

The third locus of oculocutaneous albinism OCA3 is positioned on long arm of chromosome 9 (9p23). OCA3 harbors the TYRP1 (MIM# 115501) gene which

Table 1: Updated list of OCA gene and loci.

Gene###OCA###Chromo-###Total###Protein###Cellular###Biologic Function###Molecular Function

(MIM#)###Locus###somal###Reported###Encoded###localization

###Position###Mutations

TYR###OCA1###11q14.3###323###Tyrosinase###Melanosome###Melanin Biosynthetic###Monophenol Monoxygenase

(606933)###Membrane###Process from Tyrosine###Activity

OCA2###OCA2###15q12-q13.1###167###P Protein###Melanosome###Eye Pigment###L-Tyrosine transmembrane

(611409)###Membrane###Biosynthetic Process###Transporter Activity

TYRP1###OCA3###9p23###26###Tyrosinase###Melanosome###Melanocyte###Oxidoreductase Activity

(115501)###Related###Membrane###Differentiation

###Protein 1###Endosome###Melanosome

###Membrane###Organization

SLC45A2###OCA4###5p13.2###86###Solute###Melanosome###Visual Perception###Transport Substances

(606202)###Carrier###Membrane###Melanin Biosynthetic###Required for Melanin

###Family 45###Process###Biosynthesis

###Member 2###Developmental

###Pigmentation

Unknown###OCA5###4q24###-###-###-###-###-

SLC24A5###OCA6###15q21.1###10###Solute###Melanosome###Ion Transport###Ca+2 K+:Na+ Antiporter

(609802)###Carrier###Membrane###Activity Symporter Activity

###Family 24

###Member 5

C10orf11###OCA7###10q22.2-q22.3###6###Leucine-###Melanoblasts###Melanocyte###Under Investigation

(614537)###rich repeat-###and###Differentiation

###Containing###Melanocytes

###Protein

###C10orf11

Table 2: Gene and their reported mutations mapped in Pakistani families.

TYR###p.Arg299His13 p.Pro406Leu13 p.Gly419Arg 13 p.Arg278 13 p.Pro21Leu###13

###p.Cys35Arg###13

###p.Tyr411His###13

###p.Ile198Thr 15 c. -GA115 16 p.Gln376TER 5 p.Glu328Gln 5 p.Arg278TER 5

OCA2###p.Asp486Tyr 13 p.Leu527Arg 13 c.1045-15 T greater than G 13 p.Pro743Leu 13 p.Ala787Thr 13

TYRP1###p.Glu216GlyfsX421 p.Leu84Pro 1 p.Ala511Val 1

SLC45A2###c.889-6Tgreater than G 1

MC1R###c.917Ggreater than A 14

spans over the 17 Kb DNA fragment and consist of 8 exons. TYRP1 encodes 536 amino acid long enzyme with tyrosinase hydroxylase activity and catalyzes the oxidation of 56-dihydroxyindole-2- carboxylic acid monomer to melanin pigment in the melanin synthesis pathway. Clinical features of OCA3 associated families results in Rufous or red OCA in African individuals who have red hair and reddish brown skin (xanthism). Visual anomalies are not always detectable may be because the hypopigmentation not sufficient to alter the development7.

OCA4 (MIM# 606574)

Pathogenic sequence change in SLC45A2 (MIM# 606202) gene is the cause of OCA4 condition. This gene is located on chromosome 5p13.3 consisting of seven exons. The longest transcript of SLC45A2 encodes a solute carrier family 45 member 2 (SLC45A2) protein composed of 530 amino acids long and has a molecular weight of ~58 kDa. Its exact function is unknown but SLC45A2 is suppose to act as a melanosomal protein and substance transporter.

Phenotypic consequences of OCA4 (SLC45A2) mutant revealed absence of pigment in skin hair and eyes. Within the family variation in hair colour was observed from white to honey blonde or brown. Additionally; photophobia nystagmus foveal hypoplasia and reduced visual acuity was also reported1.

OCA5 (MIM# 615312)

The genetic identity of OCA5 locus on 4q24 is still unknown. OCA5 locus is mapped on chromosome 4q24. The clinical symptoms of OCA5 patients exhibited golden hair whitish skin and reduced visual acuity. Additional ocular problems also include nystagmus photophobia and foveal hypoplasia8.

OCA6 (MIM# 113750)

OCA6 phenotype is caused due to mutated SLC24A5 gene. SLC24A5 (solute carrier family 24 member 5) consist of 9 exons and its longest transcript encodes 500 amino acid long protein. SLC24A5 is a putative K+-dependent Na+/Ca++ exchanger 5 (NCKX5) which has been implicated in hypopigmentation. It may function in the calcium homeostasis of melanosomes or trans-Golgi network which is required for melanin biosynthesis or melanosomal protein trafficking9. The clinical manifestation of OCA6 mutation exhibit blonde hair at birth but converted to dark brown at elder age. The skin was white and iris was brownish. Nystagmus and photophobic conditions were less severe. Visual acuity in OCA6 patients was 20/100. Fundus examination showed hypopigmentatio less develop macula with central disappearance of fovea10.

OCA7 (MIM# 609446)

OCA7 locus harbor C10orf11 gene (MIM# 614537) which is located on long arm of chromosome 10 (10q22.2q22.3). This gene consist of 6 exons which encodes 198 amino acid long leucine rich repeat containing protein. Although its fully validated function is unknown but it is believed that it may be required for melanocyte differentiation on the basis of its expression pattern in melanoblast and melanocyte in human fetal cells.

Clinical synopsis of OCA7 mutant revealed light pigmentation as compared to related people. Ocular feature included nystagmus iris transillumination and sever scattered pigmentation of the peripheral fundus. Visual acuity was observed between 6/9 and 3/6011.

OCA in Pakistan

As a corollary of the inimitable socio-cultural customs in the population of Pakistan approximately 60% of marriages are consanguineous of which more than 80% are between first cousins. These large consanguineous families are a powerful resource for genetic studies of recessively inherited disorders like OCA. It is generally believe that OCA2 is more prevalent in Pakistani population than OCA1 in contrast to the Indian population. Giebel et al. 199111 identified a single point mutation (c.1117 Cgreater than T p. Arg373) in TYRP1 gene in a large consanguineous Pakistani family12. In an other genetic study; Thomas et al. (2012)13 enrolled 40 extended Pakistani families from Punjab province and screened various OCA loci candidate genes and pathogenic variants. They identified different mutations in TYR and OCA2 genes. They reported seven pathogenic variants in TYR and five mutations in OCA2 gene (Table-2).

Then Kausar et al. 2012 in a cohort study identified three new mutations in TYRP1 and one novel mutation in SLC45A21. In the same year 2012 Saleha and her coworkers discover a novel MC1R gene in a Pakistani family affected with OCA14. After this discovery Kausar and her colleagues in the subsequent year identified one novel OCA5 locus in a consanguineous Pakistani family8. And most recently Shah et al. in 2014 identified a novel mutation in TYR gene in a Pakistani family (See Table-2)15.

Discussion

Genetically inherited disorders are a big dilemma for those countries including Pakistan where inter familial marriages are part of custom. Furthermore; people living in the rural area never believe in inherited disorder but rather consider it be caused by spiritual power which is a serious hurdle in the research and remedy of these genetic disorders. Oculocuatenous albinism is a rare genetic disease with reduced pigmentation in skin hair and retinal cells1. So far seven loci and six genes have been reported to be implicated in OCA which are distributed along different chromosomes. Among these loci and genes TYR OCA2 TYRP1 MC1R SLC45A2 and OCA5 locus are reported in Pakistani population. Apart from these reported loci and gene many families are still uncharacterized. Until 2010 research on OCA did not attracted the scientists because OCA is not a life threatening disorder.

It was during 2012 when scientists among the globe diverted their attention towards Pakistani families for disease gene identification. Dr. Zubair Ahmad and his colleagues determined that TYR and OCA2 is the most prevalent gene in Pakistani population13. This effort will help in genetic counseling premarital screening and prenatal screening of families at risk. And this study will assist in understanding the molecular factors of OCA and melanin synthesis pathway to reduce its prevalence rate.

References

1. Kausar T Jaworek TJ Tariq N Sadia S Ali M Shaikh RS et al. Genetic studies of TYRP1 and SLC45A2 in Pakistani patients with nonsyndromicoculocutaneous albinism. J Invest Dermatol 2012; 133:1099-102.

2. GrAnskov K Ek J Brondum-Nielsen K. Oculocutaneous albinism. Orph J Rare Dis 2007; 2:43.

3. Boissy RE Hearing VJ King RA Oetting WS Ortonne JP eds. The Pigmentary System. 2nd ed. Malden MA: Wiley-Blackwell; 2006.

4. Tripathi RK Bundey S Musarella MA Droetto S Strunk KM Holmes SA. Mutations of the tyrosinase gene in Indo- Pakistani patients with type I (tyrosinase- deficient)oculocutaneous albinism (OCA). Am J Hum Genet 1993; 53:1173-9.

5. Tomita Y Takeda A Okinaga S Tagami H Shibahara S. Human oculocutaneous albinism caused by single base insertion in the tyrosinase gene. Biochem Biophys Res Commun 1989; 164:990-6.

6. Durham-Pierre D Gardner JM Nakatsu Y King RA Francke U Ching A et al. African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism. Nat Genet 1994; 7:176-9.

7. Boissy RE Zhao H Oetting WS Austin LM Wildenberg SC Boissy YL et al. Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as 'OCA3'. Am J Hum Genet 1996; 58:1145-56.

8. Kausar T Bhatti MA Ali M Shaikh RS Ahmed ZM. OCA5 a novel locus for non-syndromic oculocutaneous albinism maps to chromosome 4q24. (Letter) Clin Genet 2013; 84: 91-3 .

9. Lamason RL Mohideen MAPK Mest JR Wong AC Norton HL Aros MC et al. SLC24A5 a putative cation exchanger affects pigmentation in zebrafish and humans. Science. 2005; 310:1782-6.

10. Ai-Hua Wei Dong-Jie Zang Zhe Zhang Xuan-Zhu Liu Xin He Lin Yang et al. Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism. J Invest Derm 2013; 133:183440.

11. Gronskov K Dooley CM Ostergaard E Kelsh RN Hansen L Levesque MP et al. Mutations in C10orf11 a melanocyte-differentiation gene cause autosomal- recessive albinism. Am J Hum Genet 2013; 92:415-21.

12. Giebel LB Tripathi RK King RA Spritz RA. A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse. J Clin Invest 1991; 87:111922.

13. Jaworek TJ Kausar T Bell SM Tariq N Maqsood MI Sohail A et al. Molecular genetic studies and delineation ofthe oculocutaneous albinism phenotype in the Pakistani population. Orphanet J Rare Dis 2012; 7: 1-19.

14. Saleha SB Ajaml M Jamil M Nasir M Hameed A. MC1R gene mutation and its association with oculocutaneous albinism type (OCA) p henotype in a consanguineous Pakistani family. J Dermatol Sci 2012; 70:68-70.

15. Shah SA Din SU Raheem N Daud S Mubeen J Nadeem A et al. Identification of a novel mutation (p.Ile198Thr) in gene TYR in a Pakistani family with nonsyndromic oculocutaneous albinism. Clin Exp Dermatol 2014; 39:646-8.

16. Oetting WS Fryer JP King RA. A dinucleotide deletion (- delta GA115) in the tyrosinase gene responsible for type I- A (tyrosinase negative)oculocutaneous albinism in a Pakistani individual. Hum Mol Genet 1993; 2:1047-8.
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Publication:Pakistan Journal of Medical Research
Article Type:Report
Geographic Code:9PAKI
Date:Mar 31, 2015
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