Rufous Oculocutaneous Albinism in Southern African Blacks Is Caused by Mutations in the TYRP1 Gene

Manga, Prashiela; Kromberg, J. G. R.; Box, Neil F.; Sturm, Richard A.; Jenkins, Trefor; Ramsay, Michèle

doi:10.1086/301603

Cited by 136 publications

(112 citation statements)

References 26 publications

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“…Melanocyte cultures from the patient had only 7% of the amount of insoluble melanin as a result of compromised tyrosinase activity (9). Mutations in TYRP1 identified in a subpopulation of southern African blacks were designated Rufous OCA/OCA3 (92). Two different mutations were identified in the Rufous OCA population, specifically a single base substitution at codon 166 of exon 3, resulting in the alteration of a serine to a stop codon and the deletion of the single-base pair in exon 6 previously reported by Boissy et al, 1996 (92).…”

Section: Oculocutaneous Albinism In Humans (Oca3)mentioning

confidence: 87%

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Tyrp1 and Oculocutaneous Albinism Type 3

Sarangarajan

Boissy

2001

Pigment Cell Research

113

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addition to its role in eumelanin synthesis, Tyrp1 is involved in Tyrosinase-related protein 1 (Tyrp1) is a melanocyte-specific maintaining stability of tyrosinase protein and modulating its gene product involved in eumelanin synthesis. Mutations in the catalytic activity. Tyrp1 is also involved in maintenance of mouse Tyrp1 gene are associated with brown pelage, and in the human TYRP1 gene with oculocutaneous albinism type 3 melanosome ultrastructure and affects melanocyte prolifera-(OCA3). In the murine system, Tyrp1 expresses significant tion and melanocyte cell death. The current review is an dihydroxyindole carboxylic acid oxidase (i.e. DHICA oxattempt to consolidate our understanding of the role of Tyrp1 idase) activity. However, in humans, TYRP1 is enigmatic in in the melanocyte. that despite extensive efforts focused on the study of its Key words: Pigmentation, Tyrosine hydroxylase, Brown/Rufunction, its actual role in the human melanocyte is still fous Albinism, Brown locus, Protein trafficking unclear. There is mounting evidence demonstrating that in Mutations in the genes encoding some of the enzymes and regulatory proteins involved in melanin synthesis result in various forms of oculocutaneous albinism (OCA). OCA1 correlates with mutations in the tyrosinase (TYR) gene (7). Most individuals with OCA1 have completely amelanotic skin, hair and eyes with the inability to tan (i.e. OCA1A). However, some nucleotide lesions of the TYR gene result in a partially functional enzyme so that individuals with this subtype of OCA1 can exhibit moderate levels of skin and hair pigmentation and the ability to tan (i.e. OCA1B). OCA2 correlates with mutations in the P gene (8). Individuals with OCA2 present with minimal to moderate amounts of pigment remaining in the skin, hair and eyes, many of whom can develop pigmented freckles, lentigines and/or nevi with age. OCA3 correlates with mutations in the TYRP1 gene (9). Individuals with OCA3 present with minimal pigment reduction in the skin, hair and eyes. This form of albinism was previously referred to as Rufous and possibly some forms of Brown albinism.

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Section: Oculocutaneous Albinism In Humans (Oca3)mentioning

confidence: 87%

“…2) (9, 92). The phenotype of individuals with OCA3 has been classified as Brown (9) and Rufous (92). Brown OCA was initially identified in a Nigerian population (93) and was found to be prevalent in the Black or Negroid population of Africa and America (94).…”

Section: Oculocutaneous Albinism In Humans (Oca3)mentioning

confidence: 99%

Tyrp1 and Oculocutaneous Albinism Type 3

Sarangarajan

Boissy

2001

Pigment Cell Research

113

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“…We compared sensitivity of normal human melanocytes with those from an individual with oculocutaneous albinism type 3 (OCA3), which results from autosomal recessive mutations at the Tyrp1 locus. 33,34 Dose-response curves demonstrate that melanocytes from the individual with OCA3 were significantly more resistant (P Ͻ 0.01) to 4-TBP than normally pigmented melanocytes (Figure 8, left panel). To exclude the possibility that non-melanocyte proteins contributed to the resistance of OCA3 melanocytes, we compared the sensitivity of fibroblasts from the affected individual with those from normally pigmented individuals and found no significant difference (Figure 8, right panel).…”

Section: Tyrp1 Expression Modulates Sensitivity To 4-tbpmentioning

confidence: 96%

A Role for Tyrosinase-Related Protein 1 in 4-tert-Butylphenol-Induced Toxicity in Melanocytes

Manga

Sheyn

Yang

et al. 2006

The American Journal of Pathology

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Vitiligo presents with depigmented cutaneous lesions following localized melanocyte death. Multiple factors contribute to cell death, including genetically determined susceptibility to trauma, and environmental factors, such as exposure to 4-tert-butylphenol (4-TBP). We demonstrate that 4-TBP induces oxidative stress that is more readily overcome by melanocytes from normally pigmented individuals than from two individuals with vitiligo. The antioxidant catalase selectively and significantly reduced death of melanocytes derived from two individuals with vitiligo, indicating a role for oxidative stress in vitiligo pathogenesis. In normal melanocytes, oxidative stress results in reduced expression of microphthalmia-associated transcription factor (MITF). Melanocyte-stimulating hormone-induced expression of MITF protein caused increased sensitivity to 4-TBP, whereas sensitivity of melanomas correlated with MITF expression. MITF stimulates melanin synthesis by up-regulating expression of melanogenic enzymes such as tyrosinase-related protein-1 (Tyrp1). Although melanin content per se did not affect sensitivity to 4-TBP, expression of Tyrp1 significantly increased sensitivity. Melanocytes and melanomas that express functional Tyrp1 were significantly more sensitive to 4-TBP than Tyrp1-null cells. Thus, normal melanocytes respond to 4-TBP by reducing expression of MITF and Tyrp1. We hypothesize that melanocytes in vitiligo demonstrate reduced ability to withstand oxidative stress due, partly, to a disruption in

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“…[11] OCA OCA denotes a group of common autosomal recessive disorders resulting from disruption of melanin synthesis. There are four major forms: (i) OCA1 (mutated tyrosinase (TYR) gene); [12] (ii) OCA2 (mutated OCA2 gene); [13] (iii) OCA3 (mutated tyrosinase-related protein 1 (TYRP1) gene); [14] and (iv) OCA4 (mutated solute carrier family 45, member 2 (SLC45A2) gene). [15] OCAs are characterised by decreased or absent melanin in skin, hair and eyes.…”

Section: Biology Of Pigmentationmentioning

confidence: 99%

Biology and genetics of oculocutaneous albinism and vitiligo – common pigmentation disorders in southern Africa

et al. 2013

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The primary pigment that determines human skin, hair and eye colour is melanin, which is synthesised by melanocytes. Melanin protects the skin from ultraviolet (UV) radiation and there is an inverse correlation between the degree of constitutive pigmentation and the risk of sun-induced skin cancers. Besides the life-threatening cancer risk, loss of pigmentation results in premature aging, compromised cutaneous immunity and significant emotional distress to affected individuals. [1][2][3] During embryonic development, melanocyte precursors that arise from the neural crest populate several areas including the interfollicular epidermis and hair follicle bulge in the skin; the uveal tract of the eye; and the stria vascularis, vestibular apparatus and endolymphatic sac of the ear. The development of melanocytes is tightly regulated at the genetic level by a number of genes that control proliferation, survival and migration of precursor cells to the various sites of the body and their differentiation into active melanocytes. A key regulator of this process is the microphthalmia transcription factor (MITF), which has been dubbed the 'master regulator' of the melanocyte, capable of modulating expression of several melanocytespecific proteins.[4] MITF mutations result in Waardenburg syndrome type II.[5] Once the melanocyte has differentiated, MITF regulates expression of genes in response to UV exposure, facilitating the tanning response.Melanocytes produce two forms of melanin, black-brown eumelanin and red-yellow pheomelanin. Skin and hair colour Corresponding author: P Manga (prashiela.manga@nyumc.org)Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 -2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in...

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Rufous Oculocutaneous Albinism in Southern African Blacks Is Caused by Mutations in the TYRP1 Gene

Cited by 136 publications

References 26 publications

Tyrp1 and Oculocutaneous Albinism Type 3

Tyrp1 and Oculocutaneous Albinism Type 3

A Role for Tyrosinase-Related Protein 1 in 4-tert-Butylphenol-Induced Toxicity in Melanocytes

Biology and genetics of oculocutaneous albinism and vitiligo – common pigmentation disorders in southern Africa

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