Tyrp1 and Oculocutaneous Albinism Type 3

Abstract

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.

Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis

“…Generally, it has been assumed that TYRP1 is a DHICA oxidase 13. Yet, human TYRP1 was found to be devoid of DHICA activity,4 and also in our studies the intramelanosomal domain of TYRP1 did not display any DHICA activity nor tyrosine hydroxylase or l ‐DOPA oxidase activity (Figure 4).…”

The Color Loci of Mice – A Genetic Century

“…3G), and thus needed for the production of black pigment. It has been identified as a DHICA oxidase in the mouse (34), although its role may be different in humans (35).…”

Identification of c.483C>T polymorphism in the caprine tyrosinase-related protein 1 (TYRP1) gene

“…Another molecule with known effects on the phenotypic variation of coat colour is tyrosinase-related protein 1 (TYRP1), a melanosomal enzyme deeply involved in eumelanin synthesis (Sarangarajan and Boissy 2001). Classical studies performed in mouse revealed that TYRP1 loss-of-function alleles are associated with a brown coat (Bennett and Lamoreux 2003).…”