Pink-eyed dilution (p) gene in rodents: Increased pigmentation in tissue culture

Rl, Sidman; Pearlstein, Ronald M.; Waymouth, Charity

doi:10.1016/0012-1606(65)90023-0

Cited by 65 publications

(39 citation statements)

References 26 publications

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“…Defects in the corresponding murine gene (p) give rise to the pink-eyed dilution mouse (Rinchik et al, 1993), which has similar eye and coat hypopigmentation. Melanocytes from this model mouse contain melanosomes that are small, immature, and hypopigmented relative to normal melanosomes (Sidman et al, 1965;Rosemblat et al, 1998). Although these features clearly implicate OCA2 as being critical for pigmentation, the molecular function of OCA2 is still unclear.…”

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confidence: 94%

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Sitaram

Piccirillo

Palmisano

et al. 2009

MBoC

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Oculocutaneous albinism type 2 is caused by defects in the gene OCA2, encoding a pigment cell-specific, 12-transmembrane domain protein with homology to ion permeases. The function of the OCA2 protein remains unknown, and its subcellular localization is under debate. Here, we show that endogenous OCA2 in melanocytic cells rapidly exits the endoplasmic reticulum (ER) and thus does not behave as a resident ER protein. Consistently, exogenously expressed OCA2 localizes within melanocytes to melanosomes, and, like other melanosomal proteins, localizes to lysosomes when expressed in nonpigment cells. Mutagenized OCA2 transgenes stimulate melanin synthesis in OCA2-deficient cells when localized to melanosomes but not when specifically retained in the ER, contradicting a proposed primary function for OCA2 in the ER. Steady-state melanosomal localization requires a conserved consensus acidic dileucine-based sorting motif within the cytoplasmic N-terminal region of OCA2. A second dileucine signal within this region confers steadystate lysosomal localization in melanocytes, suggesting that OCA2 might traverse multiple sequential or parallel trafficking routes. The two dileucine signals physically interact in a differential manner with cytoplasmic adaptors known to function in trafficking other proteins to melanosomes. We conclude that OCA2 is targeted to and functions within melanosomes but that residence within melanosomes may be regulated by secondary or alternative targeting to lysosomes. INTRODUCTIONMelanin pigments are synthesized by specialized cell types, including dermal and epidermal melanocytes and retinal pigment epithelial cells, within unique organelles known as melanosomes . Melanosomes are members of a class of tissue-specific "lysosome-related organelles" characterized by an acidic lumenal pH and the presence of some lysosomal proteins (Dell'Angelica et al., 2000;Griffiths, 2002). Among lysosome-related organelles, melanosomes represent a subclass that coexists with bona fide lysosomes in their host cells . Melanosomes are distinguished from lysosomes by the presence of cell-type-specific cargo proteins that confer unique functional and morphological properties. How these cargo proteins are diverted from traditional lysosomes and delivered to and maintained within melanosomes is incompletely understood, and the degree of cargo cross-talk between melanosomes and lysosomes is not known.Melanosomes undergo a program of maturation within melanocytes by the ordered delivery of cargoes to nascent melanosomes via specialized trafficking pathways . Some components of the melanosomal trafficking machinery are known, largely from analyses of the sorting of well-characterized cargo proteins, such as the melanogenic enzyme tyrosinase (Tyr) and tyrosinase-related protein 1 (Tyrp1), in both wild-type melanocytes and melanocytes derived from patients or mouse models of genetic hypopigmentary diseases such as Hermansky-Pudlak Syndrome (HPS) (Di Pietro and Dell'Angelica, 2005;Wei, 2006). Tyr and Tyrp1 contain cytoplasmic a...

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confidence: 94%

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Sitaram

Piccirillo

Palmisano

et al. 2009

MBoC

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“…Because of its major role in the melanin pathway [14] and its involvement in type I Oculocutaneous albinism [24], tyrosinase is a major candidate [2] well described in humans [7] and in mice [13]. The pink-eyed dilution locus ( p) encodes a melanosomal membrane protein [29] also involved in the melanin-synthesis pathway by interference with tyrosine supply [25,31]. Mutations in the p locus result in hypopigmentation in the eye and coat [3], and are responsible for type II Oculocutaneous albinism [28].…”

Section: Introductionmentioning

confidence: 99%

A mutation in the MATP gene causes the cream coat colour in the horse

2003

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-In horses, basic colours such as bay or chestnut may be partially diluted to buckskin and palomino, or extremely diluted to cream, a nearly white colour with pink skin and blue eyes. This dilution is expected to be controlled by one gene and we used both candidate gene and positional cloning strategies to identify the "cream mutation". A horse panel including reference colours was established and typed for different markers within or in the neighbourhood of two candidate genes. Our data suggest that the causal mutation, a G to A transition, is localised in exon 2 of the MATP gene leading to an aspartic acid to asparagine substitution in the encoded protein. This conserved mutation was also described in mice and humans, but not in medaka.horse / coat colour / underwhite / cream / MATP

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“…Many proteins previously described with such a secondary structure function as transmembrane channels or transporters. It has been suggested that the p protein may function as a transporter of tyrosine because (i) culture in high concentrations of tyrosine induces pigmentation in ocular melanocytes from mice homozygous for the p allele, a null-phenotype p mutation (8), and (ii) incubation of hair follicles from persons with type II oculocutaneous albinism in high concentrations oftyrosine or dopa results in melanin deposition (9). Although homology to a bacterial tyrosine transporter has been suggested (5), we were unable to confirm this homology by rigorous analysis employing the Monte Carlo method.…”

mentioning

confidence: 99%

Identification of a melanosomal membrane protein encoded by the pink-eyed dilution (type II oculocutaneous albinism) gene.

Rosemblat

Durham‐Pierre

Gardner

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

140

114

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Pink-eyed dilution (p) gene in rodents: Increased pigmentation in tissue culture

Cited by 65 publications

References 26 publications

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

Localization to Mature Melanosomes by Virtue of Cytoplasmic Dileucine Motifs Is Required for Human OCA2 Function

A mutation in the MATP gene causes the cream coat colour in the horse

Identification of a melanosomal membrane protein encoded by the pink-eyed dilution (type II oculocutaneous albinism) gene.

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