Mislocalization of Melanosomal Proteins in Melanocytes from Mice with Oculocutaneous Albinism Type 2

Manga, Prashiela; Boissy, Raymond E.; Pifko-Hirst, Sharon; Zhou, Bao-Kang; Orlow, Seth J.

doi:10.1006/exer.2001.1006

Cited by 53 publications

(41 citation statements)

References 74 publications

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“…Melanosomes from p-null mice have also been noted to exhibit an abnormal melanosomal ultrastructure, in addition to deficient TYR activity. In studies designed to examine the distribution of the melanosomal proteins in these cells, misrouting of the TYR protein was found (Manga et al, 2001), with accumulation of TYR in premelanosome vesicles suggesting a role for the P-protein in the processing and trafficking of melanosomal proteins (Chen et al, 2002;Toyofuku et al, 2002). Heterologous expression of recombinant P-protein in yeast has revealed a novel activity associated with the OCA2 gene product in that it can modulate arsenic sensitivity of cells, with wildtype melanocytes more sensitive to these toxic compounds than p-null melanocytes (Staleva et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

A Genome Scan for Eye Color in 502 Twin Families: Most Variation is due to a QTL on Chromosome 15q

Zhu,

Evans,

Duffy

et al. 2004

Twin Res

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We have rated eye color on a 3-point scale (1 = blue/grey, 2 = hazel/green, 3 = brown) in 502 twin families and carried out a 5-10 cM genome scan (400-757 markers). We analyzed eye color as a threshold trait and performed multipoint sib pair linkage analysis using variance components analysis in Mx. A lod of 19.2 was found at the marker D15S1002, less than 1 cM from OCA2, which has been previously implicated in eye color variation. We estimate that 74% of variance in eye color liability is due to this QTL and a further 18% due to polygenic effects. However, a large shoulder on this peak suggests that other loci affecting eye color may be telomeric of OCA2 and inflating the QTL estimate. No other peaks reached genome-wide significance, although lods > 2 were seen on 5p and 14q and lods >1 were additionally seen on chromosomes 2, 3, 6, 7, 8, 9, 17 and 18. Most of these secondary peaks were reduced or eliminated when we repeated the scan as a two locus analysis with the 15q linkage included, although this does not necessarily exclude them as false positives. We also estimated the interaction between the 15q QTL and the other marker locus but there was only minor evidence for additive × additive epistasis. Elaborating the analysis to the full two-locus model including non-additive main effects and interactions did not strengthen the evidence for epistasis. We conclude that most variation in eye color in Europeans is due to polymorphism in OCA2 but that there may be modifiers at several other loci.Skin, hair and eye colors are some of the most obvious forms of human diversity (Sunderland, 1956), yet the complexities of the genetic mechanisms underlying the differences of these pigmentation phenotypes within individuals remain largely unknown. It is expected that a relatively small set of major genes contribute to the color variation of these cutaneous tissues within diverse human populations. These pigmentary genes are also expected to be specifically expressed within the melanocyte cell and act to regulate the synthesis, chemical composition, packaging and distribution of the pigment melanin, thus producing the visible differences underlying these traits (Sturm et al., 1998;Sturm et al., 2001).The iris consists of several layers of which the most important for the appearance of eye color are the anterior layer and its underlying stroma (Robins, 1991;Boissy, 1998). In the brown iris there is an abundance of melanocytes and melanosomes in the anterior layer and stroma. In individuals with blue eye color, the anterior layer and stroma contain very little melanin. As light traverses these relatively melanin-free layers, the minute protein particles of the iris scatter the short blue wavelengths to the surface. The blue color is heightened because longer wavelengths (yellow and red) are absorbed by the dark background of the pigmented retinal epithelium which also obscures the reddish hue of the adjacent blood vessels. Other colors such as yellow, green and hazel are due to varying amounts of lipid pigment granules in t...

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Section: Discussionmentioning

confidence: 99%

A Genome Scan for Eye Color in 502 Twin Families: Most Variation is due to a QTL on Chromosome 15q

Zhu,

Evans,

Duffy

et al. 2004

Twin Res

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“…OCA2 was originally thought to localize predominantly to mature melanized melanosomes based on subcellular fractionation of melanocytes (Rosemblat et al, 1994), poor extraction by detergent from melanized melanocytes relative to nonmelanized melanocytes (Donatien and Orlow, 1995), and interpretation of results from confocal immunofluorescence microscopy (IFM) analyses (Toyofuku et al, 2002). Tyrp1-containing compartments in melanocytes from OCA2-deficient mice are less acidic than in wild-type melanocytes, suggesting that OCA2 not only localizes to melanosomes but also modulates their pH (Puri et al, 2000), although this interpretation is disputed because Tyrp1 does not localize to melanosomes properly in OCA2-deficient melanocytes (Manga et al, 2001). The possibility that melanosomal pH might be affected by OCA2 deficiency is supported by an observed increase in melanin synthesis upon neutralization of organellar pH in otherwise hypopigmented OCA2-deficient melanocytes (Ancans et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Ion dysregulation could in turn have indirect consequences on other processes in OCA2-deficient cells. For example, alterations in intralumenal ion balance or pH can affect cellular membrane fusion events (Peters and Mayer, 1998;Ungermann et al, 1999;Pryor et al, 2000), perhaps explaining the accumulation of melanosomal cargo in vesicular structures in OCA2-deficient melanocytes (Manga et al, 2001). Moreover, disruption of OCA2 transport activity across the melanosomal membrane may indirectly alter ion concentrations or pH in the cytosol; for example, exogenous expression of OCA2 in Saccharomyces cerevisiae led to a depletion of cytoplasmic glutathione due to glutathione transport into the vacuole (Staleva et al, 2002).…”

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confidence: 99%

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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“…By contrast, studies of immortalized p-mutant melanocytes (the model for OCA2) have shown that tyrosinase in those cells is correctly processed through the Golgi, but it is then secreted from the cells rather than being sorted to melanosomes, thus showing that OCA2 is a hypopigmentary disease resulting from altered intracellular trafficking of tyrosinase (Manga et al, 2001;Chen et al, 2002;Toyofuku et al, 2002). In this context, investigations into the molecular basis of OCA4 are necessary to classify its mechanism into one of the above types of diseases or into yet a new distinct type.…”

mentioning

confidence: 98%

Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4

Costin

Valencia

Vieira

et al. 2003

Journal of Cell Science

165

123

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Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1(tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes,tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes.

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Mislocalization of Melanosomal Proteins in Melanocytes from Mice with Oculocutaneous Albinism Type 2

Cited by 53 publications

References 74 publications

A Genome Scan for Eye Color in 502 Twin Families: Most Variation is due to a QTL on Chromosome 15q

A Genome Scan for Eye Color in 502 Twin Families: Most Variation is due to a QTL on Chromosome 15q

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

Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4

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