Hermansky–Pudlak Syndrome and Pale Ear: Melanosome‐Making for the Millennium

Spritz, Richard A.

doi:10.1034/j.1600-0749.2000.130104.x

Cited by 36 publications

(37 citation statements)

References 39 publications

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“…It seems unlikely that vi-sually searching predators would be able to cue in on prey with such small amounts of white feathers. In humans, partial albinism has been associated with immune deficiency due to defective melanosomes, platelet granules, and lysosomes (Introne et al 1999;Baumeister et al 2000;Spritz 2000). We hypothesize that carotenoid-limitation of efficient immune function and/or free-radical scavenging is the mechanism generating reduced survival of partial albinos.…”

Section: Discussionmentioning

confidence: 99%

Albinism and Phenotype of Barn Swallows (Hirundo Rustica) From Chernobyl

Møller

Mousseau

2001

Evolution

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Abstract. The effects of mutation on phenotypic expression are supposed to be mainly deleterious because mutations disrupt the expression of genes that function relatively well under current environmental conditions. Thus, mutations are assumed to give rise to deviant phenotypes that are generally selected against. Radioactive contamination in the Chernobyl region of Ukraine is associated with a significant increase by a factor two to 10 in mutation rate in microsatellite markers of the barn swallow, Hirundo rustica. Barn swallows from Chernobyl had a temporally constant, elevated frequency of partial albinism compared to the situation before radioactive contamination and compared to birds from a control area. Albinism disproportionately affected the carotenoid-based plumage of the head, suggesting that carotenoid metabolism is particularly susceptible to the effects of radiation. Individuals with partially albinistic plumage had, on average, lower mean phenotypic values than other birds, and this was particularly the case for males. Furthermore, differences in phenotypic variation, as determined using Levene's test, were significantly larger in partial albinos compared to nonalbinos in males, but not in females, even though the null expectation would be the opposite due to the lower mean phenotypic values of partial albinos. Although small phenotypes were commonly associated with germline mutations, there was no general decrease in overall body size during the period 1991-2000, implying that small individuals were selected against. Because partial albinism is disfavored by natural selection, the effects of mutations are deleterious, giving rise to a balance between mutation and selection.

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Section: Discussionmentioning

confidence: 99%

Albinism and Phenotype of Barn Swallows (Hirundo Rustica) From Chernobyl

Møller

Mousseau

2001

Evolution

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“…H ermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding, and in most cases pulmonary fibrosis result from defects of melanosomes, platelet-dense granules, and lysosomes (1)(2)(3)(4). Somewhat similar disorders, Chediak-Higashi and Griscelli syndromes, are additionally associated with severe immunodeficiency (2,3).…”

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confidence: 99%

“…Important clues to the pathogenesis of these disorders have come from the mouse, in which Ͼ16 loci have been associated with mutant phenotypes similar to those of human HPS, Chediak-Higashi syndrome, and Griscelli syndrome (5,6). Several of these genes have been identified recently and in a number of cases have been shown to result in homologous disorders in mice and humans (2)(3)(4). Although the functions of many of the corresponding gene products remain unknown, several are involved in various aspects of trafficking proteins to nascent organelles, particularly melanosomes, lysosomes, and cytoplasmic granules.…”

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confidence: 99%

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

Suzuki

Oiso

Gautam

et al. 2003

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

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116

136

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In the mouse, more than 16 loci are associated with mutant phenotypes that include defective pigmentation, aberrant targeting of lysosomal enzymes, prolonged bleeding, and immunodeficiency, the result of defective biogenesis of cytoplasmic organelles: melanosomes, lysosomes, and various storage granules. Many of these mouse mutants are homologous to the human HermanskyPudlak syndrome (HPS), Chediak-Higashi syndrome, and Griscelli syndrome. We have mapped and positionally cloned one of these mouse loci, buff (bf), which has a mutant phenotype similar to that of human HPS. Mouse bf results from a mutation in Vps33a and thus is homologous to the yeast vacuolar protein-sorting mutant vps33 and Drosophila carnation (car). This is the first found defect of the class C vacuole͞prevacuole-associated target soluble Nethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) complex in mammals and the first mammalian mutant found that is directly homologous to a vps mutation of yeast. VPS33A thus is a good candidate gene for a previously uncharacterized form of human HPS.H ermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding, and in most cases pulmonary fibrosis result from defects of melanosomes, platelet-dense granules, and lysosomes (1-4). Somewhat similar disorders, Chediak-Higashi and Griscelli syndromes, are additionally associated with severe immunodeficiency (2, 3). Important clues to the pathogenesis of these disorders have come from the mouse, in which Ͼ16 loci have been associated with mutant phenotypes similar to those of human HPS, Chediak-Higashi syndrome, and Griscelli syndrome (5, 6). Several of these genes have been identified recently and in a number of cases have been shown to result in homologous disorders in mice and humans (2-4). Although the functions of many of the corresponding gene products remain unknown, several are involved in various aspects of trafficking proteins to nascent organelles, particularly melanosomes, lysosomes, and cytoplasmic granules. In the yeast, Ͼ65 proteins have been implicated in biogenesis of the cytoplasmic vacuole, including the products of Ͼ40 vacuolar protein-sorting (vps) loci required for trafficking newly synthesized proteins from the late Golgi͞trans-Golgi network to the vacuole (7, 8). It seems likely that at least as many proteins are associated with organellar biogenesis in mammals.We have mapped and positionally cloned the mouse buff (bf ) locus, which is characterized by recessive coat-color hypopigmentation and mild platelet-storage pool deficiency but has little if any effect on lysosomal function. We find that mouse bf results from a missense substitution in Vps33a, a homologue of yeast vps33. The bf mutation results in defective melanosome morphology and melanogenesis both in vivo and in vitro. Expression of wild-type Vps33a in transfected mouse bf-mutant melanocytes complements this aberrant phenotype, whereas expression of bf-mutant Vps33a does not. These results establish murine bf a...

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“…[1][2][3][4]. Those melanogenic proteins can be structural proteins, such as gp100, or enzymatic proteins, such as tyrosinase (TYR), 1 tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (DCT).…”

mentioning

confidence: 99%

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Watabe

Valencia

Yasumoto

et al. 2004

Journal of Biological Chemistry

122

105

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Pigmentation of the hair, skin, and eyes of mammals results from a number of melanocyte-specific proteins that are required for the biosynthesis of melanin. Those proteins comprise the structural and enzymatic components of melanosomes, the membrane-bound organelles in which melanin is synthesized and deposited. Tyrosinase (TYR) is absolutely required for melanogenesis, but other melanosomal proteins, such as TYRP1, DCT, and gp100, also play important roles in regulating mammalian pigmentation. However, pigmentation does not always correlate with the expression of TYR mRNA/protein, and thus its function is also regulated at the post-translational level. Thus, TYR does not necessarily exist in a catalytically active state, and its post-translational activation could be an important control point for regulating melanin synthesis. In this study, we used a multidisciplinary approach to examine the processing and sorting of TYR through the endoplasmic reticulum (ER), Golgi apparatus, coated vesicles, endosomes and early melanosomes because those organelles hold the key to understanding the trafficking of TYR to melanosomes and thus the regulation of melanogenesis. In pigmented cells, TYR is trafficked through those organelles rapidly, but in amelanotic cells, TYR is retained within the ER and is eventually degraded by proteasomes. We now show that TYR can be released from the ER in the presence of protonophore or proton pump inhibitors which increase the pH of intracellular organelles, after which TYR is transported correctly to the Golgi, and then to melanosomes via the endosomal sorting system. The expression of TYRP1, which facilitates TYR processing in the ER, is down-regulated in the amelanotic cells; this is analogous to a hypopigmentary disease known as oculocutaneous albinism type 3 and further impairs melanin production. The sum of these results shows that organellar pH, proteasome activity, and down-regulation of TYRP1 expression all contribute to the lack of pigmentation in TYRpositive amelanotic melanoma cells.

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Hermansky–Pudlak Syndrome and Pale Ear: Melanosome‐Making for the Millennium

Cited by 36 publications

References 39 publications

Albinism and Phenotype of Barn Swallows (Hirundo Rustica) From Chernobyl

Albinism and Phenotype of Barn Swallows (Hirundo Rustica) From Chernobyl

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

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