Clinical, Molecular, and Cell Biological Aspects of Chediak–Higashi Syndrome

Introne, Wendy J.; Boissy, Raymond E.; Gahl, William A.

doi:10.1006/mgme.1999.2927

Cited by 289 publications

(261 citation statements)

References 117 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: 93%

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: 93%

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

Møller

Mousseau

2001

Evolution

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“…Interestingly, similar to what is seen in Rab38 cht ͞Rab38 chtderived melanocytes, melanocytes from Hps1 ep ͞Hps1 ep mutants also exhibit a mislocalization of TYRP1 into membranous complexes rather than premelanosomes (38), again yielding a brown mouse. In addition to melanosome pigment defects, HPS mice exhibit enlargement of melanosomes and lysosomes and reduced platelet aggregation (27,39). This finding suggests involvement of HPS genes in early vesicle sorting events that affect both lysosomes as well as melanosomes.…”

Section: Discussionmentioning

confidence: 95%

“…Analysis of microarray expression patterns demonstrated that RAB38 had an expression profile similar to nine previously identified melanocyte genes known to function in a melanocytespecific fashion. These melanocyte genes include DCT, TRYP1, and PMEL17, which are essential for melanosome function; MELAN-A͞MART1 (24) and MLSN (25), which are important melanoma antigens; AIM-1 recently identified as the gene responsible for B in medaka (26), underwhite in mouse (3), and OCA4 in human (3); CHS1, which functions in melanosome͞ lysosome vesicle trafficking (27); and PAX3, a paired box transcription factor that regulates melanocyte gene expression (28)(29)(30), including expression of TYRP1 (31). Mutations in seven of these genes have been identified in human and͞or murine disorders associated with pigmentation variations (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mutation of melanosome protein RAB38 in chocolate mice

Loftus

Larson

Baxter

et al. 2002

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

156

170

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Mutations of genes needed for melanocyte function can result in oculocutaneous albinism. Examination of similarities in human gene expression patterns by using microarray analysis reveals that RAB38, a small GTP binding protein, demonstrates a similar expression profile to melanocytic genes. Comparative genomic analysis localizes human RAB38 to the mouse chocolate (cht) locus. A G146T mutation occurs in the conserved GTP binding domain of RAB38 in cht mice. Rab38 cht ͞Rab38 cht mice exhibit a brown coat similar in color to mice with a mutation in tyrosinase-related protein 1 (Tyrp1), a mouse model for oculocutaneous albinism. The targeting of TYRP1 protein to the melanosome is impaired in Rab38 cht ͞Rab38 cht melanocytes. These observations, and the fact that green fluorescent protein-tagged RAB38 colocalizes with end-stage melanosomes in wild-type melanocytes, suggest that RAB38 plays a role in the sorting of TYRP1. This study demonstrates the utility of expression profile analysis to identify mammalian disease genes.

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“…The beige protein is involved in cellular vesicle formation and trafficking (5). This could affect macrophage cholesterol metabolism and trafficking.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical symptoms of the beige/CHS mutation, such as oculocutaneous albinism and bleeding disorders, are suggested to be attributable to cellular vesicle secretion malfunction and an impairment in the exchange of membrane material between the trans-Golgi network and late endosomes (4,5). Patients generally succumb to infections caused primarily by defective bactericidal activity of neutrophils and Natural Killer (NK) cells (5,6). Cytotoxic T-lymphocyte, NK cell, and neutrophil activities in beige mice as well as CHS patients are defective; however, less attention has been paid to macrophage functions.…”

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confidence: 99%

Participation of macrophages in atherosclerotic lesion morphology in LDLr−/− mice

Schiller

Black

Bradshaw

et al. 2004

Journal of Lipid Research

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Lyst beige (beige) mice crossed with LDL receptordeficient (LDLr ؊ / ؊ ) mice had a distinct atherosclerotic lesion morphology that was not observed in LDLr ؊ / ؊ mice. This morphology is often associated with a stable plaque phenotype. We hypothesized that macrophage expression of the beige mutation accounted for this distinct morphology. Cultured bone marrow-derived macrophages from LDLr ؊ / ؊ and beige,LDLr ؊ / ؊ mice were compared for their ability to accumulate cholesterol, efflux cholesterol, migrate in response to chemotactic stimuli through Matrigel ® -coated membranes, and express matrix metalloproteinase 9 (MMP9). No differences in cholesterol metabolism were identified. Beige,LDLr ؊ / ؊ macrophage invasion in vitro appeared to be less than LDLr ؊ / ؊ macrophage invasion but did not achieve significance. Nevertheless, tumor necrosis factor-␣ -induced MMP9 expression, secretion, and enzymatic activity of beige,LDLr ؊ / ؊ macrophages were all significantly decreased compared with those of LDLr ؊ / ؊ macrophages ( P Ͻ 0.05).

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Clinical, Molecular, and Cell Biological Aspects of Chediak–Higashi Syndrome

Cited by 289 publications

References 117 publications

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

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

Mutation of melanosome protein RAB38 in chocolate mice

Participation of macrophages in atherosclerotic lesion morphology in LDLr−/− mice

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