Mouse<i>silver.</i>mutation is caused by a single base insertion in the putative cytoplasmic domain of Pmel 17

Kwon, Byoung S.; Halaban, Ruth; Ponnazhagan, Selvarangan; Kim, Kack K.; Chintamaneni, C; Bennett, Dorothy C.; Pickard, Richard T.

doi:10.1093/nar/23.1.154

Cited by 71 publications

(69 citation statements)

References 20 publications

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“…SILV encodes a melanosomal protein important in pigmentation (28) and maps to HSA12q13-q14, which exhibits conservation of synteny with CFA10 (29). A single base insertion in SILV causes the silver phenotype in the mouse (23), and polymorphisms in this gene are associated with the dominant white, dun, and smoky plumage color variants in chickens (30). The dilute coloration of Charolais cattle has also recently been attributed to a mutation in SILV (24).…”

Section: Resultsmentioning

confidence: 99%

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Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog

Clark

Wahl

Rees

et al. 2006

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

227

242

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Merle is a pattern of coloring observed in the coat of the domestic dog and is characterized by patches of diluted pigment. This trait is inherited in an autosomal, incompletely dominant fashion. Dogs heterozygous or homozygous for the merle locus exhibit a wide range of auditory and ophthalmologic abnormalities, which are similar to those observed for the human auditory-pigmentation disorder Waardenburg syndrome. Mutations in at least five genes have been identified as causative for Waardenburg syndrome; however, the genetic bases for all cases have not been determined. Linkage disequilibrium was identified for a microsatellite marker with the merle phenotype in the Shetland Sheepdog. The marker is located in a region of CFA10 that exhibits conservation of synteny with HSA12q13. This region of the human genome contains SILV, a gene important in mammalian pigmentation. Therefore, this gene was evaluated as a candidate for merle patterning. A short interspersed element insertion at the boundary of intron 10͞exon 11 was found, and this insertion segregates with the merle phenotype in multiple breeds. Another finding was deletions within the oligo(dA)-rich tail of the short interspersed element. Such deletions permit normal pigmentation. These data show that SILV is responsible for merle patterning and is associated with impaired function of the auditory and ophthalmologic systems. Although the mutant phenotype of SILV in the human is unknown, these results make it an intriguing candidate gene for human auditory-pigmentation disorders.short interspersed element ͉ pigmentation ͉ linkage disequilibrium

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Section: Resultsmentioning

confidence: 99%

“…SILV (also known as Pmel17; gp100) is a pigment gene best known as the Silver locus responsible for a recessive trait in an inbred strain of black mice in which the hair color dilutes with age (22,23). Although this gene is known to have a central role in pigmentation, the precise function of SILV remains controversial (24).…”

mentioning

confidence: 99%

Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog

Clark

Wahl

Rees

et al. 2006

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

227

242

View full text Add to dashboard Cite

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“…cDNA was obtained using random hexamer primers and the SuperScript First-Strand Synthesis System for RT-PCR (Invitrogen Life Technologies, Carlsbad, CA). The quantities of gp100 and ␤-actin mRNAs were evaluated by PCR primers using intronspanning primers (11,12) at 25, 30, and 35 cycles and digital capture.…”

Section: Rna Preparation and Rt-pcrmentioning

confidence: 99%

Vaccine-Stimulated, Adoptively Transferred CD8+ T Cells Traffic Indiscriminately and Ubiquitously while Mediating Specific Tumor Destruction

Palmer

Balasubramaniam

Hanada

et al. 2004

The Journal of Immunology

106

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It has been suggested that antitumor T cells specifically traffic to the tumor site, where they effect tumor destruction. To test whether tumor-reactive CD8+ T cells specifically home to tumor, we assessed the trafficking of gp100-specific pmel-1 cells to large, vascularized tumors that express or do not express the target Ag. Activation of tumor-specific CD8+ pmel-1 T cells with IL-2 and vaccination with an altered peptide ligand caused regression of gp100-positive tumors (B16), but not gp100-negative tumors (methylcholanthrene 205), implanted on opposing flanks of the same mouse. Surprisingly, we found approximately equal and very large numbers of pmel-1 T cells (>25% of all lymphocytes) infiltrating both Ag-positive and Ag-negative tumors. We also found evidence of massive infiltration and proliferation of activated antitumor pmel-1 cells in a variety of peripheral tissues, including lymph nodes, liver, spleen, and lungs, but not peripheral blood. Most importantly, evidence for T cell function, as measured by production of IFN-γ, release of perforin, and activation of caspase-3 in target cells, was confined to Ag-expressing tumor. We thus conclude that CD8+ T cell-mediated destruction of tumor is the result of specific T cell triggering at the tumor site. The ability to induce ubiquitous homing and specific tumor destruction may be important in the case of noninflammatory metastatic tumor foci.

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“…4). The requirement of Pmel17 for the generation of functional melanin has been shown in a number of different organisms, because, for example, certain point mutations in the Pmel17/silver gene result in hypopigmentation phenotypes (5)(6)(7). The most characteristic domain within Pmel17 is a specific lumenal proline/serine/threonine rich repeat domain (see Fig.…”

mentioning

confidence: 99%

Formation of Pmel17 Amyloid Is Regulated by Juxtamembrane Metalloproteinase Cleavage, and the Resulting C-terminal Fragment Is a Substrate for γ-Secretase

Kummer

Maruyama

Huelsmann

et al. 2009

Journal of Biological Chemistry

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The formation of insoluble cross ␤-sheet amyloid is pathologically associated with disorders such as Alzheimer, Parkinson, and Huntington diseases. One exception is the nonpathological amyloid derived from the protein Pmel17 within melanosomes to generate melanin pigment. Here we show that the formation of insoluble M␣C intracellular fragments of Pmel17, which are the direct precursors to Pmel17 amyloid, depends on a novel juxtamembrane cleavage at amino acid position 583 between the furin-like proprotein convertase cleavage site and the transmembrane domain. The resulting Pmel17 C-terminal fragment is then processed by the ␥-secretase complex to release a shortlived intracellular domain fragment. Thus, by analogy to the Notch receptor, we designate this cleavage the S2 cleavage site, whereas ␥-secretase mediates proteolysis at the intramembrane S3 site. Substitutions or deletions at this S2 cleavage site, the use of the metalloproteinase inhibitor TAPI-2, as well as small interfering RNA-mediated knock-down of the metalloproteinases ADAM10 and 17 reduced the formation of insoluble Pmel17 fragments. These results demonstrate that the release of the Pmel17 ectodomain, which is critical for melanin amyloidogenesis, is initiated by S2 cleavage at a juxtamembrane position.Folding of proteins is a highly regulated process ensuring their correct three-dimensional structure. Under pathological circumstances, a soluble protein can be folded into highly stable cross ␤-sheet amyloid structures, which are believed to play pathological roles in disorders such as Alzheimer, Parkinson, and Huntington diseases. An exception to this general concept is the physiological amyloid structure of the melanosomal matrix formed by the protein Pmel17. Melanosomes are lysosome-related organelles that contain pigment granules (melanin) in melanocytes and retinal epithelial cells (reviewed in Ref. 1). Melanogenesis is believed to proceed through several sequential maturation steps, classified by melanosomes from stage I to stage IV. Maturation of stage II melanosomes requires the formation of Pmel17 intralumenal fibers (2, 3).Pmel17 (also called gp100, ME20, RPE1, or silver) is a type I transmembrane glycoprotein of up to 668 amino acids in humans (reviewed in Ref. 4). The requirement of Pmel17 for the generation of functional melanin has been shown in a number of different organisms, because, for example, certain point mutations in the Pmel17/silver gene result in hypopigmentation phenotypes (5-7). The most characteristic domain within Pmel17 is a specific lumenal proline/serine/threonine rich repeat domain (see Fig. 1A), that is imperfectly repeated 13 times in the M␣ fragment. Importantly, deletion of the rich repeat domain results in a complete loss of fibril formation, pointing to the requirement of Pmel17, and especially the rich repeat domain, in melanin formation (8). Pmel17 exists in different isoforms generated by alternative splicing. Pmel17-i 2 is the most abundant isoform, whereas the Pmel17-l isoform contains a 7-amino acid in...

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Mousesilver.mutation is caused by a single base insertion in the putative cytoplasmic domain of Pmel 17

Cited by 71 publications

References 20 publications

Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog

Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog

Vaccine-Stimulated, Adoptively Transferred CD8+ T Cells Traffic Indiscriminately and Ubiquitously while Mediating Specific Tumor Destruction

Formation of Pmel17 Amyloid Is Regulated by Juxtamembrane Metalloproteinase Cleavage, and the Resulting C-terminal Fragment Is a Substrate for γ-Secretase

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