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Silver-Locus

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Das Gen ist bei der Maus auf dem Chromosom 10 und beim Menschen auf dem Chromosom 12 lokalisiert. Der Phänotyp ergrauter Haare durch den Verlust follikulärer Melanosomen wird durch eine Mutation hervorgerufen, die den Verlust eines Zielsignals zur Folge hat, so daß das Protein im Melanocyten fehlgeleitet wird. Es handelt sich bei dem Protein möglicherweise um strukturelles Matrixprotein der Melanosomen.

The SILV protein appears to be necessary for the formation of the fibril matrix upon which melanin intermediates are deposited late in melanosome maturation (24). Other studies have shown that SILV may also participate in melanin biosynthesis by accelerating the conversion of 5,6-dihydroxyindole-2-carboxylic acid to melanin (34, 35). The mutant phenotype of SILV in the human is unknown (28).

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

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Mermbranständiges Molekül in den Melanosomen. Spielt eine Rolle bei der Melaninsynthese, Schäden am Gen können zum vorzeitigen Absterben der Melanozyten in den Haarzwiebeln führen. Kein Leuzismus: Zellen wandern normal aus der Neuralleiste aus, und verteilen sich normal im Körper.

si/si mouse, which are diluted in coat color,

Pmel 17 is regulated by the same environmental stimuli that control tyrosinase.

New insights on the structure of the mouse silver locus and on the function of the silver protein.

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The melanosomal proteins encoded by the silver locus play important roles in melanogenesis. The human locus yields two proteins, PMEL17 and GP100, by alternative mRNA splicing. The mouse si locus was reported to encode a Pmel17 protein, and later gp87, a GP100 homologue. When we re-examined the products of wild-type and silver-mutant mouse si loci, RT-PCR of wild-type RNA and genomic DNA sequence accounted for gp87 but excluded the occurrence of Pmel17. Analysis of cDNA from the silver (si/si) melanocyte line, melan-si, showed that the pathogenic mutation is a G to A substitution at nt 1808, which yields a premature stop codon and a predicted protein truncated in the C-terminus. This was confirmed by reaction of a specific anti-gp87 antiserum with si/si melanocyte extracts. To further explore gp87 function, we compared the DHICA oxidase activity of extracts from B16, melan-si (heterozygous for the brown mutation and homozygous for the silver mutation) and Cloudman S91 cells (homozygous for the brown mutation), since both TRP1 and gp87 are thought to be involved in DHICA oxidation/polymerization. Cloudman extracts do not oxidize significantly DHICA and its methyl ester, supporting the involvement of native mouse TRP1 in DHICA oxidation. Extracts from B16 and melan-si do not show significant differences for the oxidation of free acid and methylated dihydroxyindoles, indicating that the mechanism is not decarboxylative. Melan-si extracts are very efficient in catalyzing dihydroxyindole oxidation, in spite of being heterozygous for the TRP1 mutation, consistent with a stablin effect for the wild-type gp87 protein. On the other hand, aggregated and degraded forms of that mutant gp87 protein are found in the cytosolic fraction of melan-si, suggesting that misrouting and aberrant processing of the gp87 and tyrosinase may also be related to the high DHICA oxidase activity of these melanocytes.

Characterization and subcellular localization of human Pmel 17/silver, a 110-kDa (pre)melanosomal membrane protein associated with 5,6,-dihydroxyindole-2-carboxylic acid (DHICA) converting activity.

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Pmel 17 is preferentially expressed in pigment cells in a manner suggestive of involvement in melanin biosynthesis. The gene is identical to the silver (si) pigmentation locus in mice. We now produced a recombinant glutathione-S-transferase-human Pmel 17 infusion protein and raised polyclonal antibodies against it to confirm the ultrastructural location and presumed site of action predicted by the deduced primary structure of Pmel 17/silver, and to authenticate the specificity of the DHICA converting function as inherent to the silver-locus protein. Full-length Pmel 17 cDNA also produced in insect cells in a baculovirus expression vector to ensure that activity did not originate from a co-precipitated protein. Natural hPmel 17 from human melanoma cells has an approximate molecular size of 100 kDa. By immunoperoxidase electron microscopic cytochemistry, the antigen was localized to the limiting membranes of premelanosomes and presumed premelanogenic cytosolic vesicles and, to a minor extent, in the premelanosomal matrix. In an in vitro assay, both the natural and the recombinant Pmel 17 accelerated the conversion of DHICA to melanin. This activity was inhibited by the anti-Pmel 17 polyclonal antibodies, indicating that the acceleration of DHICA conversion by natural protein is genuine and cannot be due to contaminating complexed proteins. We suggest that in situ Pmel 17/silver is a component of a postulated premelanosomal/melanosomal complex of membrane-bound melanogenic oxidoreductive enzymes and cofactors, in analogy to the electron transfer chain in mitochondria.

The Pmel 17/silver locus protein. Characterization and investigation of its melanogenic function.

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SILV silver homolog (mouse) (Homo sapiens)

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Pmel17 ist die einzige Melanozytenspezifische Komponente der Fibrillen.

  1. the RPT domain of PMEL17/GP100 is essential for its function in generating the fibrillar matrix of melanosomes and that the luminal domain is necessary for its correct processing and trafficking to those organelles

Die RPT-Domäne von Pmel17 ist notwendig für ihre Fähigkeit, die Fibrillenmatrix der Melanosomen zu bilden und die ins Zellumen reichende Domäne ist für ihre korrekte Behandlung und den Transport zu diesen Organellen nötig.

  1. Pmel17 is a critical component of melanogenesis.

Pmel17 ist ein notwendiger Teil der Farbstoffproduktion.

  1. Data show that the melanosomal protein Pmel17 is sorted into intralumenal vesicles by a mechanism that is dependent upon lumenal determinants and conserved in non-pigment cells.
  1. The PMEL17 (SILV) protein catalyzes the polymerization of 5,6-dihydroxyindole-2-carboxylic acid to melanin.
  2. Data suggest that MART-1 is indispensable for Pmel17 function and thus plays an important role in regulating mammalian pigmentation.
  3. Pmel17 is proteolytically processed in a post-Golgi compartment and is enriched in multivesicular endosomes prior to incorporation in stage II melanosomes.
  4. A proteolytic fragment of Pmel17, generated by proprotein convertase cleavage, is the major biogenetic component of the underlying fibrillar matrix of melanosome precursors.
  5. PMEL17 is rapidly processed in the endoplasmic reticulum and glycosylated in the early Golgi
  6. CD8 T lymphocytes recognized a nonameric peptide on melanoma cells that comprises two noncontiguous segments of melanocytic glycoprotein gp100(PMEL17); the production of this peptide involves the excision of four amino acids and splicing of the fragments
  7. truncation of the repeat region within Pmel17 alters either fibrillogenic activity or the interaction of Pmel17 with melanin intermediates
  8. Antigen-specific T lymphocyte reactivity to gp100 peptides was seen in 15 of 17 (88%) vitiligo patients, with many demonstrating very high reactivity at levels comparable with those observed with common recall antigens
  9. Data show that MITF appears to regulate the expression of the SILV and MLANA genes.
  10. we identified the gp100/pMel17 melanosomal protein as the shared antigen recognized by three independent CD8+ CTL clones in HLA-A*6801-restricted fashion.

Si silver [ Mus musculus ]

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Silver dapple in Horses

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The silver dappled colour in horses is controlled by a dominant allele that dilutes the black pigment eumelanin. A black or brown horse that carries the allele becomes diluted in mainly mane and tail, while the hair of the body remains darker. The genetically black horses are diluted to dark brown or almost black colour with silver grey or white mane and tail. The genetically bay or brown individuals are diluted to a lighter brown or almost chestnut-like colour with silver grey or white mane and tail. The silver brown individuals can be hard to distinguish from a chestnut horse with flaxen mane and tail, but it often has a darker shade on the legs (Bowling, 1996) and lighter eyelashes (See Picture 1 and 2). In some countries and some breeds one distinguishes between a large variety of silver variants that are believed to depend on the basic colour of the horse. For example, the bay individuals are thought to be the ones that gives the typical “red silvers” while the brown silvers are believed to have a darker brown shade as a basic colour (Sponenberg, 2003). Chestnut horses can carry the silver allele and inherit it to the offspring, but will not be affected in colour because the gene only affects the black pigment. This means that the silver allele will only change the phenotype on E- individuals. The silver allele is assumed to be fully dominant, i.e. silver heterozygotes and homozygotes are indistinguishable (Furugren, 2002).

The silver dapple colour is common in the Icelandic horse population and has also been observed in for example Shetland pony, Norwegian nordland, Rocky Mountain pony and Ardenne. The reason for the presence of the silver coat colour in Icelandic horse, Shetland pony, Norwegian Nordland and Rocky Mountain is probably due to connections between Norway, Iceland and Great Britain during the colonisation of Iceland. The silver locus in the Swedish Ardenne horse comes from Belgium and therefore it is possible that the mutation causing the silver colour has arised more than once (Furugren, 2002). The colour has also been registered in Mountain Pleasure Horse, Kentucky Mountain Saddle Horse and Arabians. Silver dappled horses could also be present in several other breeds, but are likely to be inaccurate identified and therefore not recorded (Sponenberg, 2003).

In some breeds, several silver horses have ocular abnormalities, varying from minimal to quite severe eye defects. The defect is not properly documented but some researchers believe that it is a part of the gene action at this locus and that homozygotes are more severely affected than the heterozygotes (Sponenberg, 2003). In many breeds, however, there is no problem with eye defects among the silver dappled individuals. The ocular defect could therefore be a founder effect; i.e. the silver dappled colour in the Rocky Mountain pony comes from a family that has a problem with this eye defect.

TKY284 is situated near the SILV gene at chromosome 6, and therefore this result gives a support for SILV being the causative gene for the phenotype. The other markers that show linkages are situated close to each other and show that the linkage analysis is accurate. The DNA-sequence for SILV differed from the one already published in exon 6. These differences in DNA-sequence also lead to differences in the amino acid sequence. When aligning the two different amino acid sequences to other SILV-homologues, the sequence obtained in this project aligns more well than the sequence already published. Because of the large number of animals sequenced in this project, the distinct sequences and the alignment with the protein in other species, the sequence obtained in this project seems correct.

To know for sure what mutation that is responsible for the silver phenotype it is necessary to sequence the rest of the gene. In many of the other species that carry mutations in the SILV/Pmel17 several SNPs, insertions and deletions are found. But there is a possibility that the introduced Cys is enough to disrupt the protein domain in the beginning of the cytoplasmic region. This region of the Pmel protein is a rather well conserved region between species. Of the mammals, the majority has at least two arginines in the beginning of the cytoplasmic region. Also the chicken and other vertebrates have arginines in these positions. For more detailed information about the amino acid sequence among the vertebrates, see Table 5. The missense mutation in the cytoplasmic region is interesting, not only because of the conserved region, but also because the very same mutation has been found in Pmel17 of chicken. This mutation in chicken is associated with the dun phenotype. In the dun phenotype however, more mutations were found such as a deletion of five amino acids in the transmembrane region. It is still not known what mutation that causes the phenotype in chicken, which like the silver phenotype in horse leads to a diluting effect on the black pigment (Kerje et al., 2004). But our findings so far argue for that the identified missense mutation is the one responsible for the silver phenotype.

Association of DNA polymorphism and the silver phenotype To investigate the nucleotide substitution silver horses as well as non-silvers in different breeds were tested for the SNP using pyrosequencing. In total 25 silver horses from three breeds and 55 non-silvers of different colours from 11 breeds were successfully genotyped for the SNP. For detailed information about the number of individuals from each breed, see Table 4. Individuals with an ambiguous result of the genotyping was re-typed or sequenced. All tested silver dappled horses had the genotype T/C (silver heterozygote) or T/T (silver homozygote), while the non-silvers all had C/C. This means a complete association between this polymorphism and the silver phenotype.

SILV as a candidate gene

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The gene product of SILV/Pmel17 has an important role in melanogenesis. Melanosomes that produce eumelanin go through four maturation stages. The first two stages generate a matrix consisting of intralumenal striations that are composed of fibrillar material. In the two later stages of maturation melanosomes are deposited on the matrix and will then blacken (Raposo and Marks, 2002). The major polypeptide in the matrix is pre-melanosomal protein (Pmel17), the product of SILV/Pmel17 (Kobyashi et al., 1994). Except from being a component of the fibril matrix, Pmel17 is also important when this is formed. This protein, together with other known melanosomal proteins are proteolytically cleaved in the stage I melanosomes. For many other proteins this inhibits the catalytic function, but for Pmel17 this cleavage is essential for the protein to change from a membrane-bound to a free form that can be a part of the fibrillar matrix (Kushimoto, 2001). Pmel17 could also have further features important for the melanin synthesis, as protecting the pigment cells from toxic intermediates (Berson et al., 2001).

Humans

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The human SILV-gene codes for at least three different isoforms, which have been confirmed with reverse transcriptase-PCR. This will lead to a difference in 21 bp and 7 amino acids, where the major form is the longer one (Bailin et al., 1996). Another form lacks 42 bp and can occur together with the other (Nichols, 2003).

In human, there is no known mutations in SILV, but it is believed that the gene could be linked to some forms of albinism (Kwon et al., 1996) and red hair (Kerje et al., 2004). Some researchers also believe that the protein could be involved in some forms of Waardenburg sha syndrome (WS), which is an auditory pigmentation disorder in humans. The symptoms of WS is similar to the one connected to the merle phenotype in dogs (Clark et al., 2006).

Qelle

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sonstige

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  • Alexander C. Theos*, Joanne F. Berson*, Sarah C. Theos*, Kathryn E. Herman*, Dawn C. Harper*, Danièle Tenza, Elena V. Sviderskaya, M. Lynn Lamoreux, Dorothy C. Bennett, Graça Raposo, and Michael S. Marks*: Dual Loss of ER Export and Endocytic Signals with Altered Melanosome Morphology in the silver Mutation of Pmel17 Originally published as MBC in Press, 10.1091/mbc.E06-01-0081 on June 7, 2006, Vol. 17, Issue 8, 3598-3612, August 2006, http://www.molbiolcell.org/cgi/content/abstract/17/8/3598
  • T. Hoashi, J. Muller, W. D. Vieira, F. Rouzaud, K. Kikuchi, K. Tamaki, and V. J. Hearing

The Repeat Domain of the Melanosomal Matrix Protein PMEL17/GP100 Is Required for the Formation of Organellar Fibers J. Biol. Chem., July 28, 2006; 281(30): 21198 - 21208. http://jcs.biologists.org/cgi/content/abstract/119/6/1080

  • L. A. Clark, J. M. Wahl, C. A. Rees, and K. E. Murphy

From The Cover: Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog PNAS, January 31, 2006; 103(5): 1376 - 1381. http://www.pnas.org/cgi/content/abstract/103/5/1376

  • S. Kerje, P. Sharma, U. Gunnarsson, H. Kim, S. Bagchi, R. Fredriksson, K. Schutz, P. Jensen, G. von Heijne, R. Okimoto, and L. Andersson

The Dominant white, Dun and Smoky Color Variants in Chicken Are Associated With Insertion/Deletion Polymorphisms in the PMEL17 Gene Genetics, November 1, 2004; 168(3): 1507 - 1518. http://www.genetics.org/cgi/content/abstract/168/3/1507

Maus

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  • Baxter LL, Pavan WJ.: Pmel17 expression is Mitf-dependent and reveals cranial melanoblast migration during murine development. PMID 14643677, Gene Expr Patterns. 2003 Dec;3(6):703-7.

In situ hybridization (ISH) analysis of the murine melanosomal gene, Pmel17, demonstrated robust expression in the presumptive retinal pigmented epithelium (RPE) starting at E9.5, and in neural crest-derived melanoblasts starting at E10.5. Pmel17 expression is not detectable in embryos mutated for Microphthalmia-associated transcription factor (Mitf), demonstrating transcriptional dependence of Pmel17 on Mitf in the RPE. Pmel17 expression in dorsal regions precedes dopachrome tautomerase (Dct) ISH expression, suggesting Pmel17 identifies melanoblasts at an earlier developmental stage. Dorsally localized Pmel17-positive cells at the forebrain/midbrain and midbrain/hindbrain boundaries at E10.5 reveal migratory pathways for cranial melanoblasts that have not been previously described in mouse using Dct expression.

Sisi

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http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=alleleDetail&key=1209

random inviability of melanoblasts in hair follicles results in mice that are variegated for white, partially pigmented (gray) hairs, and fully pigmented hairs other pigment loci influence appearance: nonagouti mice display silvering more on the belly than on the back and become more silvery with age, with nonagouti and brown, mice display fewer white and partially white hairs, and with agouti the yellow band at the tip of hairs is not affected but the base of each hair is lightened creating a whiteish "underfur" and silvering decreases with age

This mutation arose in an unspecified English fancy stock. Individual hairs of the coat of nonagouti silvers may be all white, all black, black with white tips, or white with gray or black bands. Silvering results from a reduction in number of pigment granules. Nonagouti silvers heterozygous for brown (Si/Si a/a Tyrp1b/+) have very light underfur (J:13051). The effect of Si is so variable that it is often difficult to classify in crosses, and its usefulness as a genetic marker is therefore limited (J:13051).

http://www.informatics.jax.org/searches/reference_report.cgi?_Allele_key=1209

Kuh

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Commons: Charolais cattle – Sammlung von Bildern, Videos und Audiodateien

The molecular background of many loci affecting coat colour inheritance in cattle is still incompletely characterized, although it is known that coat colour results from the joint effects of several loci, e.g. agouti, extension and dilution. Dilution alleles are responsible for a dilution effect on the original coat colour of an individual, which is determined by the agouti and extension loci. Different loci affecting dilution of pigment are suggested in Charolais (Dc) and Simmental (Ds). To enable chromosomal mapping of the Dc mutation, 133 animals from an F(2) full-sib resource population generated from a cross of Charolais and German Holstein were scored for the coat colour dilution phenotype. Linkage analysis covering all autosomes revealed a significant linkage of the dilution phenotype with microsatellite markers on bovine chromosome 5. No recombination was observed between marker ETH10 and the Dc locus. Positional and functional information identified the bovine silver homolog (SILV) gene as a candidate for the Dc mutation. Results from comparative sequencing of the SILV gene in individuals with different dilution coat colour phenotypes confirmed the presence of a c.64G>A non-synonymous mutation, which had previously been identified in the Charolais breed. The alleles at this locus were associated with coat colour dilution in this study. However, further investigation of colour inheritance within the F(2) resource population indicated that a single diallelic mutation in the SILV gene cannot explain the total observed variation of coat colour dilution.

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