Benutzerin:Kersti Nebelsiek/15

Silver-Locus

Das Genprodukt des "silver"-Locus ist ein transmembranes Protein, dessen genaue Funktion noch nicht bekannt ist. Es wird als PMEL17 (Melanocyte protein 17) beim Menschen und als gp100 bei der Maus bezeichnet. 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. Ähnlich der TYRP1 Expression geht die Schimmelfärbung beim Pferd mit einer fehlenden und die Tumorbildung mit einer erhöhten PMEL17 Expression einher (RIEDER et al., 2000).

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).

Silver dapple in Horses

Background: The Silver coat color, also called Silver dapple, in the horse is characterized by dilution of the black pigment in the hair. This phenotype shows an autosomal dominant inheritance. The effect of the mutation is most visible in the long hairs of the mane and tail, which are diluted to a mixture of white and gray hairs. Herein we describe the identification of the responsible gene and a missense mutation associated with the Silver phenotype.

Conclusion: The present study shows that PMEL17 causes the Silver coat color in the horse and enable genetic testing for this trait.

One characteristic feature of a Silver horse is that they are often born with striped hooves (Figure 2B, T. Kvick, pers. comm.). These stripes usually disappear after about one year.

It is relatively common in the Icelandic horse population, the American Miniature Horse, and the Rocky Mountain Horse. Silver is also present in the Ardenne, the Morgan Horse, the American Paint Horse, the Quarter Horse, the American Saddlebred, the Shetland pony and the Norwegian Nordland, as well as sporadically observed in Welsh ponies, Arabians and Swedish Warmbloods. The Silver phenotype can also be found in other breeds closely related to the above breeds. The Silver mutation was possibly present within the Nordic horse breeds before the colonization of Iceland during the 9th century as it is present in the Icelandic horse population on Iceland and import of horses to Iceland was prohibited already during the 10th century.

This study describes complete linkage between the Silver locus and the PMEL17 gene, and a missense mutation completely associated with the Silver coat color.

The results of the present study strongly indicate that the Silver coat color in horses is caused by a mutation in PMEL17. This conclusion is based on the observation of no recombinants between PMEL17 and Silver in a pedigree material and the identification of a haplotype, composed of sequence variants in intron 9 and exon 11, showing complete concordance with the presence of Silver across six different breeds. Furthermore, the specific inhibition of the production of black eumelanin but with no visible effects on red pheomelanin is in perfect agreement with the observed phenotypic effects of previously described PMEL17 mutations in mouse and chicken [5-7]. We also describe a candidate causative missense mutation Arg618Cys that is a non-conservative substitution at a conserved site and mutations in the near vicinity cause a similar phenotype in chickens [7]. The second mutation showing a complete concordance with Silver, located at position 48 bp in intron 9, cannot be excluded at the present time but it appears less likely as causative since it occurs in an intronic region not well conserved among mammalian species [19]. We find it more likely that this intronic mutation was present on the ancestral haplotype in which the Silver mutation occurred and has not yet been separated by recombination events; it is located only 759 bases from the Arg618Cys missense mutation.

Interestingly, the Dun allele in chicken carries both a 12 base pairs insertion and the same missense mutation as the horse. This supports our hypothesis that the identified missense mutation may be the causative mutation in horses. It is possible that the introduced cystein residue is enough to disrupt the protein domain in the beginning of the cytoplasmic region, however this remains to be investigated. This region of the PMEL17 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 (Figure 5). Clearly, the missense mutation found in Silver colored horses occurs in a region of the PMEL17 protein that appears critical for proper eumelanin formation. Future studies could, for example, involve analysis of the consequences of the missense mutation for PMEL17 localization and function in cell culture models. Although the identified missense mutation resides in the same region of PMEL17 as the mutations in several other species (Figure 4), it was perhaps a bit surprising that we did not find any additional causative mutations, as the impact on the aminoacid sequence is less drastic in the horse. In line with this future experiments will attempt to completely sequence the longest SINE in intron 6 to fully evaluate any potential role in the Silver phenotype.

Ocular abnormalities caused by a syndrome called Anterior Segment Dysgenesis (ASD) are segregating in the Rocky Mountain Horse breed [22,23]. An unexpected high fraction of the diseased animals in a study of 514 Rocky Mountain horses had the Silver coat color [22]. The clinical and histological signs vary from minimal to quite severe defects in the frontal part of the eye.

Other animals

Mutations in PMEL17/SILV have previously been shown to regulate hypopigmented phenotypes in mouse, chicken, zebrafish, and dog [5-9]. PMEL17 encodes a transmembrane protein called pre-melanosomal protein 17 or PMEL17 (Figure 4). PMEL17 is involved in the production of eumelanin and is present in the melanosome, but its precise function remains controversial [10]. It might even be so that this protein has an additional role separate from that in melanosome biogenesis. One interesting characteristic feature of PMEL17 that seems necessary for normal melanin production is that it forms non-pathological amyloid fibrils [11,12]. Furthermore, it has been shown that the PMEL17 gene is expressed in early cranial melanoblasts in the mouse [13], suggesting an important role during development. The PMEL17-mutants identified in different species provide an opportunity to study PMEL17 protein function and its role in the pigmentation process.

The occurrence of PMEL17 gene mutations is rare. Considering how well the laboratory mouse is studied it is surprising that only two PMEL17 mutations has been identified in this species [5,6]. Several other coat color genes in the mouse carry many more mutations, like for example the transcription factor MITF that carry over 20 different mutations several of which are loss-of-function mutations [21]. There could be several explanations for this rare occurrence of PMEL17 gene mutations in different species, of which the most likely seems to be 1) That there actually are existing mutations but they do not have an effect on pigmentation and are therefore missed, 2) That the mutations are lethal. The fact that all of the mutations within the PMEL17 gene identified in different species so far – except the zebrafish – are located within or near the last exons implies that mutations in the "earlier" exons could lead to total loss of PMEL17 function and that this perhaps is lethal. This in turn implies that PMEL17 has a function outside melanosome biogenesis as pigmentation is not critical for survival.

Ocular abnormalities caused by a syndrome called Anterior Segment Dysgenesis (ASD) are segregating in the Rocky Mountain Horse breed [22,23]. An unexpected high fraction of the diseased animals in a study of 514 Rocky Mountain horses had the Silver coat color [22]. The clinical and histological signs vary from minimal to quite severe defects in the frontal part of the eye. Interestingly, many of the eye defects observed in the Silver horses are similar to those associated with congenital aniridia or malformation of the anterior segment in humans [23]. The ASD syndrome also has a relatively close resemblance to the defects observed in Small eye mice and rats [23]. Microphthalmia is well described in homozygous blue merle Australian Shepherd dogs [24]. It is hypothesized that horses homozygous for the Silver mutation have more severe symptoms of the ASD syndrome than heterozygotes [25]. The ASD syndrome is also present in the Kentucky Saddle horse and Mountain Pleasure horse breeds [26], both closely related to the Rocky Mountain Horse. However, in ASD it is the morphology of the eye that is affected and not the pigmentation. Further, in several horse breeds no eye defects have been detected among silver individuals. The ocular defects could therefore be a founder effect. This is in line with the fact that part of the horses examined for ASD could be traced back to one founder animal [23].

The majority – if not all – of the Silver horses in the Icelandic horse breed have striped hooves during the first year of their lives (T. Kvick, pers. comm.). These observations are based on about 100 Silver colored foals and even more non-Silver foals of the Icelandic horse breed. The stripes are vertical and broader at the base, i.e. "triangular" (Figure 2B). It is tempting to speculate that the striped pattern could be associated with a particular color or pattern of the hair on the leg just above the striped hoof in these silver horses. In fact these horses are dappled on the legs right above the hoof (visible when shaving the hair) and this might be related to the stripes. The molecular mechanism for how different types of spatial pattern are formed in animals is largely unknown.

Mice

The silver (si) mutation in mice consists of a point mutation that leads to a premature stop codon and a truncated protein missing the last 25 amino acids [6], although it was first reported that the silver mutation in mice consists of a single base insertion that leads to a frameshift and an elongation of 12 residues of the protein [5]. The effect of the mutation results in premature graying of the hair due to loss of follicular melanocytes [14]. No eye defects have been reported for the mouse and chicken mutations.

In the mouse two different silver mutations have been described, of which the most widely referenced one leads to a premature stop codon and truncation of the protein so that the last 25 amino acids are missing [6]. This mutation also affects the cytoplasmic domain of the Pmel17 protein so that endoplasmatic reticulum (ER) export and endocytic signals are lost [20].

Chicken

In frame insertion/deletions in the same gene are associated with the Dominant white, Dun and Smoky coat colors in the chicken [7]. No eye defects have been reported for the mouse and chicken mutations.

Several different PMEL17 mutations associated with inhibition of black pigment have also been documented in the domestic chicken. In this species both insertion and deletion polymorphisms were associated with hypopigmentation [7]. However the exact role and importance of each mutation in diluting the pigment is not clear. Interestingly, the Dun allele in chicken carries both a 12 base pairs insertion and the same missense mutation as the horse.

Zebrafish

The zebrafish mutant fading vision (fdv) exhibit defects in vision and hypopigmentation and has a point mutation in PMEL17 leading to a truncated protein [8]. The merle patterning of the domestic dog is characterized by patches of diluted pigment and is caused by a retrotransposon insertion in the border of intron 10 and exon 11 of PMEL17 [9].

In the zebrafish mutant the hypopigmentation is seen in both the retinal pigment epithelium (RPE) and body melanocytes [8]. Also in this species the mutation leads to a truncation of the PMEL17 protein. This mutation results in a premature stop codon that is located within exon 8.

One still unanswered question is what the phenotype of a complete loss-of-function is in mammals? As the mutation in the zebrafish creates the most truncated version of the PMEL17 protein identified today, it can possibly shed some light on this question. This mutant is called fading vision and lacks the terminal 355 amino acid residues that encodes for one domain and two motives important for localization and function of PMEL17. These include the transmembrane domain, the proteolytic cleavage site and the AP3 binding motif [8]. The mutation seems to result in a total loss of function of the PMEL17 protein in zebrafish as it is shown that the mutation not only has an effect on melanosome biosynthesis, but also is important for normal vision development [8].

Dog

Dogs that carry the merle mutation suffer from both auditory and ophthalmologic abnormalities. Both the dog and the zebrafish mutants show pigmentation defects in both the coat and in retinal pigment epithelium (RPE). Both the dog and the zebrafish mutants show pigmentation defects in both the coat and in retinal pigment epithelium (RPE).

The PMEL17 mutations identified in other species have a more dramatic effect on the amino acid sequence (Figure 4). A short interspersed element (SINE) insertion at the boundary of intron 10 and exon 11 within the PMEL17 gene in dogs is associated with the merle coat color patterning [9]. It was also discovered that deletions within the oligo (dA)-rich tail of the SINE restored normal pigmentation in the dogs.

Human Waardenburg

These defects are similar to those of the human auditory-pigmentation disorder Waardenburg syndrome [9]. No mutations in human PMEL17 associated with variation in pigmentation have yet been described, but they are likely to exist. The predicted phenotype for such mutants could perhaps be red or blond hair color, fair skin and lightly colored eyes.

Quelle

• Emma Brunberg, Leif Andersson, Gus Cothran, Kaj Sandberg, Sofia Mikko und Gabriella Lindgren: A missense mutation in PMEL17 is associated with the Silver coat color in the horse. BMC Genet. 2006; 7: 46. Published online 2006 October 9. doi: 10.1186/1471-2156-7-46, [1] CC 2.0!

Silver dapple in Horses

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

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).

Silv in others

The silver gene was first identified in mouse, where it was shown to be involved in a recessive coat colour dilution that affects black pigment (Dunn and Thigpen, 1930). The human cDNA of the gene was called Pmel17 and has been shown to be expressed in melanocytes but not in non-pigmented cells (Kwon, 1991). The gene in human has been sequenced and mapped to human chromosome 12, the corresponding gene in mouse is situated on mouse chromosome 10 (Kwon, 1991). The human gene (SILV, OMIM: 155550) consists of 11 exons and is around 11.8 kb long (see Figure 1) (Bailin et al., 1996), in other mammals the gene is between 7.4 and 13.7 kb long and has between 11 and 13 exons (Ensembl). Researchers have sequenced and isolated Pmel homologues in rat (XP_343147), horse (AAC97108, Rieder et al. 2000), cow (XP_582778, Kim and Wistow, 1992) dog (XP_538223), chicken (AAT58245, Kerje et al, 2004), quail (AAS12180), Xenopus (AAH77508, AAH75473), zebrafish (AAT37511) and Tetraodon nigroviridis (CAG11762).

The gene product consists of one N-terminal signal sequence (Maresh, 1994), lumenal domain N-terminal region (NTR), polycystic kidney disease region (PKD) (Bycroft et al., 1999), one repeat domain (RPT) (Kwon et al 1991), cleavage site (CS) (Berson, 2003), kringle-like domain (KLD), Trans membrane spanning domain (TM) and a cytoplasmic domain (CYT) (see Figure 2). The most conserved regions are the cytoplasmic domain, polycystic kidney disease, kringle like domain and N-terminal signal sequence (Theos et al., 2005)

Humans

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).

Mice

Mice with the silver coat colour (si/si) have been shown to have nine nucleotide substitutions and one insertion compared with the wild type. The substitutions do not seem to be harmful to the function of the gene. The insertion is predicted to shift the reading frame and create a new termination codon in the cytoplasmic domain that extends the protein by 12 amino acids. This is therefore thought to be the mutation causing the silver coat colour in mice (Martinez-Esparza et al., 1999).

Chicken

In chicken, the homologue is called PMEL17 and causes different diluting colour variants. The colour variants are probably due to dominant insertions/deletions in rather well conserved regions of PMEL17, like the transmembrane region and cytoplasmic region. The different colour variants in chicken (dun, smoky and dominant white) also carry a large amount of other polymorphisms in the gene. All colour variations dilute the black pigment in different amounts (Kerje et al., 2004). It is also possible that mutations in PMEL17 in chicken can decide the pecking order (Keeling, 2004).

Dog, Merle

(haupt) In dog, the merle phenotype has recently been associated to SILV. The merle dogs have patches of diluted pigment and the colour is inherited in an autosomal dominant way. Dogs with this phenotype have a short interspersed element insertion in the border between intron 10/exon 11, which seems to be responsible for the lack of pigment, and also a number of deletions in the oligo(dA)-rich tail of the SINE . Many merle dogs have ocular abnormalities and auditory dysfunction. Individuals that are homozygote for the mutation also have problems with skeletal, cardiac and reproductive systems (Clark et al., 2006).

Qelle

• Emma Brunberg: Mapping of the silver coat colour locus in the horse, Institutionen för husdjursgenetik Sveriges Landbruksuniversitet, Uppsala, Sweden, 2006 http://ex-epsilon.slu.se/archive/00001232/

sonstige

• 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

• 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.

Si^si

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

dog, merle

(andere) 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.

• Leigh Anne Clark, Jacquelyn M. Wahl, Christine A. Rees und Keith E. Murphy: Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog, S. 1376–1381