Abstract
The albino mouse was already known in ancient times and was apparently selectively bred in Egypt, China, and Japan. Thus, it is not surprising that the c or albino locus (now the Tyr locus) was among the first used to demonstrate Mendelian inheritance in mammals at the dawn of the past century. This locus is now known to encode tyrosinase, the rate-limiting enzyme in the production of melanin pigment, and the molecular basis of the albino (Tyr c) mutation is known. Here we describe the congenic series of Tyr-locus alleles, from wild type to null (albino). We compare eye and skin pigmentation phenotypes and the genetic lesions that cause each. We suggest that this panel of congenic mutants contains rich, untapped resources for the study of many questions of basic cell biological interest.
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The albino mouse was already known in ancient times and, over a century ago, was used to first demonstrate Mendelian inheritance of a genetic trait in mammals (Castle and Allen 1903). Very early on it was suggested that the albino gene locus was responsible for a “factor” that is necessary for melanin pigment to form in the melanocytes. This “factor” has been identified as tyrosinase, the rate-limiting enzyme for melanogenesis (Coleman 1982). Tyrosinase is encoded at the albino (Tyr) locus of the mouse on Chromosome 7 (Kwon et al. 1989b), where multiple natural mutations and manmade mutations (Fig. 1) have helped to define the functions and interactions of this enzyme with other proteins that together effect normal pigmentation. In human, the defect in tyrosinase is called oculocutaneous albinism type 1 (OCA1) and is often specified as OCA1A or OCA1B to distinguish between no pigment or less pigment, respectively. The genetic defect in the tyrosinase gene affects the quantity of pigment produced within the melanosome; melanin is absent or reduced, but melanocytes are present in the skin and hair follicles and they contain melanosomes. In addition to effects on pigmentation, albino mice have defects in the visual projections at the optic chiasm (Jeffery et al. 1994), decreased numbers of rod photoreceptors (Donatien and Jeffery 2002; Rachel et al. 2002a), and spatiotemporal defects in neuronal production (Rachel et al. 2002a). Furthermore, a role for tyrosinase in the occurrence of glaucoma by a mechanism apparently unlinked to melanin production has recently been suggested (Libby et al. 2003).
Melanin pigment is produced primarily in two different cell types, the neural crest-derived melanocytes found in skin, hair follicle, and the choroid, ciliary body, and iris of the eye, and the retinal pigment epithelium, a cell layer of the retina that is derived from the optic cup. In the pigment cells, melanin is synthesized and deposited within endolysosome-like organelles, termed “melanosomes,” by a series of enzymatic reactions beginning with tyrosine as substrate, and involving the copper–glycoenzyme tyrosinase (Garcia–Borron and Solano 2002). The melanin product is deposited within the melanosome as eumelanic (brown or black) or pheomelanic (yellow/red) pigment. It had long been believed that the first two reactions in the melanogenic pathway—the hydroxylation of tyrosine to dopa (3,4-dihydroxyphenylalanine) and the oxidation of dopa to dopaquinone—are catalyzed by the enzyme tyrosinase (del Marmol and Beermann 1996). More recent chemical analyses have suggested, however, that tyrosinase-catalyzed oxidation of tyrosine leads directly to dopaquinone, which then can lead to eumelanin formation via spontaneous formation of dopachrome (Wakamatsu and Ito 2002). Accordingly, dopa itself can act as a cofactor in tyrosine oxidation and is not derived by tyrosinase enzyme activity, but indirectly by reduction of dopaquinone (Riley 1999). The pheomelanic pathway is thought to be initiated by a reaction between cysteine and dopaquinone, thus leading to cysteinyldopa, and further to benzothiazoles. Accordingly, the balance between pheomelanin and eumelanin may be determined by the availability of cysteine as precursor (Land and Riley 2000).
Besides tyrosinase, two other enzymes function in melanogenesis, dopachrome tautomerase (DCT) and tyrosinase-related protein 1 (TYRP1). DCT is encoded at the slaty (now Dct) locus of the mouse, and TYRP1 is encoded at the black/brown (now Tyrp1) locus. When all three of these enzymes function normally, eumelanin pigment is deposited within the melanosome (Fig. 2). Analysis of mice that are mutant at the Tyr or Tyrp1 locus has shown that mutation in one may affect the phenotype associated with the other. Accordingly, TYRP1 may affect stability of tyrosinase (Manga et al. 2000), and both proteins are transported together from the endoplasmic reticulum to the melanosome (Toyofuku et al. 2001). Mice lacking Tyrp1 [Tyrp1 deletions (Rinchik et al. 1994)] or Dct [Dct knockout (Guyonneau et al. 2004)] are only slightly affected in pigmentation and show a rather brown (Tyrp1 deficiency) or dark gray (Dct deficiency) coat color. Several other gene loci function within the melanosome and are necessary for normal pigmentation but have not been shown to be so intimately interactive with tyrosinase protein (Bennett and Lamoreux 2003). These loci include pink-eyed dilution (p, mutation causing OCA2 in human) (Chiu et al. 1993), underwhite (uw, now Matp, mutation causing OCA4 in human) (Newton et al. 2001; Costin et al. 2003), and MITF (Mitf) that modulates the expression of a number of melanocyte-specific genes, including Tyr and Tyrp1, at the transcriptional level and influences the eumelanin/pheomelanin switch (Goding 2000; Widlund and Fisher 2003).
Eumelanin (which is black or brown depending upon the genotype at the Tyrp1 locus) is produced in the melanosome as a result of the normal activity of the MSH (melanocyte stimulating hormone) receptor, which regulates levels of cyclic AMP (cAMP) within the cell and is present in melanocyte cell membranes (Fig. 2). The MSH receptor (MC1R) is encoded at the melanocortin-1 receptor (Mc1r) locus [formerly extension (e) locus] in the mouse and is responsive to the environment of the hair follicle in which the melanocyte resides. It is thus capable of switching from an active state that raises cAMP levels and results in the production of eumelanin within the melanosomes of the cell to an inactive state, when pheomelanin is produced (Barsh 2003). In the eumelanic state, elevated cAMP levels are followed by an increase in activity of tyrosinase, DCT, and TYRP1. In the pheomelanic state, the melanosomes produce yellow-colored melanin, cAMP levels are reduced, tyrosinase activity is lower, and DCT and TYRP1 activities are absent (Lamoreux et al. 1995). Mutation at Mc1r can result in melanocortin receptors that are not responsive to the environment and are constitutively active, resulting in production of only eumelanin, as in the sombre (Mc1r E-so) mutant, or constitutively inactive, resulting primarily in the production of pheomelanin as in the hair follicles of the yellow mutant (Mc1r e) mouse. Tyrosinase is required for both types of pigment, but activity is reduced in pheomelanic melanocytes. Wild-type MC1R is active unless blocked by the protein encoded at the agouti locus, thus switching pigment synthesis from the eumelanin pathway toward the pheomelanin pathway (Barsh 2003). Thus, mice that are yellow because of mutation at the agouti locus continue to produce the agouti-locus protein inappropriately and do not switch back and forth from the production of eumelanin to the production of pheomelanin as is normal in wild-type agouti mice. In addition, several other pigment loci encode proteins that interact with the Mc1r/agouti protein switch mechanism. These include mahogany (Atrn) and mahoganoid, both of which result in a reduction of pheomelanin, or rather an increase in eumelanin, in the hair coats of mutant mice (He et al. 2003). Interestingly, the Tyr-locus mutants (except for platinum) preferentially reduce the amount of pheomelanin compared with the reduction in eumelanin. Hence, the impact of Tyr-locus mutations is greater in pheomelanic mice than in eumelanic mice (Lamoreux and Pendergast 1987; Lamoreux et al. 2001) and also in pheomelanic locations on a mouse as for example the belly.
Availability of multiple mouse Tyr (albino) locus alleles with various sorts of genetic lesions provides an opportunity to evaluate the dynamic interactions in the processes that intervene between the transcription of the tyrosinase gene and the resulting phenotype of the animal. These include transcription, translation, post-translational processing, and transport mechanisms, as well as interactions with the products of other loci. Moreover, many other mutations causing albinism act via tyrosinase by affecting tyrosinase processing [e.g., pink-eyed dilution (Chen et al. 2002)] or tyrosinase trafficking [e.g., forms of Hermansky–Pudlak syndrome (Huizing et al. 2002)]. In this review, we report on the current state of knowledge regarding the molecular bases and phenotypic consequences of mutations at the mouse Tyr (albino) gene locus (Fig. 3, Table 1).
The allelic series
In the absence of mutations at other loci, mice that are wild type at the Tyr locus are fully pigmented and are black (Tyr+/Tyr+, a/a). Wild type is dominant to all other alleles at the locus, though one semidominant mutant (albino-strong, Tyr c-s) is reported at the JAX web site (http://www.informatics.jax.org/searches/mlc.cgi?14347). Mice that are lacking the Tyr locus as a result of overlapping deletions (Tyr c-6H/ Tyr c-14CoS) are unpigmented, although melanosomes are present, confirming the requirement of the Tyr locus and a functional tyrosinase for pigment production (Russell et al. 1982; Rinchik et al. 1993). Similarly, two natural mutations have been identified that result in an albino phenotype associated with lack of tyrosinase activity, Tyr c and Tyr c-2J. The classic mouse albino mutation, Tyr c, which is present in common albino mouse strains such as BALB/c or FVB, is characterized by the complete absence of pigmentation in both skin and eyes and by aberrant decussation of the optic nerve at the level of the chiasm (Guillery 1974; LaVail et al. 1978). Even though tissue homogenates of BALB/c mice might retain a slight amount of tyrosinase-dependent melanin synthesis in vitro (Hearing 1973), Tyr c is considered a null mutation since the mutated protein is not active in vivo and is retained in the ER (Halaban et al. 2000; Toyofuku et al. 2001). The molecular change in Tyr c is a G-to-C mutation at position +387, which results in the substitution of a cysteine for a serine residue at position 103 (Kwon et al. 1989b; Shibahara et al. 1990; Yokoyama et al. 1990). The Tyr c-2J mutation arose spontaneously in C57BL/6J mice, and homozygous Tyr c-2J/Tyr c-2J mice are phenotypically identical to Tyr c/Tyr c mice. The mutation was identified as a G-to-T change at position +309, resulting in an arginine-to-leucine substitution at codon 77 and furthermore led to increased alternative splicing within exon 1 (Lefur et al. 1996, 1997). Enzymatic activity of tyrosinase is absent in normal melanocytes of these mice, but melanomas occurring on this Tyr c-2J genetic background can be pigmented and are tyrosinase positive (Cohen–Solal et al. 2002), in contrast to melanomas appearing on BALB/c or FVB mice (Tyr c) (Cohen–Solal et al. 2001). Thus, it is conceivable that Tyr c-2J is not a true null mutation and is able to produce an unstable but enzymatically active protein in melanoma cells.
Tyr locus alleles that fall between the two extremes of black and albino can be classified into several groups by phenotype. First, there are alleles affecting ocular and cutaneous pigmentation similarly. The chinchilla allele was procured in 1922 by Feldman from a fancier (Feldman 1922). C57BL/6J–Tyr c-ch/Tyr c-ch (chinchilla) mice are phenotypically very similar to mice that are wild type at the Tyr locus, with black eyes and very dark gray, almost black, hair coat, though the tyrosinase activities of their skin or eyes is approximately one third that of wild-type mice. Moyer (1966) reported that melanosomes look normal in size and number, at least in the retina. In eumelanic brown (Tyrp1 b) mice, the effect of chinchilla is not evident, in either the intensity of pigmentation or reduced tyrosinase activity or change of melanosome structure (Russell 1948; Grüneberg 1952; Lamoreux et al. 2001). Interestingly, in pheomelanic chinchilla (Tyr c-ch/Tyr c-ch) mice, pigmentation is much reduced compared with that of pheomelanic mice that are wild type at the Tyr locus. This dichotomy is typical of the phenotypes of most of the Tyr-locus mutations (Silvers 1979; Lamoreux and Pendergast 1987), with the exception of platinum. Pheomelanic chinchilla melanocytes exhibit a greatly reduced number of melanosomes compared with normal pheomelanic melanocytes. Northern blot data and RT-PCR failed to reveal any difference in expression between Tyr c-ch and wild type (Halaban et al. 1988; Ganss et al. 1994), and it was suggested that chinchilla tyrosinase enzyme is less stable than the wild-type tyrosinase enzyme (Halaban et al. 1988). Sequence analysis of the entire coding region revealed a G-to-A point mutation at nucleotide +1523, resulting in an amino acid substitution of alanine to threonine at position +482, close to the transmembrane region (Beermann et al. 1990).
Platinum occurred as a spontaneous mutation in DBA/2 (Dickie 1966). Homozygous platinum (C57BL/6J–Tyr c-p/Tyr c-p) mice are very pale with pink eyes, yet their tyrosinase activity is higher than that of chinchilla mice (Tyr c-ch /Tyr c-ch). In skin extracts of platinum mice, a large proportion of tyrosinase is present in soluble form (Townsend et al. 1981). Furthermore, phenotypic differences in intensity of pigmentation between pheomelanic and eumelanic platinum mice are not evident, and both appear equally pale. These differences between platinum and chinchilla mice suggested that tyrosinase is functional in platinum mice, as the tyrosinase activities of skin and eyes are higher than those of chinchilla mice, which have lower tyrosinase activity but much more intense pigmentation. In addition, the effect of pheomelanogenesis on tyrosinase activity is sidestepped in the case of platinum mice. Analysis of the tyrosinase protein suggested a mutation at the carboxy terminal part of the protein (Orlow et al. 1993), and electron microscope studies demonstrated tyrosinase activity in the trans-Golgi network and in nearby vesicles, but missing activity in melanosomes (Beermann et al. 1995). Instead, tyrosinase was found at the cell surface. Since melanogenesis is confined essentially to the melanosome, it is thus reasonable not to detect major differences between pheo- and eumelanogenesis in this specific mutant allele. The mutation in platinum is a G-to-A change at +1523 (Beermann et al. 1995), inferring a replacement of a lysine residue in the cytoplasmic tail by a termination codon. The lack of the cytoplasmic tail, which contains the essential di-leucine sorting motif, is causing misrouting of platinum tyrosinase to the cell surface (Beermann et al. 1995; Simmen et al. 1999).
Second, there are alleles with more effect on coat pigmentation, e.g., extreme dilution (Tyr c-e). The original Tyr c-e-mutation was found in the wild (Detlefsen 1921). C57BL/6J mice that are homozygous at this locus can be characterized as “midgray” in phenotype, more or less midway in intensity between wild type and albino but with eyes that are nearer to black. Both tyrosinase activity and amount of eumelanin are greatly reduced in C57BL/6J–Tyr c-e/Tyr c-e mice; melanosomes of Tyr c-e/Tyr c-e are reduced in both number and size (Markert and Silvers 1956; Moyer 1966). Northern blot analysis of newborns’ skins (not shown) showed no reduction in abundance of tyrosinase mRNA in Tyr c-e/Tyr c-e mice that are eumelanic. Sequencing the complete coding region demonstrated a deviation from wild type in exon 5, leading to exchange of an alanine by a threonine, the very same mutation (A482T) that had been identified in the chinchilla (Tyr c-ch) mutation (Beermann et al. 1990). A482T is the only mutation found in the coding sequence of the chinchilla (Tyr c-ch) tyrosinase gene; it affects tyrosinase in vivo (Halaban et al. 1988) and following transfections (unpublished data). Therefore, it is rather unlikely that A482T is a polymorphism, with two unidentifed mutations still existing for both chinchilla and extreme dilution. It is more likely that the Tyr c-e mutation may have occurred on a Tyr c-ch background and might contain a yet unidentified second mutation, for example, in the regulatory region.
Himalayan is a spontaneous mutation which occurred in offspring of a cross between DBA/2 and AKR/J (Green 1961). Mice homozygous for the himalayan mutation (Tyr c-h), similar to himalayan cats or rabbits, over time develop more intense pigmentation at the extremities where the body is cooler. Their body color is beige, with darker-beige extremities, and eyes are dark ruby. The mutation is an A-to-G change at nucleotide 1338 that alters a histidine residue to an arginine residue at amino acid 420 (Kwon et al. 1989a). The activity of tyrosinase isolated from skins of Tyr c-h /Tyr c-h mice is heat labile (Coleman 1962), but the protein itself has been reported not to be heat-sensitive (Townsend et al. 1985), and it has been stated that the himalayan tyrosinase binds an inhibitor differentially at different temperatures (Kidson and Fabian 1981). A similar mutation in human (Giebel et al. 1991), which is located only two codons away, results in a thermosensitive protein upon transfection into HeLa cells. Thus, the himalayan (Tyr c-h /Tyr c-h) mouse would seem to be an excellent model for the condition in man and deserves further study to understand the cause of this thermosensitivity.
Acromelanic (Tyr c-a) is a spontaneous mutation which occurred on the C3H/HeJ strain (Sweet 1987). Acromelanic mice are beige in coat color (similar to himalayan) but have dark eyes and pigment appearing on tail, ears, and extremities. We sequenced the complete coding sequence, including about 270 bp upstream of the transcription start site, and no change to the wild-type tyrosinase sequence was detected. This result is in accordance with failure to detect protein and message on Western blots (not shown) and Northern blots (not shown). The message was nevertheless detectable by RT-PCR (not shown), thus suggesting a defect in transcriptional regulation or RNA stability. No major rearrangements were detected by Southern blot analysis covering about 15 kb of tyrosinase 5′ sequence (not shown). Since the mutation affects RNA levels, three unsequenced areas remain to be tested for the presence of mutation: (1) the enhancer region (Ganss et al. 1994; Porter and Meyer 1994), (2) the 3′ noncoding sequences which might be involved in tyrosinase regulation and mRNA stability (Takeuchi et al. 2000), and (3) the exon/intron boundaries, which might affect the correct splicing (Ruppert et al. 1988; Lefur et al. 1997). A defect in the enhancer region might explain the different effect in skin melanocytes versus RPE pigmentation by affecting regulation preferentially in either cell type (Porter et al. 1999; Camacho–Hübner and Beermann 2001). On the other hand, the choroidal layer, which equally consists of neural crest-derived melanocytes, is pigmented in acromelanic mice. Thus, it might rather be the steady accumulation of low levels of melanin within the RPE (and the choroidal layer) that makes the eye pigmented but keeps the skin and hair rather unpigmented. In addition, the presence of pigment at the extremities might point to a certain temperature-sensitive effect. How this is explained without an obvious mutation in the cDNA remains to be discovered.
In homozygous dark-eyed albino (Tyr c-44H) mice, overall pigment production is greatly reduced and is obvious only in the eyes (Cattanach and Rasberry 1988). Dark-eyed-albino mice are born white with ruby-colored eyes, which darken to become almost black by 3–4 months of age. The hair coat, by contrast, remains essentially unpigmented. Enzymatic activity of tyrosinase and melanin levels in the retina of Tyr c-44H /Tyr c-44H newborn mice reached levels of only 2.6% (tyrosinase activity) and 11.8% (melanin) of wild type (Rachel et al. 2002b). By Southern blot, Northern blot, and RT-PCR analyses, it was demonstrated that the basis of the phenotype resides in the coding sequences, with a point mutation (G-to-T) in exon 1, at position +515, inferring a substitution of the amino acid serine by isoleucine (position +146) (Schmidt and Beermann 1994).
Third, alleles exist that depict a mottled or variegated coat color (Tyr c-m, Tyr c-1R, Tyr c-em). Mice carrying the chinchilla-mottled mutation (Tyr c-m) were found in the offspring of a neutron-irradiated male (Phillips 1970), and Tyr c-1R arose spontaneously in 1988 in the Oak Ridge National Laboratory in a C3Hf/RI strain (Wu et al. 1997). Northern blot analyses and RT-PCR data showed that expression of tyrosinase is significantly diminished in homozygous Tyr c-1R mutant mice when compared with wild-type controls (Wu et al. 1997). Both Tyr c-m and Tyr c-1R cause a phenotype of mottled pigmentation resembling a chimerism of chinchilla color and a paler shade in homozygous mice. In Tyr c-m, which exhibit dark and light gray stripes on the coat, the mottled pigmentation is due to differential tyrosinase gene expression and changed chromatin structure of the Tyr gene locus in melanocytes within a stripe (Porter et al. 1991). This inherited mottling, as seen also in some tyrosinase-transgenic mice, results from the formation of phenotypically different but genetically identical developmental clones among cells of the same type (Bradl et al. 1991). Eyes of Tyr c-m /Tyr c-m mice appear dark, and older findings indicate that they are chimeric, with patches of darker and lighter pigmented cells (Deol and Truslove 1980). Molecular analysis of Tyr c-m /Tyr c-m DNA demonstrated a normal coding region but a major rearrangement involving 30 kb of 5′ upstream tyrosinase regulatory sequences, including the locus control region (Porter et al. 1991; Porter and Meyer 1994; Lavado Judez and Montoliu 2002). Molecular analysis of Tyr c-1R revealed insertion of a 5.4-kb intracisternal A particle (IAP) element at −225 bp upstream of the tyrosinase promoter (Wu et al. 1997). Thus, this IAP element isolates the promoter of the tyrosinase gene from the upstream tyrosinase locus control region, thereby either increasing the distance between this enhancer and the promoter or directly negatively affecting tyrosinase gene expression. The tyrosinase locus control region, which equally exists in human tyrosinase (Fryer et al. 2003; Regales et al. 2003), has recently been shown to have boundary activity, protecting the tyrosinase gene regulation from negative effects of neighboring chromatin (Giraldo et al. 2003). Thus, in the case of the mottled mutations, it is feasible that (1) the boundary activity cannot be exerted, (2) the new introduced sequences result in novel “negative” influences as hypermethylation, and (3) interaction of the enhancer sequences with promoter sequences such as the MITF binding site is affected. A third mottled mutation, extreme-dilution mottled (Tyr c-em), arose spontaneously in Harwell (UK) in breeding chinchilla mottled mice (Tyr c-m). Homozygotes for this allele possess black eyes and light gray fur that is variegated. The molecular basis of this mutation has been identified, on top of the rearrangements inherent in the mottled stock (Tyr c-m, see above), as a point mutation (C to T) in exon 3 of tyrosinase at position +1197 (+1220 according to the numbering of the authors), implying a substitution of the amino acid threonine by isoleucine (position +373) (Lavado Judez and Montoliu 2002).
Conclusion
We have reviewed and described alleles at the Tyr locus in the mouse and have added some new information. Most mice congenic with C57BL/6J should soon be available and thus offer a unique resource for the study of genic action and interactions. Regarding pigmentation of the albino series, it is striking that effects on eye and fur pigmentation seem to differ. This might be due to transfer of melanosomes from neural crest-derived melanocytes in skin and hair follicles, whereas they are retained in the retinal pigment epithelial cells and the choroidal melanocytes. This is exemplified by recent analyses on the Tyr c-44H (dark-eyed albino) allele, where tyrosinase activities in the retina of homozygotes at birth were much more reduced (2.6%) compared with the melanin levels (11.8% of wild type) (Rachel et al. 2002b). Alternatively, there might exist differences in tyrosinase gene expression between the two cell types. Initial experiments by Porter and Meyer (1994) had indicated that the enhancer region (dominant control region) of the mouse tyrosinase gene could be a candidate for such a differential regulation. The presence of the enhancer increased melanin deposition primarily in the neural crest cells (e.g., iris) but not to the same degree in cells of the retinal pigment epithelium (Porter and Meyer 1994). This observation was confirmed later using transgenic mice and transfection experiments (Porter et al. 1999; Camacho–Hübner and Beermann 2001), suggesting that there might be a differential regulation between optic cup-derived and neural crest-derived pigment cells.
Several of the mutants at the Tyr locus indirectly affect phenotypes associated with other loci. For example, brown (TYRP1) protein and tyrosinase protein interact rather closely to produce the pigment phenotype. A chinchilla mutant (Tyr c-ch) mouse that is black (Tyrp1+) exhibits a slight but visible reduction in pigment intensity. In contrast, the difference between a brown (Tyrp1 b) mouse and a brown chinchilla mutant (Tyrp1 b, Tyr c-ch) mouse is not obvious. It has been shown that tyrosinase-negative albinism, at least in some instances, is an ER-retention disease, with tyrosinase retained in the ER, which also affects localization of TYRP1 (Toyofuku et al. 2001). The availability of multiple alleles at this Tyr gene locus which is essential for pigmentation and retinal development but dispensable for survival, and which contains various genetic lesions, provides an opportunity to evaluate the dynamic interactions in the processes that intervene between the transcription of the tyrosinase gene and the resulting phenotype of the animal. This rich source of mutations has allowed and will allow studies to address various cellular mechanisms ranging from defects in transcriptional regulation to protein mislocalization and retinal development/organization.
References
G Barsh (2003) ArticleTitleWhat controls variation in human skin color? PLoS Biol 1 019–022 Occurrence Handle10.1371/journal.pbio.0000027 Occurrence Handle1:CAS:528:DC%2BD3sXotlWitr0%3D
F Beermann S Ruppert E Hummler FX, Müller G Bosch et al. (1990) ArticleTitleRescue of the albino phenotype by introduction of a functional tyrosinase gene into mice EMBO J 9 2819–2826 Occurrence Handle1:CAS:528:DyaK3cXlvVGrs74%3D Occurrence Handle2118105
F Beermann SJ Orlow RE Boissy A Schmidt YL Boissy et al. (1995) ArticleTitleMisrouting of tyrosinase with a truncated cytoplasmic tail as a result of the murine platinum (cp) mutation Exp Eye Res 61 599–607 Occurrence Handle1:CAS:528:DyaK2MXpt1OlsLg%3D Occurrence Handle8654502
D Bennett M Lamoreux (2003) ArticleTitleThe color loci of mice —a genetic century Pigment Cell Res 16 333–344 Occurrence Handle10.1034/j.1600-0749.2003.00067.x Occurrence Handle1:CAS:528:DC%2BD3sXntV2lt7k%3D Occurrence Handle12859616
NJ Bentley T Eisen CR Goding (1994) ArticleTitleMelanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator Mol Cell Biol 14 7996–8006 Occurrence Handle1:CAS:528:DyaK2MXisVWgt74%3D Occurrence Handle7969139
M Bradl L Larue B Mintz (1991) ArticleTitleClonal coat color variation due to a transforming gene expressed in melanocytes of transgenic mice Proc Natl Acad Sci USA 88 6447–6451 Occurrence Handle1:CAS:528:DyaK3MXlsFKisbk%3D Occurrence Handle1650469
A Camacho–Hübner F Beermann (2001) ArticleTitleIncreased transgene expresssion by the mouse tyrosinase enhancer is restricted to neural crest-derived pigment cells Genesis 29 180–187 Occurrence Handle10.1002/gene.1022 Occurrence Handle11309851
W Castle G Allen (1903) ArticleTitleThe heredity of albinism Proc Am Acad Arts Sci 38 603–621
B Cattanach C Rasberry (1988) ArticleTitleDark-eyed albinism Mouse News Lett 81 64
K Chen P Manga S Orlow (2002) ArticleTitlePink-eyed dilution protein controls the processing of tyrosinase Mol Biol Cell 13 1953–1964 Occurrence Handle10.1091/mbc.02-02-0022. Occurrence Handle1:CAS:528:DC%2BD38XltVWqtr8%3D Occurrence Handle12058062
E Chiu M Lamoreux S Orlow (1993) ArticleTitlePostnatal ocular expression of tyrosinase and related proteins: disruption by the Pink-eyed Unstable (pun) mutation Exp Eye Res 57 301–305 Occurrence Handle10.1006/exer.1993.1128 Occurrence Handle1:CAS:528:DyaK2cXlsFSr Occurrence Handle7901045
K Cohen–Solal K Reuhl K Ryan K Roberts S Chen (2001) ArticleTitleDevelopment of cutaneous amelanotic melanoma in the absence of a functional tyrosinase Pigment Cell Res 14 466–474
K Cohen–Solal S Crespo–Carbone J Namkoong K Mackason K Roberts et al. (2002) ArticleTitleProgressive appearance of pigmentation in amelanotic melanoma lesions Pigment Cell Res 15 282–289 Occurrence Handle10.1034/j.1600-0749.2002.02024.x Occurrence Handle1:CAS:528:DC%2BD38Xms1Sisr0%3D Occurrence Handle12100494
D Coleman (1962) ArticleTitleEffect of genic substitution on the incorporation of tyrosine into the melanin of the mouse skin Arch Biochem Biophys 96 562–568 Occurrence Handle1:CAS:528:DyaF38XktVKku7c%3D Occurrence Handle13880466
G Costin J Valencia W Vieira M Lamoreux V Hearing (2003) ArticleTitleTyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4 J Cell Sci 116 3203–3212 Occurrence Handle10.1242/jcs.00598 Occurrence Handle1:CAS:528:DC%2BD3sXmslKlt7w%3D Occurrence Handle12829739
V Marmol Particledel F Beermann (1996) ArticleTitleTyrosinase and related proteins in mammalian pigmentation FEBS Lett 381 165–168 Occurrence Handle10.1016/0014-5793(96)00109-3 Occurrence Handle8601447
M Deol G Truslove (1980) ArticleTitle Nonrandom distribution of unpigmented melanocytes in the retina of chinchilla-mottled mice and its significance Proc XIth Int Pigment Cell Conf, Sendai, Japan . 153–157
J Detlefsen (1921) ArticleTitleA new mutation in the house mouse Am Naturalist 55 469–473 Occurrence Handle10.1086/279832
M Dickie (1966) ArticleTitlePlatinum Mouse News Lett 34 30
P Donatien G Jeffery (2002) ArticleTitleCorrelation between rod photoreceptor numbers and levels of ocular pigmentation Invest Ophthalmol Vis Sci 43 1198–1203 Occurrence Handle11923266
H Feldman (1922) ArticleTitleA fourth allelomorph in the albino series of mice Am Naturalist 56 573–574 Occurrence Handle10.1086/279899
J Fryer W Oetting R King (2003) ArticleTitleIdentification and characterization of a DNase hypersensitive region of the human tyrosinase gene Pigment Cell Res 16 679–684 Occurrence Handle10.1046/j.1600-0749.2003.00099.x Occurrence Handle1:CAS:528:DC%2BD3sXhtVWjs7bN Occurrence Handle14629726
R Ganss L Montoliu A Monaghan G Schütz (1994) ArticleTitleA cell-specific enhancer far upstream of the mouse tyrosinase gene confers high level and copy number-related expression in transgenic mice EMBO J 13 3083–3093 Occurrence Handle1:CAS:528:DyaK2cXlsFShsb0%3D Occurrence Handle8039502
J Garcia–Borron F Solano (2002) ArticleTitleMolecular anatomy of tyrosinase and its related proteins: beyond the histidine-bound metal catalytic center Pigment Cell Res 15 162–173 Occurrence Handle10.1034/j.1600-0749.2002.02012.x Occurrence Handle1:CAS:528:DC%2BD38XltFSmsro%3D Occurrence Handle12028580
LB Giebel RK Tripathi RA King RA Spritz (1991) ArticleTitleA tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse J Clin Invest 87 1119–1122 Occurrence Handle1:CAS:528:DyaK3MXhsFygt7w%3D Occurrence Handle1900309
P Giraldo A Martinez L Regales A Lavado A Garcia–Diaz et al. (2003) ArticleTitleFunctional dissection of the mouse tyrosinase locus control region identifies a new putative boundary activity Nucleic Acids Res 31 6290–6305 Occurrence Handle10.1093/nar/gkg793 Occurrence Handle1:CAS:528:DC%2BD3sXos1anu74%3D Occurrence Handle14576318
C Goding (2000) ArticleTitleMitf from neural crest to melanoma: signal transduction and transcription in the melanocyte lineage Genes Dev 14 1712–1728 Occurrence Handle1:CAS:528:DC%2BD3cXltFCrurw%3D Occurrence Handle10898786
M Green (1961) ArticleTitleHimalayan, a new allele of albino in the mouse J Hered 52 73–75
H Grüneberg (1952) Genetics of the Mouse Nijhoff The Hague
R Guillery (1974) ArticleTitleVisual pathways in albinos Sci Am 230 44–54 Occurrence Handle1:STN:280:CSuC2crgt1c%3D Occurrence Handle4822986
L Guyonneau F Murisier A Rossier A Moulin F Beermann (2004) ArticleTitleMelanocytes and pigmentation are affected in Dopachrome tautomerase knockout mice Mol Cell Biol 24 3396–3403 Occurrence Handle10.1128/MCB.24.8.3396-3403.2004 Occurrence Handle1:CAS:528:DC%2BD2cXjtFKjt7g%3D Occurrence Handle15060160
R Halaban G Moellmann A Tamura B Kwon E Kuklinska et al. (1988) ArticleTitleTyrosinases of murine melanocytes with mutations at the albino locus Proc Natl Acad Sci USA 85 7241–7245 Occurrence Handle1:CAS:528:DyaL1cXmt1Ogurw%3D Occurrence Handle3140237
R Halaban S Svedine E Cheng Y Smicun R Aron et al. (2000) ArticleTitleEndoplasmic reticulum retention is a common defect associated with tyrosinase-negative albinism Proc Natl Acad Sci USA 97 5889–5894 Occurrence Handle10.1073/pnas.97.11.5889 Occurrence Handle1:CAS:528:DC%2BD3cXjvFaktbg%3D Occurrence Handle10823941
L He A Eldridge P Jackson T Gunn G Barsh (2003) ArticleTitleAccessory proteins for melanocortin signaling: attractin and mahogunin Ann NY Acad Sci 994 288–298 Occurrence Handle1:CAS:528:DC%2BD3sXmtVCktLY%3D Occurrence Handle12851328
V Hearing (1973) ArticleTitleTyrosinase activity in subcellular fractions of black and albino mice Nat New Biol 245 81–83 Occurrence Handle1:CAS:528:DyaE2cXhtFOltw%3D%3D Occurrence Handle4199613
M Huizing R Boissy W Gahl (2000) ArticleTitleHermansky–Pudlak syndrome: vesicle formation from yeast to man Pigment Cell Res 15 405–419 Occurrence Handle10.1034/j.1600-0749.2002.02074.x
G Jeffery G Schütz L Montoliu (1994) ArticleTitleCorrection of abnormal retinal pathways found with albinism by introduction of a functional tyrosinase gene in transgenic mice Dev Biol 166 460–464 Occurrence Handle10.1006/dbio.1994.1329 Occurrence Handle1:CAS:528:DyaK2MXjtVWkt7Y%3D Occurrence Handle7813769
S Kidson B Fabian (1981) ArticleTitleThe effect of temperature on tyrosinase activity in himalayan mouse skin J Exp Zool 215 91–97 Occurrence Handle1:CAS:528:DyaL3MXhtlGjs7s%3D Occurrence Handle6785376
B Kwon R Halaban C Chintamaneni (1989a) ArticleTitleMolecular basis of mouse himalayan mutation Biochem Biophys Res Commun 161 252–260 Occurrence Handle1:CAS:528:DyaK3cXhtlentrs%3D
B Kwon A Haq M Wakulchik D Kestler D Barton et al. (1989b) ArticleTitleIsolation, chromosomal mapping and expression of the mouse tyrosinase gene J Invest Dermatol 93 589–594 Occurrence Handle10.1111/1523-1747.ep12319693 Occurrence Handle1:CAS:528:DyaK3cXhsl2m
M Lamoreux P Pendergast (1987) ArticleTitleGenetic controls over melanocyte differentiation: interaction of agouti-locus and albino-locus genetic defects J Exp Zool 243 71–79 Occurrence Handle1:CAS:528:DyaL2sXlsFWrtrk%3D Occurrence Handle2886546
M Lamoreux B Zhou S Rosemblat S Orlow (1995) ArticleTitleThe pinkeyed-dilution protein and the eumelanin/pheomelanin switch: in support of a unifying hypothesis Pigment Cell Res 8 263–270 Occurrence Handle1:CAS:528:DyaK28XhtVKqurY%3D Occurrence Handle8789201
M Lamoreux K Wakamatsu S Ito (2001) ArticleTitleInteraction of major coat color gene functions in mice as studied by chemical analysis of eumelanin and pheomelanin Pigment Cell Res 14 23–31 Occurrence Handle10.1034/j.1600-0749.2001.140105.x Occurrence Handle1:CAS:528:DC%2BD3MXisVCit7k%3D Occurrence Handle11277491
E Land P Riley (2000) ArticleTitleSpontaneous redox reactions of dopaquinone and the balance between the eumelanic and phaeomelanic pathway Pigment Cell Res 13 273–277 Occurrence Handle10.1034/j.1600-0749.2000.130409.x Occurrence Handle1:CAS:528:DC%2BD3cXmtFOgtL4%3D Occurrence Handle10952395
A Lavado Judez L Montoliu (2002) ArticleTitleHistological, enzymatic and molecular analysis of chinchilla-mottled (Tyrc-m) and extreme dilution mottled (Tyrc-em) mouse mutant tyrosinase alleles Pigment Cell Res 15 IssueID Suppl 9 63
J La Vail R Nixon R Sidman (1978) ArticleTitleGenetic control of retinal ganglion cell projections J Comp Neurol 182 399–421 Occurrence Handle1:STN:280:CSaD28fgslQ%3D Occurrence Handle102659
N Lefur SR Kelsall B Mintz (1996) ArticleTitleBase substitution at different alternative splice donor sites of the tyrosinase gene in murine albinism Genomics 37 245–248 Occurrence Handle10.1006/geno.1996.0551 Occurrence Handle1:CAS:528:DyaK28XmsFGntb8%3D Occurrence Handle8921397
N Lefur SR Kelsall WK Silvers B Mintz (1997) ArticleTitleSelective increase in specific alternative splice variants of tyrosinase in murine melanomas — a projected basis for immunotherapy Proc Natl Acad Sci USA 94 5332–5337 Occurrence Handle10.1073/pnas.94.10.5332 Occurrence Handle1:CAS:528:DyaK2sXjtleltbg%3D Occurrence Handle9144237
R Libby R Smith O Savinova A Zabaleta J Martin et al. (2003) ArticleTitleModification of ocular defects in mouse developmental glaucoma models by tyrosinase Science 299 1578–1581 Occurrence Handle10.1126/science.1080095 Occurrence Handle1:CAS:528:DC%2BD3sXhs1yiu7w%3D Occurrence Handle12624268
P Manga K Sato L Ye F Beermann M Lamoreux et al. (2000) ArticleTitleMutational analysis of the modulation of tyrosinase by tyrosinase-related proteins 1 and 2 in vitro Pigment Cell Res 13 364–374 Occurrence Handle10.1034/j.1600-0749.2000.130510.x Occurrence Handle1:CAS:528:DC%2BD3cXnsVegtb8%3D Occurrence Handle11041214
C Markert W Silvers (1956) ArticleTitleThe effects of genotype and cell environment on melanoblast differentiation in the house mouse Genetics 41 429–450
F Moyer (1966) ArticleTitleGenetic variations in the fine structure and ontogeny of mouse melanin granules Am Zool 6 43–66 Occurrence Handle1:STN:280:CCmD2svitlc%3D Occurrence Handle5902512
J Newton O Cohen–Barak N Hagiwara J Gardner M Davisson et al. (2001) ArticleTitleMutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4 Am J Hum Genet 69 981–988
SJ Orlow RE Boissy DJ Moran S Pifko–Hirst (1993) ArticleTitleSubcellular distribution of tyrosinase and tyrosinase-related protein-1: implications for melanosomal biogenesis J Invest Dermatol 100 55–64 Occurrence Handle10.1111/1523-1747.ep12354138 Occurrence Handle1:CAS:528:DyaK3sXpvVKrsw%3D%3D Occurrence Handle8423398
R Phillips (1970) ArticleTitleChinchilla-mottled Mouse News Lett 42 26
SD Porter CJ Meyer (1994) ArticleTitleA distal tyrosinase upstream element stimulates gene expression in neural-crest-derived melanocytes of transgenic mice: position-independent and mosaic expression Development 120 2103–2111 Occurrence Handle1:CAS:528:DyaK2cXmvFChtbk%3D Occurrence Handle7925014
S Porter L Larue B Mintz (1991) ArticleTitleMosaicism of tyrosinase-locus transcription and chromatin structure in dark vs. light melanocyte clones of homozygous chinchilla-mottled mice Dev Genet 12 393–402 Occurrence Handle1:CAS:528:DyaK38Xks1CitL0%3D Occurrence Handle1822431
S Porter J Hu C Gilks (1999) ArticleTitleDistal upstream tyrosinase S/MAR-containing sequence has regulatory properties specific to subsets of melanocytes Dev Genet 25 40–48 Occurrence Handle10.1002/(SICI)1520-6408(1999)25:1<40::AID-DVG5>3.0.CO;2-L Occurrence Handle1:CAS:528:DyaK1MXkslyqt7s%3D Occurrence Handle10402671
R Rachel G Dolen N Hayes A Lu L Erskine et al. (2002a) ArticleTitleSpatiotemporal features of early neurogenesis differ in wild-type and albino mouse retina J Neurosci 22 4249–4263 Occurrence Handle1:CAS:528:DC%2BD38XksFWgtL8%3D
R Rachel C Mason F Beermann (2002b) ArticleTitleInfluence of tyrosinase levels on pigment accumulation in the retinal pigment epithelium and on the uncrossed retinal projection Pigment Cell Res 15 273–281 Occurrence Handle10.1034/j.1600-0749.2002.02019.x Occurrence Handle1:CAS:528:DC%2BD38Xms1Sisrw%3D
L Regales P Giraldo A Garcia–Diaz A Lavado L Montoliu (2003) ArticleTitleIdentification and functional validation of a 5′ upstream regulatory sequence in the human tyrosinase gene homologous to the locus control region of the mouse tyrosinase gene Pigment Cell Res 16 685–692 Occurrence Handle10.1046/j.1600-0749.2003.00100.x Occurrence Handle1:CAS:528:DC%2BD3sXhtVWjs7bO Occurrence Handle14629727
PA Riley (1999) ArticleTitleThe great DOPA mystery: The source and significance of DOPA in phase I melanogenesis Cell Mol Biol 45 951–960 Occurrence Handle1:CAS:528:DC%2BD3cXmtF2ruw%3D%3D
EM Rinchik JP Stoye WN Frankel J Coffin BS Kwon et al. (1993) ArticleTitleMolecular analysis of viable spontaneous and radiation-induced albino (c)-locus mutations in the mouse Mutat Res 286 199–207 Occurrence Handle1:CAS:528:DyaK3sXitVymtbw%3D Occurrence Handle7681531
E Rinchik J Bell P Hunsicker J Friedman I Jackson et al. (1994) ArticleTitleMolecular genetics of the brown (b)-locus region of mouse chromosome 4. I. Origin and molecular mapping of radiation-and chemical-induced lethal brown deletions Genetics 137 845–854 Occurrence Handle1:CAS:528:DyaK2MXjsFSquw%3D%3D Occurrence Handle7916309
S Ruppert G Müller B Kwon G Schütz (1988) ArticleTitleMultiple transcripts of the mouse tyrosinase gene are generated by alternative splicing EMBO J 7 2715–2722 Occurrence Handle1:CAS:528:DyaL1cXlsVersbk%3D Occurrence Handle2846281
E Russell (1948) ArticleTitleA quantitative histological study of the pigment found in the coat color mutants of the house mouse. 2. Estimates of the total volume of pigment Genetics 33 228–236
L Russell C Montgomery G Raymer (1982) ArticleTitleAnalysis of the albino-locus region of the mouse: IV. Characterization of 34 deficiencies Genetics 100 427–453 Occurrence Handle1:STN:280:BiyD3cvptVU%3D Occurrence Handle7117820
A Schmidt F Beermann (1994) ArticleTitleMolecular basis of dark-eyed albinism in the mouse Proc Natl Acad Sci USA 91 4756–4760 Occurrence Handle1:CAS:528:DyaK2cXktlanu7g%3D Occurrence Handle8197131
S Shibahara S Okinaga Y Tomita A Takeda H Yamamoto et al. (1990) ArticleTitleA point mutation in the tyrosinase gene of BALB/c albino mouse causing the cysteine–serine substitution at position 85 Eur J Biochem 189 455–461 Occurrence Handle1:CAS:528:DyaK3cXitFWrs7k%3D Occurrence Handle2110899
WK Silvers (1979) The coat colors of mice—a model for mammalian gene action and interaction Springer New York
T Simmen A Schmidt W Hunziker F Beermann (1999) ArticleTitleThe tyrosinase tail mediates sorting to the lysosomal compartment in MDCK cells via a di-leucine and a tyrosine-based signal J Cell Sci 112 45–53 Occurrence Handle1:CAS:528:DyaK1MXpvFOrsw%3D%3D Occurrence Handle9841903
H Sweet (1987) ArticleTitleAcromelanic (c a) Mouse News Lett 78 56
S Takeuchi T Takeuchi H Yamamoto (2000) ArticleTitleA possible mechanism for feedback regulation of the mouse tyrosinase gene by its 3′ non-coding RNA fragments Pigment Cell Res 13 109–115 Occurrence Handle10.1034/j.1600-0749.2000.130209.x Occurrence Handle1:CAS:528:DC%2BD3cXktVOrurs%3D Occurrence Handle10841032
D Townsend CJ Witkop J Mattson (1981) ArticleTitleTyrosinase subcellular distribution and kinetic parameters in wild type and C-locus mutant C57BL/6J mice J Exp Zool 216 113–119 Occurrence Handle1:CAS:528:DyaL3MXhvV2nsrs%3D Occurrence Handle6793688
D Townsend P Guillery R King (1985) Himalayan tyrosinase does not demonstrate temperature sensitivity J Bagnara S Klaus E Paul M. Schartel (Eds) Biological, Molecular and Clinical Aspects of Pigmentation University of Tokyo Press Tokyo
K Toyofuku I Wada J Valencia T Kushimoto V Ferrans et al. (2001) ArticleTitleOculocutaneous albinism types 1 and 3 are ER retention diseases: mutation of tyrosinase or Tyrp1 can affect the processing of both mutant and wild-type proteins FASEB J 15 2149–2161 Occurrence Handle10.1096/fj.01-0216com Occurrence Handle1:CAS:528:DC%2BD3MXnsV2msbk%3D Occurrence Handle11641241
K Wakamatsu S Ito (2002) ArticleTitleAdvanced chemical methods in melanin determination Pigment Cell Res 15 174–183 Occurrence Handle10.1034/j.1600-0749.2002.02017.x Occurrence Handle1:CAS:528:DC%2BD38XltFSmsrs%3D Occurrence Handle12028581
H Widlund D Fisher (2003) ArticleTitleMicrophthalmia-associated transcription factor: a critical regulator of pigment cell development and survival Oncogene 22 3035–3041 Occurrence Handle10.1038/sj.onc.1206443 Occurrence Handle1:CAS:528:DC%2BD3sXkt12qtbo%3D Occurrence Handle12789278
M Wu EM Rinchik E Wilkinson DK Johnson (1997) ArticleTitleInherited somatic mosaicism caused by an intracisternal particle insertion in the mouse tyrosinase gene Proc Natl Acad Sci USA 94 890–894 Occurrence Handle10.1073/pnas.94.3.890 Occurrence Handle1:CAS:528:DyaK2sXhtVOksrY%3D Occurrence Handle9023352
T Yokoyama DW Silversides KG Waymire BS Kwon T Takeuchi et al. (1990) ArticleTitleConserved cysteine to serine mutation in tyrosinase is responsible for the classical albino mutation in laboratory mice Nucleic Acids Res 18 7293–7298 Occurrence Handle1:CAS:528:DyaK3MXls1OksQ%3D%3D Occurrence Handle2124349
Acknowledgments
Thanks are due to Andrea Schmidt for help with the DNA and RNA analyses of Tyr c-e and Tyr c-a mutant mice. Work in the laboratory of FB was supported by grants from the Swiss Cancer League, by grant 3100-066796.01 from the Swiss National Science Foundation, and by the National Center of Competence in Research (NCCR) Molecular Oncology, a research instrument of the Swiss National Science Foundation, and in the laboratory of SJO by PHS grants EY10223 and AR41880.
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Beermann, F., Orlow, S.J. & Lamoreux, M.L. The Tyr (albino) locus of the laboratory mouse. Mamm Genome 15, 749–758 (2004). https://doi.org/10.1007/s00335-004-4002-8
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DOI: https://doi.org/10.1007/s00335-004-4002-8