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|Coordinate||80,840,778 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||tyrosinase-related protein 1|
|Synonym(s)||Tyrp, isa, Oca3, TRP1, TRP-1|
|Chromosomal Location||80,834,123-80,851,719 bp (+)|
|MGI Phenotype||The major influence of mutations at this locus is to change eumelanin from a black to a brown pigment in the coat and eyes. Alleles differ in the distribution of brown pigment granules and therefore differ in color intensity.|
|Amino Acid Change||Tyrosine changed to Cysteine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted sequence gene model|
AA Change: Y296C
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||pigmentation, skin/coat/nails|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Live Mice|
|Last Updated||12/07/2016 11:52 AM by Anne Murray|
|Record Created||05/01/2013 8:28 AM by Adam Dismang|
The chi mutation was induced by ENU mutagenesis on the C57BL/6J (black) background and was discovered in G3 animals. The mutant mice exhibit a brown coat color and black eyes (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 63 mutations. Among these, only one affected a gene with known effects on pigmentation, Tyrp1. The mutation in Tyrp1 was presumed to be causative because the chi hypopigmentation phenotype mimics other known alleles of Tyrp1 (see MGI for a list of Tyrp1 alleles). The Tyrp1 mutation was identified as an A to G transition at base pair 80840778 (v38) on chromosome 4 in the GenBank genomic region NC_000070 encoding Tyrp1. The mutation corresponds to residue 1159 in the mRNA sequence (NM_031202.2) in exon 4 of 8 total exons.
The mutated nucleotide is indicated in red. The mutation results in a conversion of tyrosine (Y) to cysteine (C) at residue 296 of the tyrosinase-related protein 1 (Tyrp1).
The tyrosinase-related protein (TRP) family consists of Tyrp1 (Trp1, gp75), tyrosinase (Tyr; see the records for ghost, pale rider, and siamese), and Tyrp2 [alternatively, DOPAchrome tautomerase (DCT)]. Tyrp1 shares ~40-52% amino acid sequence homology with Tyr [reviewed in (1;2)]. The TRP proteins share homologous domains including two copper binding regions, an EGF-like/cysteine (Cys)-rich domain, a central cysteine-rich region, a transmembrane domain, a signal sequence and six putative glycosylation sites [Figure 2; (3-7); reviewed in (1;2;8;9)]:
Studies have determined that mature Tyrp1 can exist both as an intracellular form (75-80 kDa) and a secreted form (78-88 kDa) [(25); reviewed in (1;8)]. Intracellular Tyrp1 has the N-terminal signal peptide, a long N-terminal luminal domain with the N-linked glycosylation sites, a transmembrane region, and the C-terminal domain (25). In contrast, soluble Tyrp1 lacks the transmembrane domain, the C-terminal tail, and a small region in the luminal domain (25).
The chi mutation resides within the catalytic domain of Tyrp1, a domain that contains the copper-binding motifs and one of the EGF-like domains. A mutation within the catalytic domain could alter the association of Tyrp1 to Tyr and/or the DHICA oxidase function of Tyrp1.
TGF-β1 inhibits the activity of Tyrp1
Transforming growth factor (TGF)-β1 is a multifunctional cytokine that regulates several processes, including proliferation, differentiation, adhesion, and migration, in many cell types [reviewed in (26;27)]. TGF-β1 negatively regulates the activities of both Tyrp1 and Tyr in mouse melanoma cells by reducing their abundance; Tyrp2 activity is not changed (28). Martinez-Esparza et al. propose that the TGF-β1-mediated changes to the Tyrp1 protein level are due to post-translational events (28). Other factors that regulate the expression of Tyrp1 are described in "Expression/Localization", below.
Tyrp1 is localized in melanosomes of the skin, hair follicle, inner ear, choroid, iris, and ciliary body as well as in the retinal pigment epithelium (RPE) [reviewed in (29)]. For more information on the localization of Tyrp1, please see “Transport of Typr1 in the melanosome” in the Background section, below.
The first exon of Tyrp1 is noncoding and, along with the first intron, is required for efficient gene expression, but not for pigment cell specificity [(30); reviewed in (1;29)]. The TRP proteins can be regulated by several stimuli including vitamins, interleukins (31), prostaglandins (32), sex steroids (33), interferons (34), ultraviolet light (35), and melanocyte stimulating hormone (36).
The TRP proteins all contain an M-box motif (AGTCATGTGCT) upstream of the TATA box (between positions -44 and -34) in their respective promoters that can bind to microphthalmia transcription factor (MITF), a basic helix-loop-helix transcription factor [(37-41); reviewed in (8;9;29)]. Binding of MITF to the Tyrp1 promoter increased Tyrp1 promoter activity (37). cAMP (cyclic AMP) facilitates the upregulation of MITF and the subsequent association of MITF with Tyrp1 (37). cAMP-elevating agents stimulated the transcriptional activity of the Tyrp1 promoter, subsequently leading to an increase in Tyrp1 mRNA; the protein levels were also increased (37). Bertolotto et al. determined that the cAMP-elevating agents stimulated the transcription of Tyrp1 via the cAMP-dependent protein kinase (PKA) pathway (37).
T-box factor Tbx2 by binds to two elements, MSEu and MSEi, to negatively regulate Tyrp1 expression (42;43). The MSE elements are comprised of a six nucleotide sequence, GTGTGA. Pax3, a member of the paired box (PAX) family of transcription factors, also binds the Tyrp1 promoter at the MSE elements, subsequently upregulating Tyrp1 activity in melanocytes (40).
Promoter analysis determined that Tyrp1 expression is regulated by different factors in melanocytes of the skin, hair follicle, inner ear, choroid, iris, and ciliary body versus the RPE (41). For example, the homeobox factor, Otx2, controls RPE-specific expression of Tyrp1 (44). Murisier et al. identified a highly conserved region at -15 kb that acts as a melanocyte-specific enhancer of Tyrp1 expression; the transcription factor Sox10 binds and transactivates this enhancer (41).
The production of melanin in the skin, hair follicle, inner ear, choroid, iris, ciliary body, and RPE results in pigmentation [reviewed in (29)]. Tyr, Tyrp1, and Tyrp2 are Cu++/Zn++ metalloenzymes that function in melanogenesis leading to the formation of two types of pigments, eumelanins (brown or black) and pheomelanins (yellow or red) [Figure 3; reviewed in (4;8;13;45)]. The pigments are synthesized in melanosomes, which arise from the endosomal or secretory pathway and progress through four stages of maturation (I-IV), as defined by their electron microscopic appearance (46). Melanin synthesis begins with the chemical conversion of tyrosine to dopaquinone, a reaction catalyzed by Tyr. Both eumelanin and pheomelanin derive from dopaquinone, thus Tyr determines the rate and total amount of melanin production. Pheomelanin production proceeds spontaneously following dopaquinone production, while eumelanin production further requires Tyrp1 and Tyrp2 [reviewed in (46;47)]. Tyrp2 catalyzes the non-decarboxylative rearrangement of L-dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA); the function of Tyrp1 is described below (48). For more information about melanogenesis, please see the record for ghost.
Several enzymatic activities have been attributed to murine Tyrp1: tyrosine hydroxylase and DOPA oxidase activities (49-51), DOPAchrome tautomerase function (along with Tyrp2) (52), DHICA oxidase activity (53;54), and catalase activity (hydrogen-peroxide:hydrogen-peroxide oxidoreduction) (55). The primary function attributed to Tyrp1 is that of a DHICA oxidase (53;54), catalyzing the oxidation of DHICA to indole-5,6-quinone-2-carboxylic acid, a product eventually converted to eumelanin (54). The role of TYRP1 in human melanocytes, in contrast, is currently unclear (17). For example, Boissy et al. found that human TYRP1 did not have DHICA oxidase activity (56). In addition, Zhao et al. determined that human TYRP1 did not exhibit DOPA oxidase activity; TYRP1 exhibited tyrosine hydrolase activity in this study (51).
Transport of Tyrp1 in the melanosome
Tyrp1 is synthesized in the ER, transported to the Golgi where it undergoes post-translational processing, then from the trans-Golgi network (TGN) to an endosomal compartment [Figure 4; (57-60)]. Early endosomes are requisite intermediates in the trafficking of Tyrp1 from the Golgi to the late stage melanosomes (61). Within the endosomal intermediate, Tyrp1 is sorted away from both late endocytic and pre-melanosomal cargoes (61). Tyrp1 associates with several proteins that are essential for proper trafficking of Tyrp1 to melanosomes including Rab7, Rab38, Rab32, ESCRT-I, Varp (VPS9-ankyrin-repeat protein), syntaxin-3, PI3-kinase, BLOC (biogenesis of lysosome-related organelles complex)-1, BLOC-2, and AP-1 [Table 1; (58;59;62-65)]. Whereas the dileucine motif of tyrosinase interacts with the adaptor complex AP-3 (see the record for bullet gray), studies have shown that AP-3 does not interact with Tyrp1 (66-68). In AP-3 deficient melanocytes, tyrosinase is mislocalized, but Tyrp1 is properly targeted (66;67).
Table 1. Essential proteins for Tyrp1 trafficking
TYRP1 mutations cause hypopigmentation
Mutations in TYRP1 are linked to oculocuaneous albinism type III [OCA3; OMIM: # 203290; (76;77)] and variations in skin/hair/eye pigmentation linked to 9p23 in Melanesians [OMIM: # 612271; (78)]. Individuals with OCA3 have reduced pigment of the skin, hair, and eyes (76). Melanocytes isolated from a patient with OCA3 did not express TYRP1, subsequently resulting in reduced melanin production; TYR transcription and translation were normal (76). Tyrp1 mutations have also been linked to pigmentation changes in domestic cats (79;80), dogs (81;82), cattle (83), horses (84), and mice (see “Putative Mechanism”, below).
Additional functions of Tyrp1
In addition to its role in melanogenesis, Tyrp1 also promotes melanocyte viability/survival (15;85-87), protects melanocytes against oxidative stress (88), and is a melanocyte differentiation marker (8;89).
Tyrp1 functions to protect melanocytes from the cytotoxicity of melanin intermediates produced by Tyr; Tyrp1 does not protect against Tyr-mediated cell death in nonmelanocytic cells (15;90). Through the formation of the Tyr-Tyrp1-Tyrp2 complex in melanocytes, the leakage of toxic melanin intermediates is decreased [see “Protein Prediction”, above, for information about the Tyr-Tyrp1-Tyrp2 complex] (12;14;16). Luo et al. propose that Tyrp1 participates in scavenging cytotoxic melanin intermediates via an interaction with Lamp1 (87).
Loss of TYRP1 expression in cutaneous neoplastic melanocytes is linked to the appearance of transformed melanocytes in the underlying dermis (39;91). TYRP1 mRNA and protein expression are reduced in several melanoma cell lines and specimens due to decreased expression of MITF (39;91-93). In TYRP1-melanoma cells, binding of MITF to the TYRP1 M box is inhibited due to activation of factors that interfere with binding (39). Gene profiling in skin and lymph nodes (i.e., the most frequent sites of melanoma metastases) revealed an inverse correlation between the level of TYRP1 expression and patient survival (94).
To-date 58 mouse Tyrp1 mutant alleles have been documented (MGI). Homozygous Tyrp1 mutants [e.g., brown, MGI:1855960; cordovan, MGI: 1855961; light, MGI:1855962; white-based brown, MGI: 1855963] exhibit a brown coat color on a non-agouti background [reviewed in (29)]. The brown mutation (Cys86Tyr) is within the EGF-like/Cys-rich domain and results in a mutant protein that is mislocalized and does not get delivered to melanosomes (95;96). Kobayashi et al. propose that the mutant protein is unable to associate with Tyr, subsequently leading to decreased stabilization of Tyr and degradation of Tyr (4;13). Melanosomes from brown homozygotes are round, particulate, and disorganized compared to the lamellar and regular structures observed in normal animals (4). The light mutation (Arg38Cys) results in premature death of follicular melanocytes due to pigment production-induced cytotoxicity (90). The light mouse has lightly (or non) pigmented hair at the tip; pigmentation is absent at the base of the hair. This phenotype persists for each hair cycle, but the light base progresses with age; older mice can have almost completely pale gray fur (90). Tyrp1 mRNA expression is normal in this model. Similar to the light mouse, the white-based brown mouse exhibits absence (or reduction) in pigment at the base of the hair (90;97). The white-based brown mutation is an insertion of DNA or a chromosomal translocation at the 3’ end of the first intron of Tyrp1; Tyrp1 transcripts are not produced (97). The white-based brown mutation leads to premature melanocyte death, similar to the light mutant. The chi mutation also results in hypopigmentation. It is unknown whether the chi mutation results in the death of follicular melanocytes. Tyrp1 expression and Tyrp1 localization have not been examined.
chi(F):5'- ACACACTCACTGACTCCTTAGCAGG -3'
chi(R):5'- GGTGCTTAACGTGCAACTGCATTG -3'
chi_seq(F):5'- TCACTGACTCCTTAGCAGGTAGAG -3'
chi_seq(R):5'- GCAACTGCATTGATTCTCTGAAG -3'
Chi genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
Chi(F): 5’- ACACACTCACTGACTCCTTAGCAGG -3’
Chi(R): 5’- GGTGCTTAACGTGCAACTGCATTG -3’
Chi_seq(F): 5’- TCACTGACTCCTTAGCAGGTAGAG -3’
1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40X
6) 72°C 10:00
7) 4°C ∞
The following sequence of 456 nucleotides (from Genbank genomic region NC_000070 for linear DNA sequence of Tyrp1) is amplified:
1 acacactcac tgactcctta gcaggtagag agctaaagga aaaggacacc agggctaagc
61 aagccaggac acaagatgtt agcagaagca gagaccacta atggatttct atgatctagg
121 agatgctgca ggagccttct ttctcccttc cttactggaa ttttgcaact gggaaaaacg
181 tctgcgatgt ctgcactgat gacttgatgg gatccagaag caacttcgat tctactctta
241 taagccccaa ctctgtcttt tctcaatgga gagtggtctg tgaatccttg gaagagtacg
301 ataccctggg aacactttgt aacagtaaga cccaaatgac agctactatt cacaattctt
361 tattctataa atgactgtgt tgcctgtaag gtccctcttc agagtgaaat ctgctatctc
421 tcttcagaga atcaatgcag ttgcacgtta agcacc
Primer binding sites are underlined and the sequencing primer is highlighted; the mutated nucleotide is shown in red text.
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