|Coordinate||80,844,868 bp (GRCm38)|
|Base Change||C ⇒ T (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 (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a melanosomal enzyme that belongs to the tyrosinase family and plays an important role in the melanin biosynthetic pathway. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III. [provided by RefSeq, Mar 2009]
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 in varying degrees. Semidominant mutants result in melanocyte degeneration causing reduced pigmentation and progressive hearing loss. [provided by MGI curators]
|Amino Acid Change||Glutamine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000006151] [ENSMUSP00000099895] [ENSMUSP00000119167]|
AA Change: Q331*
|Predicted Effect||probably null|
AA Change: Q331*
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.9755|
|Is this an essential gene?||Probably nonessential (E-score: 0.223)|
|Candidate Explorer Status||CE: failed initial filter|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Live Mice|
|Last Updated||2016-12-07 11:29 AM by Anne Murray|
|Record Created||2014-07-16 12:36 PM by Tiana Purrington|
The ca-los phenotype was identified among N-ethyl-N-nitrosourea (ENU)-induced G3 mice of the pedigree R1172, some of which exhibited a brown coat color and black eyes (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 60 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 ca-los hypopigmentation phenotype mimics other known alleles of Tyrp1 (see MGI for a list of Tyrp1 alleles and the chi page). The Tyrp1 mutation is a C to T transition at base pair 80,844,868 (v38) on chromosome 4, or base pair 10,661 in the GenBank genomic region NC_000070. The mutation corresponds to residue 1,280 in the mRNA sequence NM_031202 within exon 5 of 8 total exons.
The mutated nucleotide is indicated in red lettering and results in the conversion of glutamine 331 to a stop codon (Q331*) in the Tyrp1 protein.
Tyrp1 (alternatively, Trp1 or gp75) is a member of the tyrosinase-related protein (TRP) family that also consists of tyrosinase (Tyr; see the records for ghost, pale rider, and siamese) and Tyrp2 [alternatively, DOPAchrome tautomerase (DCT)]. The TRP proteins share homologous domains including a signal sequence, an EGF-like/cysteine (Cys)-rich domain, a catalytic domain that has two copper binding regions and a Cys-rich region, a transmembrane domain, and six putative glycosylation sites (Figure 2) (1-5). Mature Tyrp1 can exist both as an intracellular form (75-80 kDa) and a secreted form (78-88 kDa) [(6); reviewed in (4;7)]. Intracellular Tyrp1 has the N-terminal signal peptide, a long N-terminal luminal domain with the N-linked glycosylation sites, the transmembrane region, and the C-terminal domain (6). In contrast, soluble Tyrp1 lacks the transmembrane domain, the C-terminal tail, and a small region in the luminal domain (6). The ca-los mutation is within the catalytic domain of Tyrp1 and would result in the loss of coding of the transmembrane domain and the cytoplasmic tail; the expression and localization of Tyrp1ca-los has not been examined.
For more information on Tyrp1, please see the record for chi.
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). The primary function attributed to Tyrp1 is that of a DHICA oxidase (8;9), catalyzing the oxidation of DHICA to indole-5,6-quinone-2-carboxylic acid, a product that is eventually converted to eumelanin. Mutations in TYRP1 are linked to oculocuaneous albinism type III [OCA3; OMIM: #203290; (10)] and variations in skin/hair/eye pigmentation linked to 9p23 in Melanesians [OMIM: #612271; (11)]. Individuals with OCA3 have reduced pigment of the skin, hair, and eyes (10). Homozygous Tyrp1 mutant mice [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. Loss of pigmentation in brown and light is attributed to disorganized, round melanosomes (12) or to premature death of follicular melanocytes (13), respectively. Similar to the above-mentioned mouse mutants, the Tyrp1 mutation in ca-los results in hypopigmentation, indicating loss of Typr1 function. It is unknown whether the ca-los mutation results in the death of follicular melanocytes or in disorganization of melanosomes.
1. Negroiu, G., Branza-Nichita, N., Petrescu, A. J., Dwek, R. A., and Petrescu, S. M. (1999) Protein Specific N-Glycosylation of Tyrosinase and Tyrosinase-Related Protein-1 in B16 Mouse Melanoma Cells. Biochem J. 344 Pt 3, 659-665.
2. Furumura, M., Solano, F., Matsunaga, N., Sakai, C., Spritz, R. A., and Hearing, V. J. (1998) Metal Ligand-Binding Specificities of the Tyrosinase-Related Proteins. Biochem Biophys Res Commun. 242, 579-585.
3. Bennett, D. C. (1991) Colour Genes, Oncogenes and Melanocyte Differentiation. J Cell Sci. 98 ( Pt 2), 135-139.
4. Sarangarajan, R., and Boissy, R. E. (2001) Tyrp1 and Oculocutaneous Albinism Type 3. Pigment Cell Res. 14, 437-444.
5. del Marmol, V., and Beermann, F. (1996) Tyrosinase and Related Proteins in Mammalian Pigmentation. FEBS Lett. 381, 165-168.
6. Xu, Y., Setaluri, V., Takechi, Y., and Houghton, A. N. (1997) Sorting and Secretion of a Melanosome Membrane Protein, gp75/TRP1. J Invest Dermatol. 109, 788-795.
7. Ghanem, G., and Fabrice, J. (2011) Tyrosinase Related Protein 1 (TYRP1/gp75) in Human Cutaneous Melanoma. Mol Oncol. 5, 150-155.
8. Kobayashi, T., Urabe, K., Winder, A., Jimenez-Cervantes, C., Imokawa, G., Brewington, T., Solano, F., Garcia-Borron, J. C., and Hearing, V. J. (1994) Tyrosinase Related Protein 1 (TRP1) Functions as a DHICA Oxidase in Melanin Biosynthesis. EMBO J. 13, 5818-5825.
9. Jimenez-Cervantes, C., Solano, F., Kobayashi, T., Urabe, K., Hearing, V. J., Lozano, J. A., and Garcia-Borron, J. C. (1994) A New Enzymatic Function in the Melanogenic Pathway. the 5,6-Dihydroxyindole-2-Carboxylic Acid Oxidase Activity of Tyrosinase-Related Protein-1 (TRP1). J Biol Chem. 269, 17993-18000.
10. Boissy, R. E., Sakai, C., Zhao, H., Kobayashi, T., and Hearing, V. J. (1998) Human Tyrosinase Related Protein-1 (TRP-1) does Not Function as a DHICA Oxidase Activity in Contrast to Murine TRP-1. Exp Dermatol. 7, 198-204.
11. Kenny, E. E., Timpson, N. J., Sikora, M., Yee, M. C., Moreno-Estrada, A., Eng, C., Huntsman, S., Burchard, E. G., Stoneking, M., Bustamante, C. D., and Myles, S. (2012) Melanesian Blond Hair is Caused by an Amino Acid Change in TYRP1. Science. 336, 554.
12. Kobayashi, T., Imokawa, G., Bennett, D. C., and Hearing, V. J. (1998) Tyrosinase Stabilization by Tyrp1 (the Brown Locus Protein). J Biol Chem. 273, 31801-31805.
|Science Writers||Anne Murray|
|Authors||Joel Purrington Tiana Purrington|