|Mutation Type||critical splice donor site|
|Coordinate||80,840,806 bp (GRCm38)|
|Base Change||T ⇒ A (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|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000006151 †] [ENSMUSP00000099895 †] [ENSMUSP00000117080] † probably from a misspliced transcript|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.9496|
|Is this an essential gene?||Probably nonessential (E-score: 0.223)|
|Candidate Explorer Status||CE: excellent candidate; human score: 0; ML prob: 0.532|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-09-04 9:43 PM by Katherine Timer|
|Record Created||2016-04-27 10:04 AM by Carlos Reyna|
The butter phenotype was identified among G3 mice of the pedigree R4703, 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 94 mutations. The coat pigmentation phenotype was linked to a mutation in Tyrp1: a T to A transversion at base pair 80,840,806 (v38) on chromosome 4, or base pair 6,599 in the GenBank genomic region NC_000070 encoding Tyrp1. The mutation is within the donor splice site of intron 4, 2 base pairs from the previous exon (exon 4 out of 8 total exons). Linkage was found with a recessive model of inheritance (P = 3.583 x 10-6), wherein 6 affected mice were homozygous for the variant allele, and 39 unaffected mice were either heterozygous (N = 20) or homozygous (N = 19) for the reference allele (Figure 2).
The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in the use of a cryptic site in intron 4, resulting in a transcript that has a 61 base pair insertion in intron 4. The insertion would cause a frame-shifted protein product beginning after amino acid 304 of the protein, and premature termination after the inclusion of 17 aberrant amino acids.
The donor splice site of intron 4, which is destroyed by the butter mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
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 3) (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 butter mutation is predicted to cause a splicing defect in intron 4; the expression and localization of Tyrp1butter 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). 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 butter results in hypopigmentation, indicating loss of Typr1 function. It is unknown whether the butter mutation results in the death of follicular melanocytes or in disorganization of melanosomes.
1) 94°C 2:00
The following sequence of 418 nucleotides is amplified (chromosome 4, + strand):
1 tgttagcaga agcagagacc actaatggat ttctatgatc taggagatgc tgcaggagcc
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
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|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Carlos Reyna, Jamie Russell, and Bruce Beutler|