Phenotypic Mutation 'ca-los' (pdf version)
Alleleca-los
Mutation Type nonsense
Chromosome4
Coordinate80,763,105 bp (GRCm39)
Base Change C ⇒ T (forward strand)
Gene Tyrp1
Gene Name tyrosinase-related protein 1
Synonym(s) Oca3, isa, TRP-1, Tyrp, TRP1
Chromosomal Location 80,752,360-80,769,956 bp (+) (GRCm39)
MGI Phenotype 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]
Accession Number

Ncbi RefSeq: NM_031202.2; MGI:98881

MappedYes 
Amino Acid Change Glutamine changed to Stop codon
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000006151] [ENSMUSP00000099895] [ENSMUSP00000119167]
AlphaFold P07147
SMART Domains Protein: ENSMUSP00000006151
Gene: ENSMUSG00000005994
AA Change: Q331*

DomainStartEndE-ValueType
signal peptide 1 24 N/A INTRINSIC
Pfam:Tyrosinase 182 417 1.7e-37 PFAM
transmembrane domain 479 501 N/A INTRINSIC
Predicted Effect probably null
SMART Domains Protein: ENSMUSP00000099895
Gene: ENSMUSG00000005994
AA Change: Q331*

DomainStartEndE-ValueType
signal peptide 1 24 N/A INTRINSIC
Pfam:Tyrosinase 182 417 4.9e-38 PFAM
transmembrane domain 479 501 N/A INTRINSIC
Predicted Effect probably null
SMART Domains Protein: ENSMUSP00000119167
Gene: ENSMUSG00000005994

DomainStartEndE-ValueType
Pfam:Tyrosinase 1 51 1e-12 PFAM
Predicted Effect probably benign
Meta Mutation Damage Score 0.9755 question?
Is this an essential gene? Probably nonessential (E-score: 0.193) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance  
Alleles Listed at MGI

All mutations/alleles(60) : Chemically and radiation induced(1) Chemically induced (ENU)(8) Chemically induced (other)(14) Radiation induced(28) Spontaneous(8) Targeted(1)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL01508:Tyrp1 APN 4 80759002 missense possibly damaging 0.95
IGL01586:Tyrp1 APN 4 80763135 missense probably benign 0.00
IGL01620:Tyrp1 APN 4 80763039 nonsense probably null
IGL02126:Tyrp1 APN 4 80755845 nonsense probably null
IGL02174:Tyrp1 APN 4 80763063 nonsense probably null
IGL02601:Tyrp1 APN 4 80759012 missense probably null 0.00
IGL02630:Tyrp1 APN 4 80758994 missense possibly damaging 0.95
Browncoat UTSW 4 80753399 missense probably damaging 1.00
butter UTSW 4 80759043 critical splice donor site probably null
chi UTSW 4 80759015 missense probably damaging 1.00
R0011:Tyrp1 UTSW 4 80759030 missense probably damaging 1.00
R0011:Tyrp1 UTSW 4 80759030 missense probably damaging 1.00
R0145:Tyrp1 UTSW 4 80759015 missense probably damaging 1.00
R1172:Tyrp1 UTSW 4 80763105 nonsense probably null
R1173:Tyrp1 UTSW 4 80763105 nonsense probably null
R1175:Tyrp1 UTSW 4 80763105 nonsense probably null
R1886:Tyrp1 UTSW 4 80759043 critical splice donor site probably null
R2099:Tyrp1 UTSW 4 80753616 missense possibly damaging 0.69
R2273:Tyrp1 UTSW 4 80755771 missense probably damaging 0.99
R2274:Tyrp1 UTSW 4 80755771 missense probably damaging 0.99
R2275:Tyrp1 UTSW 4 80755771 missense probably damaging 0.99
R2312:Tyrp1 UTSW 4 80755801 nonsense probably null
R2427:Tyrp1 UTSW 4 80769108 missense probably benign 0.00
R2440:Tyrp1 UTSW 4 80764843 missense probably benign 0.41
R2915:Tyrp1 UTSW 4 80755692 missense possibly damaging 0.46
R4343:Tyrp1 UTSW 4 80768078 missense possibly damaging 0.92
R4512:Tyrp1 UTSW 4 80755749 missense probably damaging 1.00
R4703:Tyrp1 UTSW 4 80759043 critical splice donor site probably null
R4732:Tyrp1 UTSW 4 80763172 missense possibly damaging 0.67
R4733:Tyrp1 UTSW 4 80763172 missense possibly damaging 0.67
R4788:Tyrp1 UTSW 4 80763180 nonsense probably null
R4834:Tyrp1 UTSW 4 80764833 nonsense probably null
R4911:Tyrp1 UTSW 4 80769144 utr 3 prime probably benign
R4938:Tyrp1 UTSW 4 80758883 missense probably damaging 1.00
R5129:Tyrp1 UTSW 4 80764844 missense probably damaging 1.00
R5154:Tyrp1 UTSW 4 80768954 missense probably benign 0.00
R6249:Tyrp1 UTSW 4 80769009 missense possibly damaging 0.93
R6492:Tyrp1 UTSW 4 80759018 missense probably null 1.00
R6617:Tyrp1 UTSW 4 80764984 missense probably benign 0.24
R6870:Tyrp1 UTSW 4 80769014 missense probably benign 0.37
R6990:Tyrp1 UTSW 4 80753674 missense probably damaging 1.00
R7275:Tyrp1 UTSW 4 80755821 missense possibly damaging 0.78
R7684:Tyrp1 UTSW 4 80758862 missense probably damaging 1.00
R7980:Tyrp1 UTSW 4 80758864 missense probably damaging 1.00
R8001:Tyrp1 UTSW 4 80758907 missense probably benign 0.10
R8051:Tyrp1 UTSW 4 80755897 missense probably damaging 1.00
R8233:Tyrp1 UTSW 4 80769190 missense unknown
R8326:Tyrp1 UTSW 4 80768921 missense probably benign 0.06
R8831:Tyrp1 UTSW 4 80753399 missense probably damaging 1.00
R8907:Tyrp1 UTSW 4 80755798 missense probably damaging 1.00
R8998:Tyrp1 UTSW 4 80763094 missense probably damaging 1.00
R8999:Tyrp1 UTSW 4 80763094 missense probably damaging 1.00
R9732:Tyrp1 UTSW 4 80758930 missense possibly damaging 0.52
R9751:Tyrp1 UTSW 4 80759012 missense probably null 0.00
Z1176:Tyrp1 UTSW 4 80763126 nonsense probably null
Z1177:Tyrp1 UTSW 4 80768054 missense probably benign
Mode of Inheritance Autosomal Recessive
Local Stock Live Mice
MMRRC Submission 037530-MU
Last Updated 2016-12-07 11:29 AM by Anne Murray
Record Created 2014-07-16 12:36 PM by Tiana Purrington
Record Posted 2014-10-27
Phenotypic Description
Figure 1. The ca-los mouse has brown fur and black eyes.

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.

1265 CGTCTTCCTGAGCCACAGGATGTCACTCAGTGC
326  -R--L--P--E--P--Q--D--V--T--Q--C-

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. 

Illustration of Mutations in
Gene & Protein
Protein Prediction
Figure 2. Domain structure of tyrosinase-related protein 1 (Tyrp1). The ca-los mutation results in a conversion of glutamine 331 to a stop codon (Q331*).  SP, signal peptide; EGF-like, epidermal growth factor-like domain; TM, transmembrane; CT, cytoplasmic tail. Glycosylation and copper binding sites are indicated in light pink and purple, respectively. The EGF-like/Cysteine-rich domain (EGF-like) is labeled. A central cysteine-rich (Cys-rich) region is between the copper binding regions (CuA and CuB; the exact amino acid residues that comprise the Cys-rich region are not documented). The CuA, Cys-rich, and CuB regions comprise the catalytic domain of Tyrp1. Image is interactive, click on the image to view other Tyrp1 mutations.

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.

Putative Mechanism
Figure 3. Biochemical pathway leading to the synthesis of eumelanin and pheomelanin. The TRP proteins are labeled in red. Tyrp1 primarily functions as a 5,6-dihydorxyindole 2-carboxylic acid (DHICA) oxidase.

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.

Primers
References
Science Writers Anne Murray
Illustrators Peter Jurek
AuthorsJoel Purrington Tiana Purrington