Phenotypic Mutation 'siamese' (pdf version)
Allelesiamese
Mutation Type missense
Chromosome7
Coordinate87,087,252 bp (GRCm39)
Base Change T ⇒ C (forward strand)
Gene Tyr
Gene Name tyrosinase
Synonym(s) skc35, Oca1
Chromosomal Location 87,073,979-87,142,637 bp (-) (GRCm39)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]
PHENOTYPE: Numerous mutations at this locus result in albinism or hypopigmentation. Albinism is associated with reduced number of optic nerve fibers and mutants can have impaired vision. Some alleles are lethal. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_011661; Ensembl: ENSMUST00000004770; MGI: 98880

MappedYes 
Amino Acid Change Histidine changed to Arginine
Institutional SourceBeutler Lab
Gene Model not available
AlphaFold P11344
SMART Domains Protein: ENSMUSP00000004770
Gene: ENSMUSG00000004651
AA Change: H420R

DomainStartEndE-ValueType
signal peptide 1 18 N/A INTRINSIC
low complexity region 91 112 N/A INTRINSIC
Pfam:Tyrosinase 170 403 4.8e-45 PFAM
transmembrane domain 474 496 N/A INTRINSIC
Predicted Effect probably damaging

PolyPhen 2 Score 0.991 (Sensitivity: 0.71; Specificity: 0.97)
(Using ENSMUST00000004770)
Meta Mutation Damage Score Not available question?
Is this an essential gene? Probably nonessential (E-score: 0.194) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance 100% 
Alleles Listed at MGI

All alleles(104) : Spontaneous(26) Chemically induced(9) Radiation induced(69) Other(1)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL01568:Tyr APN 7 87087156 missense probably damaging 1.00
IGL01594:Tyr APN 7 87133022 splice site probably benign
IGL02963:Tyr APN 7 87133205 missense probably benign
IGL03356:Tyr APN 7 87141922 missense possibly damaging 0.71
ghost UTSW 7 87121703 missense probably damaging 1.00
pale UTSW 7 87087175 missense probably damaging 1.00
pale_rider UTSW 7 87087231 missense probably damaging 1.00
rufus UTSW 7 87141914 missense probably damaging 1.00
shocked UTSW 7 87142330 missense probably damaging 1.00
Venusaur UTSW 7 87141914 missense probably damaging 1.00
waffle UTSW 7 87142429 missense possibly damaging 0.94
R0322:Tyr UTSW 7 87142125 missense probably benign 0.35
R0479:Tyr UTSW 7 87142429 missense possibly damaging 0.94
R1544:Tyr UTSW 7 87141914 missense probably damaging 1.00
R1546:Tyr UTSW 7 87087200 missense probably benign 0.02
R1606:Tyr UTSW 7 87087179 missense probably benign 0.01
R1666:Tyr UTSW 7 87142149 missense probably damaging 1.00
R2064:Tyr UTSW 7 87142051 missense probably benign 0.13
R2213:Tyr UTSW 7 87142086 missense probably damaging 1.00
R2420:Tyr UTSW 7 87078397 missense probably benign 0.17
R4013:Tyr UTSW 7 87087148 missense probably benign 0.00
R4014:Tyr UTSW 7 87087148 missense probably benign 0.00
R4015:Tyr UTSW 7 87087148 missense probably benign 0.00
R4016:Tyr UTSW 7 87087148 missense probably benign 0.00
R4202:Tyr UTSW 7 87078276 missense possibly damaging 0.92
R4205:Tyr UTSW 7 87078276 missense possibly damaging 0.92
R4206:Tyr UTSW 7 87078276 missense possibly damaging 0.92
R4361:Tyr UTSW 7 87078284 missense probably benign 0.01
R4738:Tyr UTSW 7 87141855 missense probably null 1.00
R5306:Tyr UTSW 7 87087222 missense probably damaging 1.00
R5378:Tyr UTSW 7 87121703 missense probably damaging 1.00
R5395:Tyr UTSW 7 87121698 missense probably damaging 0.98
R5782:Tyr UTSW 7 87142224 missense probably damaging 1.00
R7007:Tyr UTSW 7 87142548 missense probably benign 0.04
R7609:Tyr UTSW 7 87133092 missense probably benign 0.06
R7767:Tyr UTSW 7 87142218 missense probably benign 0.37
R7794:Tyr UTSW 7 87133028 critical splice donor site probably null
R8158:Tyr UTSW 7 87121724 missense probably damaging 0.99
R8383:Tyr UTSW 7 87133200 missense probably damaging 1.00
R8403:Tyr UTSW 7 87087175 missense probably damaging 1.00
R8544:Tyr UTSW 7 87142000 missense probably benign 0.05
R8822:Tyr UTSW 7 87142330 missense probably damaging 1.00
R8837:Tyr UTSW 7 87087223 missense probably damaging 1.00
R9492:Tyr UTSW 7 87121705 missense possibly damaging 0.63
R9492:Tyr UTSW 7 87121704 missense probably damaging 1.00
R9748:Tyr UTSW 7 87142072 missense possibly damaging 0.89
Mode of Inheritance Autosomal Recessive
Local Stock Sperm, gDNA
Repository

none

Last Updated 2016-05-13 3:09 PM by Peter Jurek
Record Created 2011-01-04 6:15 PM by Amanda L. Blasius
Record Posted 2011-01-14
Phenotypic Description

Siamese homozygotes display a cream colored coat with darkening at the extremities and dark red eyes.  This phenotype is identical to that of Himalayan mice with a hypomorphic mutation in the Tyr gene encoding tyrosinase, an enzyme critical for melanin biosynthesis.

Nature of Mutation

Due to phenotypic similarities with other Tyr mutant animals, the Tyr gene was directly sequenced as a candidate gene, and an A to G transition was found at position 1320 of the Tyr transcript using Genbank record NM_011661, in exon 4 of 5 total exons. 

1304 AATGCACCTATCGGCCATAACAGAGACTCTTAC
415  -N--A--P--I--G--H--N--R--D--S--Y-

The mutated nucleotide is indicated in red lettering, and causes a histidine to arginine substitution at residue 420 of tyrosinase.

Illustration of Mutations in
Gene & Protein
Protein Prediction
Figure 3. Domain structure of tyrosinase. The siamese mutation causes a histidine to arginine substitution at residue 420 of tyrosinase. SP, signal peptide; EGF-like, epidermal growth factor-like laminin domain; TM, transmembrane; CT, cytoplasmic tail. Glycosylation and copper binding sites are indicated in light and dark pink, respectively. Click on the image to view other mutations found in TYR. Click on each mututation for more specific information.

The residue altered by the siamese mutation occurs in the extracellular region of tyrosinase C-terminal to the active site (Figure 3).  Although this is a histidine, it is not one of the copper-binding histidines critical for catalytic function.  Nevertheless, this residue is highly conserved in vertebrates. 

Please see the record for ghost for more information on the Tyr gene 

Putative Mechanism

The siamese mutation in Tyr is identical to the one found in the classical Himalayan mouse (1).  This mutation results in reduced tyrosinase activity that is temperature-sensitive and allows pigment production in cooler areas of the body, such as the extremities.  Mutations that cause similar temperature-sensitive tyrosinase activity are also found in humans, Siamese cats, and Himalayan minks (2-4).  Studies of the temperature-sensitive enzyme from humans suggests that these mutations affect the thermal stability of the tyrosinase polypeptide (2).   

Primers Primers cannot be located by automatic search.
Genotyping
Siamese 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. 
 
Primers
Siamese(F): 5’- TGACTAGGAAGGCCAAAGCCCATAG -3’
Siamese(R): 5’- GCCCACCATTAGGATGGATTTCCAC -3’
 
PCR program
1) 95°C             2:00
2) 95°C             0:30
3) 56°C             0:30
4) 72°C             1:00
5) repeat steps (2-4) 29X
6) 72°C             7:00
7) 4°C               8
 
Primers for sequencing
Siamese_seq(F): 5'- AGGCAACTGAGCTTTACCTG -3'
Siamese_seq(R): 5'- GGTAGGCTCTGCCTTAAAAAC-3'
 
The following sequence of 1387 nucleotides (NCBI Mouse Genome Build 37.1, Chromosome 7, bases 94,585,858 to 94,587,244) is amplified:

 
gcccaccatt aggatggatt tccactgtcc ttggtttgtt tgtttgtttg tttgtttgtt
ttgttttggt cgctatttcc tattcctaga atggttttgt cttgttgcct gaatagtagt
catgtggtca cataaaagct ttatgggaag ctggaaatgg gctgtttcat cttctatcat
taaaggtagg ctctgcctta aaaacatgat ctttcctaac cataagacaa agactgaaat
acctgatata gagaaaaaca aaaagtgatt atggtctagt cttttgtcaa tttagtttta
tatggttttt cttttgactt tctttgcatt tttaaagtta tatttaatat tatgacaata
tttcatgaaa acaaatgttg aattctgaaa cctctatact atctataaaa gtttaatttt
cataaggaaa atttgaagtt atcctcacac tacttctgat gaatgacctt cttcaggaca
tgaaattgta acttgtcaaa gtttgaagat agcacttgat caagtcttgt gatatcaata
attgtctttt aagaacttaa aatttacacc ttataaataa aatgttcctg actctgagta
acccttccct ctgtagtatt tttgaacaat ggctgcgaag gcaccgccct cttttggaag
tttacccaga agccaatgca cctatcggcc ataacagaga ctcttacatg gttcctttca
taccgctcta tagaaatggt gatttcttca taacatccaa ggatctggga tatgactaca
gctacctcca agagtcaggt aaagctcagt tgccttcaga tgaactatgg aatgcaatgt
gggtaacctc tttgggggca gttaaaaaca cctactgtat actcaatttt ttttctaaaa
cttctaaaga aactatatta tgccaattta taattgtgta aactagaact gtatttcaat
gattcctaaa tttataacta ttccatctag tataggaatt ttatacagtt aaattgttga
agaatatagg attgggaagc ttttgaacca tgaattccaa tgaattatgt cagctgtttt
atgacctagg gatattcttt caattctgtg aatcatattt tattcattat atatttagat
aggaataact gtatttttct gaatcaggtt aaagaattca gtctacgaat catatggtat
taacaatttg tgatcttcca tcttgagact cttggtagga ttaccaatgc aataatggaa
actttcaaaa tgaactaata ttgggtttca taataattct ttaatgttaa ctattatacc
tttggctaga agcataatgt aaagccttag gactggaagt agctatgggc tttggccttc
ctagtca
 
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated A is indicated in red. 
References
Science Writers Nora G. Smart
Illustrators Diantha La Vine
AuthorsAmanda L. Blasius, Bruce Beutler
Edit History
2011-09-12 4:54 PM (current)
2011-03-24 11:16 AM
2011-02-02 7:21 AM
2011-02-01 9:34 AM
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2011-01-17 9:49 AM
2011-01-17 9:49 AM
2011-01-14 3:26 PM
2011-01-14 3:26 PM
2011-01-14 1:10 PM