Phenotypic Mutation 'casper' (pdf version)
Mutation Type missense
Coordinate75,645,875 bp (GRCm38)
Base Change A ⇒ G (forward strand)
Gene Kit
Gene Name KIT proto-oncogene receptor tyrosine kinase
Synonym(s) SCO5, Dominant white spotting, Tr-kit, belly-spot, CD117, Gsfsow3, Gsfsco5, SOW3, SCO1, Steel Factor Receptor, c-KIT, Gsfsco1
Chromosomal Location 75,574,916-75,656,722 bp (+)
MGI Phenotype FUNCTION: The c-Kit proto-oncogene is the cellular homolog of the transforming gene of a feline retrovirus (v-Kit). The c-kit protein includes characteristics of a protein kinase transmembrane receptor. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mutations at this locus affect migration of embryonic stem cell populations, resulting in mild to severe impairments in hematopoiesis, and pigmentation. Some alleles are homozygous lethal, sterile, or result in the formation of gastrointestinal tumors. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_021099; MGI: 96677

Amino Acid Change Aspartic acid changed to Glycine
Institutional SourceBeutler Lab
Gene Model not available
AlphaFold P05532
PDB Structure Structure of a class III RTK signaling assembly [X-RAY DIFFRACTION]
SMART Domains Protein: ENSMUSP00000005815
Gene: ENSMUSG00000005672
AA Change: D680G

low complexity region 10 18 N/A INTRINSIC
low complexity region 25 38 N/A INTRINSIC
IG 43 113 3.02e0 SMART
IG_like 122 206 1.09e2 SMART
IGc2 225 300 3.79e-4 SMART
IG 323 413 1.21e-2 SMART
IG_like 429 501 1.88e0 SMART
transmembrane domain 524 546 N/A INTRINSIC
TyrKc 592 926 2.5e-138 SMART
low complexity region 945 963 N/A INTRINSIC
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000005815)
SMART Domains Protein: ENSMUSP00000116465
Gene: ENSMUSG00000005672
AA Change: D676G

low complexity region 1 10 N/A INTRINSIC
low complexity region 22 30 N/A INTRINSIC
low complexity region 37 50 N/A INTRINSIC
IG 55 125 3.02e0 SMART
IG_like 134 218 1.09e2 SMART
IGc2 237 312 3.79e-4 SMART
IG 335 425 1.21e-2 SMART
IG_like 441 513 1.88e0 SMART
transmembrane domain 532 554 N/A INTRINSIC
TyrKc 600 934 2.5e-138 SMART
low complexity region 953 971 N/A INTRINSIC
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000144270)
Meta Mutation Damage Score Not available question?
Is this an essential gene? Probably essential (E-score: 0.944) question?
Phenotypic Category
Phenotypequestion? Literature verified References
hematopoietic system
immune system
reproductive system
Candidate Explorer Status CE: no linkage results
Single pedigree
Linkage Analysis Data
Penetrance 100% 
Alleles Listed at MGI

All alleles(128) : Targeted, other(12) Gene trapped(31) Spontaneous(66) Chemically induced(17) Radiation induced(2

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00466:Kit APN 5 75610819 missense probably benign 0.00
IGL00834:Kit APN 5 75645959 missense probably damaging 1.00
IGL00846:Kit APN 5 75640811 missense probably damaging 0.98
IGL01149:Kit APN 5 75610876 missense probably damaging 0.97
IGL01341:Kit APN 5 75607074 missense probably damaging 1.00
IGL02004:Kit APN 5 75621014 missense probably benign
IGL02281:Kit APN 5 75654534 missense possibly damaging 0.66
IGL02424:Kit APN 5 75639106 missense probably benign
IGL02697:Kit APN 5 75607259 missense probably benign
IGL02929:Kit APN 5 75640769 missense probably damaging 1.00
IGL03053:Kit APN 5 75610914 missense probably benign
IGL03127:Kit APN 5 75641188 missense probably benign 0.44
IGL03174:Kit APN 5 75607113 missense probably benign
IGL03381:Kit APN 5 75607128 missense probably benign 0.04
Mooyah2 UTSW 5 75652808 missense probably damaging 1.00
pretty2 UTSW 5 75649550 missense probably damaging 1.00
slimmer UTSW 5 75640757 missense possibly damaging 0.94
IGL02837:Kit UTSW 5 75639008 missense probably benign 0.00
R0022:Kit UTSW 5 75622997 missense probably benign 0.00
R0022:Kit UTSW 5 75622997 missense probably benign 0.00
R0092:Kit UTSW 5 75647754 missense possibly damaging 0.93
R0254:Kit UTSW 5 75620921 missense probably benign
R0329:Kit UTSW 5 75652829 missense probably damaging 1.00
R0609:Kit UTSW 5 75610879 missense probably benign 0.35
R1068:Kit UTSW 5 75609518 missense probably benign
R1115:Kit UTSW 5 75649532 splice site probably benign
R1480:Kit UTSW 5 75637317 missense probably benign 0.00
R1639:Kit UTSW 5 75652807 missense probably damaging 1.00
R1801:Kit UTSW 5 75648393 missense probably damaging 1.00
R1973:Kit UTSW 5 75615442 missense probably damaging 1.00
R2033:Kit UTSW 5 75637317 missense possibly damaging 0.88
R3125:Kit UTSW 5 75647827 missense probably benign 0.07
R3125:Kit UTSW 5 75647828 missense probably null 0.00
R3437:Kit UTSW 5 75645905 missense probably damaging 1.00
R3791:Kit UTSW 5 75639150 missense probably damaging 1.00
R3939:Kit UTSW 5 75609318 missense probably benign 0.00
R3940:Kit UTSW 5 75609318 missense probably benign 0.00
R3941:Kit UTSW 5 75609318 missense probably benign 0.00
R3942:Kit UTSW 5 75609318 missense probably benign 0.00
R4092:Kit UTSW 5 75610810 missense probably benign 0.28
R4376:Kit UTSW 5 75640499 missense probably benign 0.00
R4377:Kit UTSW 5 75640499 missense probably benign 0.00
R4668:Kit UTSW 5 75641220 splice site probably null
R5104:Kit UTSW 5 75615478 missense probably benign 0.00
R5152:Kit UTSW 5 75620847 missense probably benign 0.00
R5154:Kit UTSW 5 75640540 missense probably damaging 0.99
R5508:Kit UTSW 5 75649548 missense probably damaging 1.00
R5624:Kit UTSW 5 75609394 missense probably benign 0.40
R5731:Kit UTSW 5 75654415 missense possibly damaging 0.93
R6270:Kit UTSW 5 75609509 missense probably benign
R6565:Kit UTSW 5 75645853 missense probably damaging 1.00
R6694:Kit UTSW 5 75640757 missense possibly damaging 0.94
R6805:Kit UTSW 5 75652808 missense probably damaging 1.00
R6823:Kit UTSW 5 75652649 missense probably benign 0.01
R6848:Kit UTSW 5 75607212 missense probably benign
R7021:Kit UTSW 5 75620967 missense probably benign 0.00
R7080:Kit UTSW 5 75607281 missense probably damaging 0.99
R7117:Kit UTSW 5 75607098 missense probably benign 0.18
R7156:Kit UTSW 5 75615374 missense probably benign 0.14
R7379:Kit UTSW 5 75647752 missense probably damaging 1.00
R7427:Kit UTSW 5 75645847 missense possibly damaging 0.92
R7438:Kit UTSW 5 75639000 missense probably benign 0.01
R7531:Kit UTSW 5 75607040 missense probably damaging 0.99
R7711:Kit UTSW 5 75637359 missense probably damaging 0.97
R7810:Kit UTSW 5 75609322 missense probably benign 0.11
R7819:Kit UTSW 5 75645932 missense probably benign 0.41
R8021:Kit UTSW 5 75615491 missense possibly damaging 0.79
R8139:Kit UTSW 5 75652805 missense probably damaging 0.99
R8165:Kit UTSW 5 75620880 missense possibly damaging 0.94
R8249:Kit UTSW 5 75641408 missense probably damaging 0.97
R8288:Kit UTSW 5 75654489 missense probably damaging 1.00
R8290:Kit UTSW 5 75641169 missense probably benign
R8829:Kit UTSW 5 75639131 missense probably benign 0.41
R8832:Kit UTSW 5 75639131 missense probably benign 0.41
U24488:Kit UTSW 5 75623014 nonsense probably null
Mode of Inheritance Autosomal Dominant
Local Stock Lost


Last Updated 2019-06-23 3:54 PM by Diantha La Vine
Record Created unknown
Record Posted 2008-02-05
Phenotypic Description

Casper was identified as a coat color phenotype in the G1 generation. Heterozygous mice have white patches on the belly, similar to WV/+ heterozygotes that bear a mutation at the c-kit locus (1). Homozygous Casper mice are completely white, with pink skin and black eyes. While Casper heterozygotes are fertile, homozygotes display sterility. Casper homozygotes have few or no mast cells.

Nature of Mutation
The Casper mutation corresponds to an A to G transition at position 2055 of the Kit transcript on Chromosome 5. The mutation exists in exon 14 of 21 total exons.
671  -Y--C--C--Y--G--D--L--L--N--F--L-
The mutated nucleotide is indicated in red lettering, and results in the amino acid substitution D676G.
Illustration of Mutations in
Gene & Protein
Protein Prediction
Figure 2. Domain structure of KIT. The position of the Casper mutation is indicated and results in the amino acid substitution D676G. Click on the image to view other mutations found in Kit.
Figure 2. Crystal structure of the bipartite KIT kinase domain. The N-lobe is shown in blue, the C-lobe is shown in green, the hinge region that forms part of the ATP binding site is shown in purple, and magnesium ions are shown in gray.  β-strands are represented by arrows and α-helices by coils. UCSF Chimera model is based on PDB 1PKG, Mol et al., J. Biol. Chem. 278, 31461-31464 (2003). The location of the Casper mutation is indicated. Click on the image to view other mutations found within the KIT kinase domain. Click again to view it rotate.

KIT is a 975 amino acid protein of the class III receptor tyrosine kinase (RTK) family, which contains five extracellular immunoglobulin (Ig) domains, a single transmembrane domain, a split tyrosine kinase domain, and a unique distribution of cysteine residues within the ligand binding domain (Figure 1) (2;3). The KIT tyrosine kinase domain has the characteristic bi-lobed architecture of all protein kinases (Figure 2; PDB ID 1PKG). Residues 582-671 comprise the small N-terminal lobe (N-lobe), and residues 678-953 comprise the large C-terminal lobe (C-lobe) [(4;5) and reviewed in (6)]. The cleft created between the two lobes contains the catalytic site. The Casper mutation results in the substitution of aspartic acid 676 by glycine. D676 resides in the hinge segment linking the two lobes of the kinase.

Please see the record for Pretty2 for information about Kit.
Putative Mechanism
Like the Pretty2 mutation (I787F), the Casper mutation likely prevents proper activation of KIT kinase activity. D676 lies in the hinge between the N- and C-lobes of the kinase domain, and forms part of the nucleotide binding site of the protein (4). In the crystal structure of active KIT, ADP is found to bind by inserting the adenine base into a hydrophobic pocket; hydrogen bonds with E671 and C673 (human protein numbering) stabilize the binding interaction (4). D677 (corresponding to mouse D676), along with R796 and G596, forms hydrogen bonds with hydroxyl groups on the ribose sugar. Replacing D676 with a glycine residue may prevent such hydrogen bonding by eliminating the oxygen atom that forms the bond. Thus, mutation of D676 may prevent or impair nucleotide binding to the KIT kinase domain, and thereby inhibit kinase activity.
Primers Primers cannot be located by automatic search.
Casper 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. This protocol has not been tested.
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              ∞
Primers for sequencing
The following sequence of 627 nucleotides (from Genbank genomic region NC_000071 for linear genomic sequence of Kit) is amplified:
70600                                           a gaaaggggct tgcttgtgct
70621 acttcactca gcacaatgct gccttttttg atgagcggtg ttaacagata gaattatgtt
70681 gggactaaga aggcttagcc actgaatctg aatgttaata gccgcggtca cccatgggta
70741 tttttacagg aggcgggatt atctaaggta tatcatcttg cctataccta acattgtctt
70801 ctatcctcat agggcccacc ctggtcatta cagaatattg ttgctatggt gatcttttga
70861 attttttgag aaggaagcgt gactcgttta ttttctcaaa gcaagaagag caggcagaag
70921 cggcacttta taagaacctt ctgcactcaa cggagccttc ctggtaaggc tgatttgcat
70981 aaacagtcag ctgttgacag gcagttcatg gggtcataag ggtttgcaat caaggctgat
71041 tcttttaaaa aatgagcaga ggtgctccta ggtgtgaaat cagaattatt aaattgttta
71101 agcgtgatta actattccgg aagttcagat agtagtaccc ttgaagattc aaattgagat
71161 ttgtcactga tttctcttaa atgtgtgtct ctgtccttcc ttcagcctta gtcctgtggg
71221 attgga
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated A is indicated in red.
 1.  Little, C. C. and Cloudman, A. M. (1937) The Occurrence of a Dominant Spotting Mutation in the House Mouse, Proc. Natl. Acad. Sci. U. S. A 23, 535-537.
 2.  Coussens, L., Yang-Feng, T. L., Liao, Y. C., Chen, E., Gray, A., McGrath, J., Seeburg, P. H., Libermann, T. A., Schlessinger, J., Francke, U., and . (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene, Science 230, 1132-1139.
 3.  Yarden, Y., Escobedo, J. A., Kuang, W. J., Yang-Feng, T. L., Daniel, T. O., Tremble, P. M., Chen, E. Y., Ando, M. E., Harkins, R. N., Francke, U., and . (1986) Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors, Nature 323, 226-232.
 4.  Mol, C. D., Lim, K. B., Sridhar, V., Zou, H., Chien, E. Y., Sang, B. C., Nowakowski, J., Kassel, D. B., Cronin, C. N., and McRee, D. E. (2003) Structure of a c-kit product complex reveals the basis for kinase transactivation, J Biol. Chem. 278, 31461-31464.
 5.  Mol, C. D., Dougan, D. R., Schneider, T. R., Skene, R. J., Kraus, M. L., Scheibe, D. N., Snell, G. P., Zou, H., Sang, B. C., and Wilson, K. P. (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase, J Biol. Chem. 279, 31655-31663.
 6.  Roskoski, R., Jr. (2005) Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor, Biochem. Biophys. Res. Commun. 338, 1307-1315.
Science Writers Eva Marie Y. Moresco
Illustrators Diantha La Vine
AuthorsXin Du, Bruce Beutler
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