Phenotypic Mutation 'guotie2' (pdf version)
Allele | guotie2 |
Mutation Type |
missense
|
Chromosome | 1 |
Coordinate | 138,022,037 bp (GRCm39) |
Base Change | A ⇒ G (forward strand) |
Gene |
Ptprc
|
Gene Name | protein tyrosine phosphatase receptor type C |
Synonym(s) | Ly-5, T200, CD45, B220, Lyt-4 |
Chromosomal Location |
137,990,599-138,103,446 bp (-) (GRCm39)
|
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitosis, and oncogenic transformation. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus is classified as a receptor type PTP. This PTP has been shown to be an essential regulator of T- and B-cell antigen receptor signaling. It functions through either direct interaction with components of the antigen receptor complexes, or by activating various Src family kinases required for the antigen receptor signaling. This PTP also suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. Alternatively spliced transcripts variants of this gene, which encode distinct isoforms, have been reported. [provided by RefSeq, Jun 2012] PHENOTYPE: Homozygous null mutants have defective T cell, B cell, and NK cell morphology and physiology. Mice carrying an engineered point mutation exhibit lymphoproliferation and autoimmunity that leads to premature death. [provided by MGI curators]
|
Accession Number | NCBI RefSeq: NM_001111316 (variant 1), NM_011210 (variant 2), NM_001268286 (variant 3); MGI:1924753
|
Mapped | Yes |
Amino Acid Change |
Serine changed to Proline
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000138800]
[ENSMUSP00000138275]
[ENSMUSP00000138350]
|
AlphaFold |
P06800 |
SMART Domains |
Protein: ENSMUSP00000107667 Gene: ENSMUSG00000026395
Domain | Start | End | E-Value | Type |
Pfam:PTP_N
|
5 |
30 |
5.8e-13 |
PFAM |
low complexity region
|
31 |
64 |
N/A |
INTRINSIC |
Pfam:CD45
|
70 |
129 |
1.8e-24 |
PFAM |
FN3
|
233 |
317 |
2.28e0 |
SMART |
FN3
|
333 |
411 |
3.48e-1 |
SMART |
transmembrane domain
|
426 |
447 |
N/A |
INTRINSIC |
PTPc
|
500 |
762 |
7.57e-127 |
SMART |
PTPc
|
791 |
1077 |
1.39e-102 |
SMART |
|
Predicted Effect |
noncoding transcript
|
SMART Domains |
Protein: ENSMUSP00000138800 Gene: ENSMUSG00000026395 AA Change: S405P
Domain | Start | End | E-Value | Type |
Pfam:PTP_N
|
7 |
32 |
4.2e-13 |
PFAM |
low complexity region
|
33 |
66 |
N/A |
INTRINSIC |
Pfam:CD45
|
72 |
131 |
2.3e-24 |
PFAM |
FN3
|
235 |
319 |
2.28e0 |
SMART |
FN3
|
335 |
413 |
3.48e-1 |
SMART |
transmembrane domain
|
428 |
449 |
N/A |
INTRINSIC |
PTPc
|
502 |
764 |
7.57e-127 |
SMART |
PTPc
|
793 |
1079 |
1.39e-102 |
SMART |
|
Predicted Effect |
possibly damaging
PolyPhen 2
Score 0.783 (Sensitivity: 0.85; Specificity: 0.93)
(Using ENSMUST00000182283)
|
SMART Domains |
Protein: ENSMUSP00000138275 Gene: ENSMUSG00000026395 AA Change: S381P
Domain | Start | End | E-Value | Type |
Pfam:PTP_N
|
7 |
34 |
5.5e-13 |
PFAM |
Pfam:CD45
|
48 |
107 |
2.3e-24 |
PFAM |
FN3
|
211 |
295 |
2.28e0 |
SMART |
FN3
|
311 |
389 |
3.48e-1 |
SMART |
transmembrane domain
|
404 |
425 |
N/A |
INTRINSIC |
PTPc
|
478 |
740 |
7.57e-127 |
SMART |
PTPc
|
769 |
1055 |
1.39e-102 |
SMART |
|
Predicted Effect |
possibly damaging
PolyPhen 2
Score 0.676 (Sensitivity: 0.86; Specificity: 0.92)
(Using ENSMUST00000182755)
|
SMART Domains |
Protein: ENSMUSP00000138350 Gene: ENSMUSG00000026395 AA Change: S544P
Domain | Start | End | E-Value | Type |
Pfam:PTP_N
|
7 |
33 |
2.7e-13 |
PFAM |
low complexity region
|
111 |
128 |
N/A |
INTRINSIC |
low complexity region
|
170 |
205 |
N/A |
INTRINSIC |
Pfam:CD45
|
211 |
270 |
2.1e-24 |
PFAM |
FN3
|
374 |
458 |
2.28e0 |
SMART |
FN3
|
474 |
552 |
3.48e-1 |
SMART |
transmembrane domain
|
567 |
588 |
N/A |
INTRINSIC |
PTPc
|
641 |
903 |
7.57e-127 |
SMART |
PTPc
|
932 |
1218 |
1.39e-102 |
SMART |
|
Predicted Effect |
probably damaging
PolyPhen 2
Score 0.971 (Sensitivity: 0.77; Specificity: 0.96)
(Using ENSMUST00000183301)
|
Meta Mutation Damage Score |
0.6467 |
Is this an essential gene? |
Non Essential (E-score: 0.000) |
Phenotypic Category |
Autosomal Recessive |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(6) : Endonuclease-mediated(1) Gene trapped(3) Targeted(2)
|
Lab Alleles |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
lochy
|
APN |
1 |
138011528 |
splice site |
probably benign |
|
IGL00486:Ptprc
|
APN |
1 |
138043359 |
missense |
probably damaging |
0.97 |
IGL00771:Ptprc
|
APN |
1 |
138041415 |
missense |
probably benign |
0.00 |
IGL00833:Ptprc
|
APN |
1 |
138006230 |
missense |
possibly damaging |
0.55 |
IGL00919:Ptprc
|
APN |
1 |
138041380 |
missense |
probably damaging |
1.00 |
IGL01020:Ptprc
|
APN |
1 |
138047911 |
critical splice acceptor site |
probably null |
0.00 |
IGL01024:Ptprc
|
APN |
1 |
138008650 |
missense |
probably damaging |
1.00 |
IGL01302:Ptprc
|
APN |
1 |
138027369 |
missense |
possibly damaging |
0.82 |
IGL01548:Ptprc
|
APN |
1 |
138027219 |
critical splice donor site |
probably null |
0.00 |
IGL01620:Ptprc
|
APN |
1 |
137996148 |
missense |
possibly damaging |
0.88 |
IGL01775:Ptprc
|
APN |
1 |
137992497 |
missense |
probably damaging |
1.00 |
IGL01820:Ptprc
|
APN |
1 |
137993936 |
missense |
probably damaging |
1.00 |
IGL02340:Ptprc
|
APN |
1 |
137998957 |
missense |
probably damaging |
1.00 |
IGL02943:Ptprc
|
APN |
1 |
138027251 |
missense |
probably damaging |
0.99 |
IGL03169:Ptprc
|
APN |
1 |
138041357 |
missense |
probably benign |
0.15 |
IGL03308:Ptprc
|
APN |
1 |
138054058 |
missense |
possibly damaging |
0.70 |
IGL03404:Ptprc
|
APN |
1 |
138020739 |
missense |
probably damaging |
1.00 |
belittle
|
UTSW |
1 |
138137493 |
intron |
probably benign |
|
Benighted
|
UTSW |
1 |
138054039 |
critical splice donor site |
probably null |
|
bletchley
|
UTSW |
1 |
138045600 |
missense |
probably benign |
|
Blush
|
UTSW |
1 |
138045458 |
intron |
probably benign |
|
bruise
|
UTSW |
1 |
137992509 |
missense |
probably damaging |
1.00 |
chor_muang
|
UTSW |
1 |
138041300 |
critical splice donor site |
probably null |
|
crystal
|
UTSW |
1 |
137999993 |
critical splice donor site |
probably null |
|
Dumpling
|
UTSW |
1 |
137995628 |
missense |
probably damaging |
1.00 |
fluorescent
|
UTSW |
1 |
138028930 |
missense |
probably damaging |
0.97 |
fuchsia
|
UTSW |
1 |
138028779 |
critical splice donor site |
probably null |
|
Gentian
|
UTSW |
1 |
137995623 |
critical splice donor site |
probably null |
|
guotie
|
UTSW |
1 |
137996139 |
nonsense |
probably null |
|
Guotie3
|
UTSW |
1 |
138006189 |
missense |
possibly damaging |
0.92 |
Gyoza
|
UTSW |
1 |
138011305 |
missense |
probably damaging |
1.00 |
Half_measure
|
UTSW |
1 |
137998987 |
missense |
probably damaging |
0.98 |
jirisan
|
UTSW |
1 |
138041416 |
nonsense |
probably null |
|
mauve
|
UTSW |
1 |
138027423 |
missense |
probably benign |
|
Perverse
|
UTSW |
1 |
138028782 |
missense |
probably benign |
0.02 |
petechiae
|
UTSW |
1 |
138041446 |
nonsense |
probably null |
|
ultra
|
UTSW |
1 |
138006183 |
critical splice donor site |
probably null |
|
violaceous
|
UTSW |
1 |
138011377 |
missense |
possibly damaging |
0.77 |
R0013:Ptprc
|
UTSW |
1 |
138041297 |
splice site |
probably null |
|
R0189:Ptprc
|
UTSW |
1 |
138010453 |
missense |
probably benign |
0.10 |
R0390:Ptprc
|
UTSW |
1 |
138050313 |
missense |
possibly damaging |
0.71 |
R0504:Ptprc
|
UTSW |
1 |
138016435 |
missense |
probably damaging |
1.00 |
R0602:Ptprc
|
UTSW |
1 |
138017223 |
splice site |
probably benign |
|
R0627:Ptprc
|
UTSW |
1 |
137996058 |
missense |
probably damaging |
0.99 |
R0632:Ptprc
|
UTSW |
1 |
138001348 |
missense |
probably benign |
0.01 |
R0751:Ptprc
|
UTSW |
1 |
138020668 |
missense |
probably damaging |
1.00 |
R0839:Ptprc
|
UTSW |
1 |
138028870 |
missense |
possibly damaging |
0.47 |
R0942:Ptprc
|
UTSW |
1 |
137996139 |
nonsense |
probably null |
|
R0943:Ptprc
|
UTSW |
1 |
138038902 |
missense |
probably damaging |
0.96 |
R1159:Ptprc
|
UTSW |
1 |
138000057 |
missense |
probably damaging |
1.00 |
R1442:Ptprc
|
UTSW |
1 |
138000050 |
missense |
probably damaging |
1.00 |
R1489:Ptprc
|
UTSW |
1 |
138047824 |
missense |
possibly damaging |
0.91 |
R1728:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1728:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1728:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1728:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1728:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1729:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1729:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1729:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1729:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1729:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1730:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1730:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1730:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1730:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1730:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1739:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1739:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1739:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1739:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1739:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1762:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1762:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1762:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1762:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1762:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1783:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1783:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1783:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1783:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1783:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1784:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1784:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1784:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1784:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1784:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1785:Ptprc
|
UTSW |
1 |
138027414 |
missense |
probably benign |
0.05 |
R1785:Ptprc
|
UTSW |
1 |
138035561 |
missense |
probably benign |
0.22 |
R1785:Ptprc
|
UTSW |
1 |
138039992 |
missense |
possibly damaging |
0.53 |
R1785:Ptprc
|
UTSW |
1 |
138035575 |
missense |
probably benign |
0.09 |
R1785:Ptprc
|
UTSW |
1 |
138035562 |
missense |
probably benign |
0.04 |
R1862:Ptprc
|
UTSW |
1 |
138039965 |
missense |
probably benign |
0.13 |
R2145:Ptprc
|
UTSW |
1 |
138001419 |
missense |
probably damaging |
1.00 |
R2290:Ptprc
|
UTSW |
1 |
138038926 |
missense |
probably benign |
0.00 |
R2403:Ptprc
|
UTSW |
1 |
138016270 |
missense |
probably damaging |
1.00 |
R2439:Ptprc
|
UTSW |
1 |
137993890 |
missense |
possibly damaging |
0.67 |
R2887:Ptprc
|
UTSW |
1 |
138007916 |
missense |
probably damaging |
1.00 |
R2906:Ptprc
|
UTSW |
1 |
137992272 |
missense |
possibly damaging |
0.93 |
R3774:Ptprc
|
UTSW |
1 |
137992511 |
missense |
probably damaging |
0.97 |
R3775:Ptprc
|
UTSW |
1 |
137992511 |
missense |
probably damaging |
0.97 |
R3776:Ptprc
|
UTSW |
1 |
137992511 |
missense |
probably damaging |
0.97 |
R3834:Ptprc
|
UTSW |
1 |
138011305 |
missense |
probably damaging |
1.00 |
R4019:Ptprc
|
UTSW |
1 |
138006254 |
missense |
probably damaging |
1.00 |
R4377:Ptprc
|
UTSW |
1 |
137995663 |
missense |
probably benign |
0.04 |
R4580:Ptprc
|
UTSW |
1 |
137998989 |
missense |
probably benign |
0.09 |
R4923:Ptprc
|
UTSW |
1 |
138006236 |
missense |
possibly damaging |
0.93 |
R4925:Ptprc
|
UTSW |
1 |
138027235 |
missense |
probably benign |
0.04 |
R4937:Ptprc
|
UTSW |
1 |
138017238 |
missense |
probably damaging |
1.00 |
R4970:Ptprc
|
UTSW |
1 |
138022037 |
missense |
probably damaging |
0.97 |
R5112:Ptprc
|
UTSW |
1 |
138022037 |
missense |
probably damaging |
0.97 |
R5145:Ptprc
|
UTSW |
1 |
138017304 |
missense |
probably benign |
0.07 |
R5158:Ptprc
|
UTSW |
1 |
138102822 |
missense |
possibly damaging |
0.75 |
R5223:Ptprc
|
UTSW |
1 |
138045600 |
missense |
probably benign |
|
R5593:Ptprc
|
UTSW |
1 |
138045458 |
intron |
probably benign |
|
R5689:Ptprc
|
UTSW |
1 |
138045515 |
missense |
probably benign |
0.01 |
R5885:Ptprc
|
UTSW |
1 |
138016246 |
missense |
probably damaging |
1.00 |
R6010:Ptprc
|
UTSW |
1 |
138028794 |
missense |
probably benign |
0.09 |
R6026:Ptprc
|
UTSW |
1 |
137998987 |
missense |
probably damaging |
0.98 |
R6047:Ptprc
|
UTSW |
1 |
138028779 |
critical splice donor site |
probably null |
|
R6173:Ptprc
|
UTSW |
1 |
137995628 |
missense |
probably damaging |
1.00 |
R6328:Ptprc
|
UTSW |
1 |
138041416 |
nonsense |
probably null |
|
R6383:Ptprc
|
UTSW |
1 |
138006189 |
missense |
possibly damaging |
0.92 |
R6436:Ptprc
|
UTSW |
1 |
138011377 |
missense |
possibly damaging |
0.77 |
R6492:Ptprc
|
UTSW |
1 |
138041300 |
critical splice donor site |
probably null |
|
R6520:Ptprc
|
UTSW |
1 |
138007881 |
nonsense |
probably null |
|
R6805:Ptprc
|
UTSW |
1 |
137995623 |
critical splice donor site |
probably null |
|
R6830:Ptprc
|
UTSW |
1 |
137999993 |
critical splice donor site |
probably null |
|
R6847:Ptprc
|
UTSW |
1 |
138016283 |
missense |
probably damaging |
0.99 |
R6960:Ptprc
|
UTSW |
1 |
138006183 |
critical splice donor site |
probably null |
|
R6995:Ptprc
|
UTSW |
1 |
138016482 |
missense |
probably damaging |
1.00 |
R7009:Ptprc
|
UTSW |
1 |
137992291 |
missense |
probably damaging |
0.97 |
R7041:Ptprc
|
UTSW |
1 |
138054047 |
missense |
probably benign |
0.04 |
R7055:Ptprc
|
UTSW |
1 |
138017309 |
missense |
probably damaging |
1.00 |
R7098:Ptprc
|
UTSW |
1 |
138027423 |
missense |
probably benign |
|
R7164:Ptprc
|
UTSW |
1 |
138045600 |
missense |
probably benign |
|
R7188:Ptprc
|
UTSW |
1 |
137998918 |
missense |
probably damaging |
1.00 |
R7191:Ptprc
|
UTSW |
1 |
138028782 |
missense |
probably benign |
0.02 |
R7204:Ptprc
|
UTSW |
1 |
138045600 |
missense |
probably benign |
|
R7316:Ptprc
|
UTSW |
1 |
137992509 |
missense |
probably damaging |
1.00 |
R7644:Ptprc
|
UTSW |
1 |
137995645 |
missense |
probably benign |
0.01 |
R7948:Ptprc
|
UTSW |
1 |
137992314 |
missense |
probably benign |
0.45 |
R8029:Ptprc
|
UTSW |
1 |
138006197 |
missense |
probably damaging |
1.00 |
R8677:Ptprc
|
UTSW |
1 |
138011335 |
missense |
probably damaging |
1.00 |
R8704:Ptprc
|
UTSW |
1 |
138043362 |
missense |
probably benign |
0.34 |
R8824:Ptprc
|
UTSW |
1 |
138041446 |
nonsense |
probably null |
|
R8921:Ptprc
|
UTSW |
1 |
138054039 |
critical splice donor site |
probably null |
|
R8998:Ptprc
|
UTSW |
1 |
138028930 |
missense |
probably damaging |
0.97 |
R8999:Ptprc
|
UTSW |
1 |
138028930 |
missense |
probably damaging |
0.97 |
R9154:Ptprc
|
UTSW |
1 |
138016302 |
missense |
probably damaging |
1.00 |
R9388:Ptprc
|
UTSW |
1 |
138011380 |
missense |
possibly damaging |
0.87 |
R9428:Ptprc
|
UTSW |
1 |
138041485 |
missense |
probably benign |
0.01 |
R9467:Ptprc
|
UTSW |
1 |
137993960 |
missense |
probably damaging |
1.00 |
R9468:Ptprc
|
UTSW |
1 |
138044754 |
missense |
probably benign |
0.01 |
R9479:Ptprc
|
UTSW |
1 |
138001388 |
missense |
probably benign |
0.38 |
R9526:Ptprc
|
UTSW |
1 |
137996111 |
missense |
probably benign |
0.02 |
R9632:Ptprc
|
UTSW |
1 |
138008627 |
missense |
probably damaging |
1.00 |
R9710:Ptprc
|
UTSW |
1 |
138008627 |
missense |
probably damaging |
1.00 |
R9714:Ptprc
|
UTSW |
1 |
138008687 |
missense |
probably damaging |
1.00 |
R9777:Ptprc
|
UTSW |
1 |
138047901 |
missense |
|
|
Z1177:Ptprc
|
UTSW |
1 |
137995645 |
missense |
probably benign |
0.01 |
|
Mode of Inheritance |
Autosomal Recessive |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:40 PM
by Diantha La Vine
|
Record Created |
2017-03-13 11:57 AM
by Bruce Beutler
|
Record Posted |
2017-10-10 |
Phenotypic Description |
The guotie2 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R4970, some of which showed reduced frequencies of B cells (Figure 1), B1a cells in B1 cells (Figure 2), B2 cells (Figure 3), IgD+ B cells (Figure 4), IgM+ B cells (Figure 5), T cells (Figure 6), naïve CD4 T cells in CD4+ T cells (Figure 7), and CD8+ T cells (Figure 8), all in the peripheral blood. Some mice also showed an increased frequency of B1b cells in the peripheral blood (Figure 9). Some mice also exhibited reduced expression of B220 (Figure 10) and IgD (Figure 11) on B cells and increased CD44 expression on CD8 T cells (Figure 12) in the peripheral blood.
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Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 56 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Ptprc: a T to C transition at base pair 138,094,299 (v38) on chromosome 1, or base pair 76,276 in the GenBank genomic region NC_000067 encoding Ptprc. The strongest association was found with a recessive model of inheritance to the B1b cell frequency, wherein two variant homozygotes departed phenotypically from five homozygous reference mice and eight heterozygous mice with a P value of 8.304 x 10-12 (Figure 13). The mutation corresponds to residue 1,669 in the mRNA sequence NM_001111316 within exon 15 of 33 total exons, residue 1,350 in the mRNA sequence NM_011210 within exon 12 of 30 total exons, and residue 1,278 in the mRNA sequence NM_001268286 within exon 11 of 29 total exons.
76263 TATGAGTTTCTGGTCTCTTTTCACAATGGAGTG
539 -Y--E--F--L--V--S--F--H--N--G--V- (NP_001104786; CD45-RABC)
400 -Y--E--F--L--V--S--F--H--N--G--V- (NP_035340; CD45-RAB)
376 -Y--E--F--L--V--S--F--H--N--G--V- (NP_001255215; CD45-RO)
|
Genomic numbering corresponds to NC_000067. The mutated nucleotide is indicated in red. The mutation results in a serine (S) to proline (P) substitution at position 544 (S544P) in variant 1 of the PTPRC protein (PolyPhen score = 0.676), a S405P substitution in variant 2, and a S381P substitution in variant 3 (PolyPhen score = 0.676).
|
Illustration of Mutations in
Gene & Protein |
|
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Protein Prediction |
Ptprc encodes CD45, a receptor-like protein tyrosine phosphatase (PTP) expressed by cells of the immune system. It is known by several names, including T200 (1), B220 for the B cell form (2), the mouse allotypic marker Ly-5 (3), and CD45. CD45 is a type I transmembrane glycoprotein containing a large N-terminal extracellular domain of ~400-500 residues (depending on the expression of several alternative exons, see below), a single transmembrane domain (22 amino acids), and a C-terminal cytoplasmic domain of 707 residues containing tandem PTP domains only one of which is enzymatically active (Figure 14). Following the PTP domains is a 79 residue C-terminal tail. Exons 4, 5, and 6 of Ptprc are alternatively spliced to generate three protein isoforms with variations in the most N-terminal domain, furthest from the cell membrane. The three peptides are designated as A, B, and C, respectively. The protein isoforms are commonly named based on the exons included, with the largest isoform (RABC) including all three exons, RAB including exons 4 and 5, etc., and the smallest isoform lacking all three exons designated RO. The D2 domain is a protein tyrosine phosphatase (PTP) domain that is enzymatically inactive, but optimal phosphatase activity in cells requires both the D1 and the D2 domains (4). Within the D2 domain is a unique acidic region of 19 residues that contains multiple sites for serine phosphorylation by casein kinase II (5;6). This modification is important for optimal CD45 phosphatase activity toward a model substrate in vitro and for cellular signaling leading to Ca2+ flux in Jurkat T cells, although the mechanistic basis for these effects is unknown. The D2 domain may also modulate substrate access and localization, as suggested by the interaction of D2 with the CD45 substrate Lck (7). The guotie2 mutation results in a serine (S) to proline (P) substitution at position 544 (S544P) in variant 1 of the PTPRC protein; amino acid 544 is within the second FN-III domain. Please see the record for belittle for information about CD45.
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Putative Mechanism | The physiological function of CD45 has been examined most extensively in T cells. Studies with CD45-deficient cell lines identified CD45 as an obligate positive regulator of antigen receptor signaling, since T cells lacking CD45 failed to proliferate or produce cytokines in response to TCR stimulation (8;9). CD45 can regulate both the activating and inhibitory tyrosines of Src family kinases. Ptprc-/- mice have profound defects in thymic development due to dysfunctional signaling through the preTCR and TCR, leading to a block in thymocyte development at β selection and at the DP stage (10-12). As a result, the absolute number of DP thymocytes is reduced twofold, and the number of single positive (SP) thymocytes is reduced five-fold. Peripheral B cell numbers are actually increased in CD45-deficient mice. CD45 deficiency has less severe consequences for B cells than for T cells. Peripheral B cell numbers are actually increased in CD45-deficient mice (10-12). Marginal zone B cells are increased, while B1 cell production is decreased, and B cell development is blocked at the transitional 2 (T2) to mature follicular B cell transition (13). Humans deficient in CD45 develop severe combined immunodeficiency (SCID) with defects in T and B cell development and function (OMIM #608971) (14;15). The immune cell phenotype of the Ptprcguotie2/guotie2 mice is similar to that of the Ptprc-/- mice suggesting that the guotie2 mutation abrogates CD45 expression. Another ENU-induced Ptprc allele, storm (MGI:4819159), exhibited decreased B cell numbers as well as reduced T cell numbers. The expression and localization of CD45guotie2 have not been examined; however, the phenotype of the guotie2 mice indicates that the guotie2 mice do not express functional CD45.
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Primers |
PCR Primer
guotie2_pcr_F: AGCAATCTCATTCAAAAGGGTTACC
guotie2_pcr_R: GCATTCTACATCCAACTCTTGTAG
Sequencing Primer
guotie2_seq_F: GGCAACATTTACATATTGACCAAGTG
guotie2_seq_R: CATCCAACTCTTGTAGATAGCAAG
|
Genotyping | PCR program 1) 94°C 2:00 2) 94°C 0:30 3) 55°C 0:30 4) 72°C 1:00 5) repeat steps (2-4) 40x 6) 72°C 10:00 7) 4°C hold
The following sequence of 656 nucleotides is amplified (chromosome 1, - strand):
1 gcattctaca tccaactctt gtagatagca agtttacttt agaaagcatg atcatactat 61 atcttaaagt actaagcctt ggtttcattt tctgaacttt ttcatttgtt cctccatttt 121 tatttattac tgacataatt actaaggttg ataaacattt ttttctatct ttttgacagc 181 atacagcaaa ataacattac agtttcagat ttaactcagt ttttgatgga aaaaatcagt 241 gttctatgag aaataatgta cagtttataa tatgccatac acacatatag tagaaaacca 301 aattcttttc tttttcttaa ctgaaattta ggtctctttt cacaatggag tgtacgaggg 361 agattcagtt ataagaaatg agtcaacaaa ttgtaagtca tcctggccta ttttttctac 421 ctctatatgt atgcacttgt ttgaacaaaa ctgttttatt ttgcatccat agattgattc 481 attacctgct tatatgtatt atataaatat ttgaaactta caaaaattac agtatcataa 541 aaatcaaatt aatagatttg atcacttggt caatatgtaa atgttgcctt aattacaagt 601 tttaagagga tttatctgca caaatatttt tggtaaccct tttgaatgag attgct
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red. |
References |
4. Desai, D. M., Sap, J., Silvennoinen, O., Schlessinger, J., and Weiss, A. (1994) The Catalytic Activity of the CD45 Membrane-Proximal Phosphatase Domain is Required for TCR Signaling and Regulation. EMBO J. 13, 4002-4010.
10. Mee, P. J., Turner, M., Basson, M. A., Costello, P. S., Zamoyska, R., and Tybulewicz, V. L. (1999) Greatly Reduced Efficiency of both Positive and Negative Selection of Thymocytes in CD45 Tyrosine Phosphatase-Deficient Mice. Eur J Immunol. 29, 2923-2933.
11. Byth, K. F., Conroy, L. A., Howlett, S., Smith, A. J., May, J., Alexander, D. R., and Holmes, N. (1996) CD45-Null Transgenic Mice Reveal a Positive Regulatory Role for CD45 in Early Thymocyte Development, in the Selection of CD4+CD8+ Thymocytes, and B Cell Maturation. J Exp Med. 183, 1707-1718.
12. Kishihara, K., Penninger, J., Wallace, V. A., Kundig, T. M., Kawai, K., Wakeham, A., Timms, E., Pfeffer, K., Ohashi, P. S., and Thomas, M. L. (1993) Normal B Lymphocyte Development but Impaired T Cell Maturation in CD45-exon6 Protein Tyrosine Phosphatase-Deficient Mice. Cell. 74, 143-156.
13. Hermiston, M. L., Tan, A. L., Gupta, V. A., Majeti, R., and Weiss, A. (2005) The Juxtamembrane Wedge Negatively Regulates CD45 Function in B Cells. Immunity. 23, 635-647.
14. Kung, C., Pingel, J. T., Heikinheimo, M., Klemola, T., Varkila, K., Yoo, L. I., Vuopala, K., Poyhonen, M., Uhari, M., Rogers, M., Speck, S. H., Chatila, T., and Thomas, M. L. (2000) Mutations in the Tyrosine Phosphatase CD45 Gene in a Child with Severe Combined Immunodeficiency Disease. Nat Med. 6, 343-345.
15. Tchilian, E. Z., Wallace, D. L., Wells, R. S., Flower, D. R., Morgan, G., and Beverley, P. C. (2001) A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID. J Immunol. 166, 1308-1313.
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Science Writers | Anne Murray |
Illustrators | Katherine Timer |
Authors | Xue Zhong and Bruce Beutler |