Phenotypic Mutation 'fuchsia' (pdf version)
Allele | fuchsia |
Mutation Type |
critical splice donor site
|
Chromosome | 1 |
Coordinate | 138,028,779 bp (GRCm39) |
Base Change | C ⇒ T (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 |
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000138800 †]
[ENSMUSP00000138275 †]
[ENSMUSP00000138350 †]
† probably from a misspliced transcript
|
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
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 |
probably null
|
SMART Domains |
Protein: ENSMUSP00000138800 Gene: ENSMUSG00000026395
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 |
probably null
|
SMART Domains |
Protein: ENSMUSP00000138275 Gene: ENSMUSG00000026395
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 |
probably null
|
SMART Domains |
Protein: ENSMUSP00000138275 Gene: ENSMUSG00000026395
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 |
probably null
|
SMART Domains |
Protein: ENSMUSP00000138350 Gene: ENSMUSG00000026395
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 null
|
SMART Domains |
Protein: ENSMUSP00000138350 Gene: ENSMUSG00000026395
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 null
|
Meta Mutation Damage Score |
0.9580 |
Is this an essential gene? |
Non Essential (E-score: 0.000) |
Phenotypic Category |
Unknown |
Candidate Explorer Status |
loading ... |
Single pedigree Linkage Analysis Data
|
|
Penetrance | |
Alleles Listed at MGI | All Mutations and Alleles(20) : Chemically induced (ENU)(9) Chemically induced (other)(2) Radiation induced(1) Targeted(7) Transgenic(1)
|
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 |
Gentian
|
UTSW |
1 |
137995623 |
critical splice donor site |
probably null |
|
guotie
|
UTSW |
1 |
137996139 |
nonsense |
probably null |
|
guotie2
|
UTSW |
1 |
138022037 |
missense |
probably damaging |
0.97 |
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 |
Unknown |
Local Stock | |
Repository | |
Last Updated |
2019-09-04 9:37 PM
by Diantha La Vine
|
Record Created |
2018-03-29 12:28 PM
by Xue Zhong
|
Record Posted |
2018-04-04 |
Phenotypic Description |
The fuchsia phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R6047, some of which showed a reduced B to T cell ratio (Figure 1), reduced frequencies of B cells (Figure 2), T cells (Figure 3), CD4+ T cells (Figure 4), CD8+ T cells (Figure 5), CD8+ T cells in CD3+ T cells (Figure 6), naive CD4 T cells in CD4 T cells (Figure 7), and naive CD8 T cells in CD8 T cells (Figure 8) with concomitant increased frequencies of B1 cells (Figure 9), CD4+ T cells in CD3+ T cells (Figure 10), central memory CD4 T cells in CD4 T cells (Figure 11), central memory CD8 T cells in CD8 T cells (Figure 12), effector memory CD4 T cells in CD4 T cells (Figure 13), and effector memory CD8 T cells in CD8 T cells (Figure 14), all in the peripheral blood. Some mice showed reduced B220 expression on peripheral blood B cells (Figure 15) as well as increased CD44 expression on peripheral blood T cells (Figure 16), CD4+ T cells (Figure 17), and CD8+ T cells (Figure 18).
|
Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 37 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Ptprc: a G to A transition at base pair 138,101,041 (v38) on chromosome 1, or base pair 74,716 in the GenBank genomic region NC_000067 within the donor splice site of intron 13. The strongest association was found with a recessive model of inheritance to the effector memory CD4 T cell frequency, wherein five variant homozygotes departed phenotypically from nine homozygous reference mice and 18 heterozygous mice with a P value of 2.397 x 10-23 (Figure 19). The effect of the mutation at the cDNA and protein levels has not been examined, but the mutation is predicted to result in skipping of the 156-nucleotide exon 13 (out of 33 total exons), resulting in an in-frame deletion of 52 amino acids (amino acids 421 to 472) of the protein (which is normally 1,293 amino acids long).
<--exon 12 <--exon 13 intron 13--> exon 14-->
1288 ……AAGAACAATTCAG ……ACAAAAGCAGATC gtaagtttttggctt…… GTCCGGACAAG……
417 ……-K--N--N--S-- ……-T--K--A--D-- R--P--D--K-……
correct deleted correct
|
The donor splice site of intron 13, which is destroyed by the fuschia mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
|
Illustration of Mutations in
Gene & Protein |
|
---|
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. 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 fuschia mutation is predicted to result in an in-frame deletion of 52 amino acids (amino acids 421 to 472) of the CD45 protein; amino acids 421 to 472 are within the first type III fibronectin (FN-III) domain. Please see the record for belittle for information about CD45.
|
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 Ptprcfuschia/fuschia mice is similar to that of the Ptprc-/- mice suggesting that the fuscia 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 CD45fushia have not been examined; however, the phenotype of the fuschia mice indicates that the fuschia mice doe not express functional CD45.
|
Primers |
PCR Primer
fuchsia_pcr_F: AGGAAGTACACTGGCTGGTG
fuchsia_pcr_R: CTTTCAGAAACTTACTAACTCAGGC
Sequencing Primer
fuchsia_seq_F: TCAACTCTGTCACTCTATCAGATAG
fuchsia_seq_R: GACCAGTTTTGAGGTGGAA
|
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 424 nucleotides is amplified (chromosome 1, - strand):
1 ctttcagaaa cttactaact caggctttct ttttaattct agaaaaatgt aaaagtttgc 61 ctaataatgt gaccagtttt gaggtggaaa gcttgaaacc ttataaatac tatgaagtgt 121 ccctacttgc ctatgtcaat gggaagattc aaagaaatgg gactgctgag aagtgcaatt 181 ttcacacaaa agcagatcgt aagtttttgg ctttaatatt tcttccatga atggcaaatg 241 acatttttat gtgaaatgca ttgctctttc tacttctgct ggcacgtttg tttacttctg 301 aagttttaaa taatttaata gaaaattatt taaccactgc aaatcaaggt tcactgtatc 361 tatctgatag agtgacagag ttgaagtaac aaagcaggag gcctcaccag ccagtgtact 421 tcct
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.
|
Science Writers | Anne Murray |
Illustrators | Diantha La Vine |
Authors | Jin Huk Choi, Xue Zhong, Evan Nair-Gill, and Bruce Beutler |