Phenotypic Mutation 'guotie' (pdf version)
Allele | guotie |
Mutation Type |
nonsense
|
Chromosome | 1 |
Coordinate | 137,996,139 bp (GRCm39) |
Base Change | G ⇒ A (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 (isoform 1), NM_011210 (isoform 2), NM_001268286 (isoform 3); MGI: 97810
|
Mapped | Yes |
Amino Acid Change |
Glutamine changed to Stop codon
|
Institutional Source | Beutler Lab |
Gene Model |
predicted gene model for protein(s):
[ENSMUSP00000138800]
[ENSMUSP00000138275]
[ENSMUSP00000138350]
|
AlphaFold |
P06800 |
SMART Domains |
Protein: ENSMUSP00000027645 Gene: ENSMUSG00000026395 AA Change: Q1068*
Domain | Start | End | E-Value | Type |
Pfam:PTP_N
|
5 |
30 |
5e-16 |
PFAM |
low complexity region
|
109 |
126 |
N/A |
INTRINSIC |
low complexity region
|
168 |
203 |
N/A |
INTRINSIC |
Pfam:CD45
|
210 |
267 |
3.1e-20 |
PFAM |
FN3
|
372 |
456 |
2.28e0 |
SMART |
FN3
|
472 |
550 |
3.48e-1 |
SMART |
transmembrane domain
|
565 |
586 |
N/A |
INTRINSIC |
PTPc
|
639 |
901 |
7.57e-127 |
SMART |
PTPc
|
930 |
1216 |
1.39e-102 |
SMART |
|
Predicted Effect |
probably null
|
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: Q931*
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 AA Change: Q907*
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 AA Change: Q1070*
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 |
0.9755 |
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/alleles(12) : Chemically induced (ENU)(5) Targeted(7)
|
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 |
|
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 |
Autosomal Recessive |
Local Stock | Sperm, gDNA |
Repository | |
Last Updated |
2019-06-06 4:08 PM
by Diantha La Vine
|
Record Created |
2014-10-26 8:56 PM
by Ming Zeng
|
Record Posted |
2015-01-14 |
Phenotypic Description |
The guotie phenotype was identified among ENU-mutagenized G3 mice of the pedigree R0942, some of which showed a decrease in the B:T cell ratio (Figure 1), a reduced frequency of B cells (Figure 2), an increased frequency of B1 cells (Figure 3), a decreased frequency of B1a cells in B1 cells (Figure 4), an increased frequency of B1b cells (Figure 5), a decreased frequency of B2 cells (Figure 6), a decreased frequency of IgM+ B cells (Figure 7), an reduced frequency of T cells (Figure 8), an increase in the CD4+ to CD8+ T cell ratio (Figure 9) due to a reduced frequency of CD4+ T cells (Figure 10), an increased frequency of CD4+ T cells in CD3+ T cells (Figure 11), a reduced frequency of CD8+ T cells (Figure 12), a reduced frequency of CD8+ T cells in CD3+ T cells (Figure 13), and a reduced frequency of naïve CD8+ T cells (Figure 14), all in the peripheral blood. Some mice had a reduced frequency of peripheral CD44+ T cells (Figure 15) including CD44+ CD4+ T cells (Figure 16) and CD44+ CD8+ T cells (Figure 17). The CD44+ T cell mean fluorescence intensity (MFI) (Figure 18) and CD44+ CD8 MFI (Figure 19) were both increased in the peripheral blood. The frequency of neutrophils (Figure 20) and CD11c+ dendritic cells (Figure 21) as well as the MFI of IgM (Figure 22) were also increased in the peripheral blood. After mouse cytomegalovirus (MCMV) infection all of the above-mentioned flow cytometry phenotypes were observed as well as a decreased B220 MFI (Figure 23), an increased frequency of central memory CD8+ T cells (Figure 24), a reduced percentage of IgD+ B cells (Figure 25), and a decreased frequency of pDCs (Figure 26). The T-dependent antibody responses to ovalbumin administered with aluminum hydroxide (Figure 27) and the response to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal), were reduced (Figure 28).
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Nature of Mutation |
Whole exome HiSeq sequencing of the G1 grandsire identified 39 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Ptprc: a C to T transition at base pair 138,068,401 (v38) on chromosome 1, or base pair 110,989 in the GenBank genomic region NC_000067. The strongest association was found with a recessive model of linkage to the normalized peripheral T cell frequency, wherein 5 variant homozygotes departed phenotypically from 5 homozygous reference mice and 18 heterozygous mice with a P value of 7.414 x 10-18 (Figure 29). A substantial semidominant effect was observed in most of the assays but the mutation is preponderantly recessive, and in no assay was a purely dominant effect observed. The mutation corresponds to residue 3,658 in the mRNA sequence NM_001111316 within exon 33 of 33 total exons, residue 3,339 in the mRNA sequence NM_011210 within exon 30 of 30 total exons, and residue 3,267 in the mRNA sequence NM_001268286 within exon 29 of 29 total exons.
110980 AGCTATGAGCAATACCAGTTCCTCTATGACATC
1207 -S--Y--E--Q--Y--Q--F--L--Y--D--I- NP_001104786 (CD45-RABC)
1063 -S--Y--E--Q--Y--Q--F--L--Y--D--I- NP_035340 (CD45-RAB)
1042 -S--Y--E--Q--Y--Q--F--L--Y--D--I- NP_001255215 (CD45-RO)
|
The mutated nucleotide is indicated in red. The mutation results in substitution of glutamine (Q)1212 (CD45-RABC), Q1068 (CD45-RAB), or Q1047 (CD45-RO) to a stop codon (*) in the CD45 protein isoforms.
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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 30). 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 guotie mutation is a premature stop codon at amino acid 1,212 in full-length CD45 (CD45RABC), amino acid 1,068 in CD45RAB, and amino acid 1,047 in CD45RO within the D2 domain of all variants. 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). 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 T cell phenotype of the Ptprcguotie/guotie mice is similar to that of the Ptprc-/- mice suggesting that the guotie mutation abrogates CD45 expression. In contrast to the Ptprc-/- mice, the peripheral frequencies of total B cells as well as B1a and B2 cell frequency were reduced in Ptprcguotie/guotie mice, while B1 and B1b cell frequencies were increased compared to wild-type levels. However, 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 CD45guotie have not been examined; however, the phenotype of the guotie mice indicates that the guotie mice doe not express functional CD45.
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Primers |
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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 | Ming Zeng, Jin Huk Choi, Kuan-Wen Wang, Apiruck Watthanasurorot, Bruce Beutler |