hm1

Prf1^tm1Sdz/Prf1^tm1Sdz
C.B6-Prf1^tm1Sdz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

tumorigenesis

altered tumor morphology ( J:77491 )

• some lymphomas have an unusual histiocytic appearance with a pale eosinophilic cytoplasm

increased lymphoma incidence ( J:77491 )

• some mice develop disseminated lymphomas

T cell derived lymphoma ( J:77491 )

• in a few mice

lung adenocarcinoma ( J:77491 )

• in a few mice, with a very late onset

• all are well differentiated papillary adenocarcinomas

sarcoma ( J:77491 )

• in a few mice

increased tumor latency ( J:77491 )

• in mice on a BALB/c background compared to mice on a C57BL/6 background

hm2

Prf1^tm1Sdz/Prf1^tm1Sdz
C57BL/6-Prf1^tm1Sdz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

increased sensitivity to induced morbidity/mortality ( J:113213 )

• all mice die between 40 and 60 days after injection of 107 MHC class-I deficient B cell lymphoma cells, while all wild-type mice survive

premature death ( J:77491 )

• Background Sensitivity: in mice on a C57BL/6 background compared to mice on a BALB/c background

immune system

abnormal leukocyte physiology ( J:17986 )

abnormal NK cell physiology ( J:113213 )

• impaired ability to clear injected MHC class-I deficient B cell lymphoma cells resulting in increased mortality

impaired natural killer cell mediated cytotoxicity ( J:17986 )

• NK-cell-mediated lysis is not evident in the spleen cells after viral infection

defective cytotoxic T cell cytolysis ( J:17986 )

• CD8+ T cells cannot lyse in vitro virus-infected, peptide-coated or allogeneic target cells of epithelial, neuroectodermal or mesodermal orgin, however activation and expansion of CD8+ T cells occurs normally

increased interleukin-10 secretion ( J:123934 )

• following infection with a monocytotropic Ehrlichia bacteria from Ixodes ovatrus ticks (IOE), IL-10 production is increased relative to infected wild-type mice

abnormal inflammatory response ( J:17986 )

• fail to develop footpad swelling upon lymphocytic choriomeningitis virus injection into the footpad

increased susceptibility to infection ( J:17986 )

increased susceptibility to bacterial infection ( J:123934 )

• following infection with a monocytotropic Ehrlichia bacteria from Ixodes ovatrus ticks (IOE), mice have a higher burden of bacteria in the liver and lungs but not spleens, develop extensive partially confluent foci of apoptosis or necrosis of contiguous hepatocytes with mild to moderate liver injury, and more macrophage-rich inflammatory infiltrates compared to infected wild-type mice

• following infection with IOE, IL-10 production is increased relative to infected wild-type mice

increased susceptibility to parasitic infection ( J:81397 )

• decreased clearance and survival after infection with Trypanosoma cruzi

increased susceptibility to viral infection ( J:17986 )

• unable to eliminate lymphocytic choriomeningitis virus 12 days after intravenous infection as in controls, with infection eventually leading to weight loss and death between days 13 and 16

reproductive system

abnormal female reproductive system physiology ( J:59892 )

• alpha-galactosylceramide induced abortion does not occur (J:59892)

tumorigenesis

increased lymphoma incidence ( J:77491 )

• develop aggressive disseminated lymphomas that affect the spleen, liver and lymph nodes from 300 days of age onwards

• most lymphomas are diffuse large cell lymphomas

B cell derived lymphoma ( J:77491 )

• lymphomas are of a B cell origin or plasmocytomas

decreased tumor latency ( J:77491 )

• Background Sensitivity: in mice on a C57BL/6 background compared to mice on a BALB/c background

mortality/aging

increased susceptibility to viral infection induced morbidity/mortality ( J:92260 , J:193137 )

• mutants die within 2 weeks of lymphocytic choriomeningitic virus (LCMV) infection unlike wild-type mice (J:92260)

• mutants depleted of CD8+ cells (by administration of antibodies against CD8+ cells) survive LCMV infection, however those depleted of CD4+ or NK cells do not survive (J:92260)

• neutralizing multiple cytokines, including TNF-alpha, IL-12, IL-18, M-CSF, and GM-CSF, with neutralizing antibodies has no effect on survival (J:92260)

• mutants treated with neutralizing antibodies against IFN-gamma survive LCMV infection, do not develop histocytic infiltrates or peripheral blood cytopenias (J:92260)

• mice die 2 weeks after LCMV infection (J:193137)

nervous system

CNS inflammation ( J:120427 )

• by 7 days after TMEV infection, inflammation is present in the meninges and gray matter of spinal cords in controls as well

• by 21 days, inflammation with macrophage infiltration persists in the gray matter in mutants but not in controls

brain inflammation ( J:92260 , J:120427 )

• 30 days after LCMV infection, the meninges show prominent mononuclear infiltrates along the dura (J:92260)

• by 7 days after TMEV infection, inflammation is present, decreasing slightly by 21 days, but widespread tissue damage is present, similar to controls (B6) (J:120427)

• by 45 days, inflammation with parenchymal disease is seen in hippocampus, striatum, and corpus callosum in some mice (J:120427)

• persistent inflammation is found in the brainstem of mutants (J:120427)

• at 180 days, brain pathology is still present (J:120427)

abnormal brain meninges morphology ( J:92260 )

• 30 days after LCMV infection, the meninges show prominent mononuclear infiltrates along the dura

demyelination ( J:120427 )

• at 45 days after infection, foci of demyelination are observed in spinal cord (in 11% of 537 quadrants examined)

• lesions are located mainly in the anterior and anterolateral white matter of the spinal cord; demyelination is chronic and progressive (16% of quadrants at 90 days and 20% of quadrants at 180 days)

• demyelinated axons in close proximity to inflammatory cells and macrophages with intracytoplasmic vacuoles containing myelin debris are seen in mutants, but not in control or other null mice

immune system

immune system phenotype ( J:120427 )

N	• delayed type hypersensitivity (DTH) reaction elicited in the ear by intradermal injection of inactive virus is comparable to that of controls (J:120427)

decreased leukocyte cell number ( J:193137 )

• in LMCV-infected mice

decreased neutrophil cell number ( J:193137 )

• lack of neutrophilia in LMCV-infected mice

increased spleen red pulp amount ( J:92260 )

• by 10-12 days after LCMV infection, red pulp is expanded when compared to wild-type mice

abnormal spleen white pulp morphology ( J:92260 )

• by 10-12 days after LCMV infection, the white pulp appears chaotic with a prominent infiltrate of macrophages and activated lymphocytes when compared to wild-type spleen

abnormal circulating cytokine level ( J:92260 )

increased circulating interferon-alpha level ( J:92260 )

• mutants exhibit elevated serum levels of IFN-alpha at 6-8 days after LCMV infection unlike wild-type mice which show peak IFN-alpha levels at day 3 of infection and undetectable levels by 4-5 days of infection

increased circulating interferon-gamma level ( J:92260 , J:193137 )

• mutants exhibit elevated (10- to 100-fold) and prolonged serum levels of IFN-gamma following LCMV infection compared to wild-type mice (J:92260)

• mutants treated with neutralizing antibodies against IFN-gamma survive LCMV infection, do not develop histocytic infiltrates or peripheral blood cytopenias (J:92260)

• in LMCV-infected mice (J:193137)

increased circulating interleukin-1 beta level ( J:193137 )

• in LMCV-infected mice

increased circulating interleukin-10 level ( J:92260 )

• increased at 12 days after LCMV infection compared to wild-type mice

increased circulating interleukin-18 level ( J:92260 )

• increased at 12 days after LCMV infection compared to wild-type mice

increased circulating interleukin-6 level ( J:92260 , J:193137 )

• increased at 12 days after LCMV infection compared to wild-type mice (J:92260)

• in LMCV-infected mice (J:193137)

increased circulating tumor necrosis factor level ( J:92260 , J:193137 )

• increased at 12 days after LCMV infection compared to wild-type mice (J:92260)

• in LMCV-infected mice (J:193137)

abnormal circulating fibrinogen level ( J:92260 )

• 8-10 days after LCMV infection, mutants develop hypofibrinogenemia compared to wild-type controls

abnormal lymph node morphology ( J:92260 )

• by 10-12 days after LCMV infection, lymph node architecture is deranged with disorganized macrophage and activated lymphocyte infiltrates replacing the normal follicular structure of lymph nodes and some lymph nodes exhibit necrotic changes compared to wild-type mice

abnormal lymphocyte physiology ( J:120427 )

• CNS-infiltrating mononuclear cells have impaired lytic activity LP- and VP2-transfected target cells in vitro (TMEV leader peptide and VP2 capsid protein), in contrast to effective lysis demonstrated by control cells

abnormal T cell activation ( J:92260 )

• mutants exhibit an elevation of antigen-specific CD8+ T and CD4+ T cells in the bone marrow, liver, and spleen following LCMV infection compared to wild-type mice

decreased NK cell degranulation ( J:193137 )

• in the presence of recombinant IL15 alone or in combination with IL2

abnormal cytotoxic T cell physiology ( J:193137 )

• impaired CD8+ T cell degranulation

• however, priming is normal

defective cytotoxic T cell cytolysis ( J:193137 )

• reduced killing of anti-CD3-loaded P815 target cells, more pronounced than in than in Rab27a^ash and Stx11^tm1.2Ics cells

abnormal macrophage activation involved in immune response ( J:92260 )

• hemophagocytic macrophages are seen in lymph node, spleen, liver and bone marrow tissues of LCMV infected mutants unlike in wild-type mice

lymph node inflammation ( J:92260 )

• by 10-12 days after LCMV infection, lymph node architecture is deranged with disorganized macrophage and activated lymphocyte infiltrates replacing the normal follicular structure

decreased interferon-gamma secretion ( J:92260 )

• IFN-gamma production by CD8+ T cells is less on a per-cell basis in response to both peptide and anti-CD3 stimulation after LCMV infection compared with wild-type mice, however the number of spontaneously IFN-gamma producing (without stimulation) CD8+ T cells is increased, indicating that ongoing antigenic stimulation results in the increased cytokine secretion

CNS inflammation ( J:120427 )

• by 7 days after TMEV infection, inflammation is present in the meninges and gray matter of spinal cords in controls as well

• by 21 days, inflammation with macrophage infiltration persists in the gray matter in mutants but not in controls

brain inflammation ( J:92260 , J:120427 )

• 30 days after LCMV infection, the meninges show prominent mononuclear infiltrates along the dura (J:92260)

• by 7 days after TMEV infection, inflammation is present, decreasing slightly by 21 days, but widespread tissue damage is present, similar to controls (B6) (J:120427)

• by 45 days, inflammation with parenchymal disease is seen in hippocampus, striatum, and corpus callosum in some mice (J:120427)

• persistent inflammation is found in the brainstem of mutants (J:120427)

• at 180 days, brain pathology is still present (J:120427)

liver inflammation ( J:92260 )

• by 10-12 days after LCMV infection, livers show prominent periportal infiltrates

increased susceptibility to viral infection ( J:92260 , J:120427 , J:193137 )

• mutants cannot clear lymphocytic choriomeningitic virus (LCMV) infection like wild-type mice can (J:92260)

• inflammation and tissue damage in the brain are greater than in control, resistant mice at 45 and 180 days (J:120427)

• at 45 days, viral mRNA is still detected in spinal cords of mutants but not in controls or Fas and Fasl mutants (J:120427)

• LMCV-infected mice develop clinical features of hemophagocytic lymphohistiocytosis including weight loss, body temperature drop, hunched posture, lethargy, pancytopenia, lack of neutrophilia, increased circulating aspartate transaminase level, increased circulating lactate dehydrogenase level, increased serum levels of IFN-gamma, IL1b, TNF-alpha and IL6, increased viral load and worsening condition compared with wild-type mice (J:193137)

• LMCV-infected mice develop more severe hemophagocytic lymphohistiocytosis than in Rab27a^ash and Stx11^tm1.2Ics homozygotes despite similar viral loads (J:193137)

increased susceptibility to viral infection induced morbidity/mortality ( J:92260 , J:193137 )

• mutants die within 2 weeks of lymphocytic choriomeningitic virus (LCMV) infection unlike wild-type mice (J:92260)

• mutants depleted of CD8+ cells (by administration of antibodies against CD8+ cells) survive LCMV infection, however those depleted of CD4+ or NK cells do not survive (J:92260)

• neutralizing multiple cytokines, including TNF-alpha, IL-12, IL-18, M-CSF, and GM-CSF, with neutralizing antibodies has no effect on survival (J:92260)

• mutants treated with neutralizing antibodies against IFN-gamma survive LCMV infection, do not develop histocytic infiltrates or peripheral blood cytopenias (J:92260)

• mice die 2 weeks after LCMV infection (J:193137)

behavior/neurological

behavior/neurological phenotype ( J:120427 )

• mice infected with TMEV and monitored daily do not show clinical signs of TMEV infecion, including unkempt appearance, decreased spontaneous movement and hind-limb paralysis, at 45 days and 90 days, whereas 12% of susceptible SJL mice show clinical disease at 90 days and 64% by 180 days (J:120427)

abnormal behavior ( J:120427 )

• some chronically infected mice demonstrate minor alterations in stride with normal activity levels, despite presence of demyelination

hunched posture ( J:92260 , J:193137 )

• mutants infected with LCMV display hunched posture 10 days after infection unlike wild-type mice (J:92260)

• in LMCV-infected mice (J:193137)

hypoactivity ( J:92260 )

• mutants infected with lymphocytic choriomeningitic virus (LCMV) display decreased activity 10 days after infection compared with wild-type controls

lethargy ( J:193137 )

• in LMCV-infected mice

hematopoietic system

abnormal T cell activation ( J:92260 )

• mutants exhibit an elevation of antigen-specific CD8+ T and CD4+ T cells in the bone marrow, liver, and spleen following LCMV infection compared to wild-type mice

decreased erythrocyte cell number ( J:193137 )

• in LMCV-infected mice

decreased leukocyte cell number ( J:193137 )

• in LMCV-infected mice

decreased neutrophil cell number ( J:193137 )

• lack of neutrophilia in LMCV-infected mice

decreased platelet cell number ( J:193137 )

• in LMCV-infected mice

pancytopenia ( J:92260 , J:193137 )

• unlike wild-type mice, mutants become pancytopenic by 10 days after LCMV infection (J:92260)

• in LMCV-infected mice (J:193137)

decreased bone marrow cell number ( J:92260 )

• bone marrow shows severe hypoplasia by 10-12 days after LCMV infection when compared to wild-type mice

increased spleen red pulp amount ( J:92260 )

• by 10-12 days after LCMV infection, red pulp is expanded when compared to wild-type mice

abnormal spleen white pulp morphology ( J:92260 )

• by 10-12 days after LCMV infection, the white pulp appears chaotic with a prominent infiltrate of macrophages and activated lymphocytes when compared to wild-type spleen

homeostasis/metabolism

increased circulating triglyceride level ( J:92260 )

• 8-10 days after LCMV infection, mutants develop hypertriglyceridemia compared to wild-type controls

abnormal circulating cytokine level ( J:92260 )

increased circulating interferon-alpha level ( J:92260 )

increased circulating interferon-gamma level ( J:92260 , J:193137 )

• mutants exhibit elevated (10- to 100-fold) and prolonged serum levels of IFN-gamma following LCMV infection compared to wild-type mice (J:92260)

• mutants treated with neutralizing antibodies against IFN-gamma survive LCMV infection, do not develop histocytic infiltrates or peripheral blood cytopenias (J:92260)

• in LMCV-infected mice (J:193137)

increased circulating interleukin-1 beta level ( J:193137 )

• in LMCV-infected mice

increased circulating interleukin-10 level ( J:92260 )

• increased at 12 days after LCMV infection compared to wild-type mice

increased circulating interleukin-18 level ( J:92260 )

• increased at 12 days after LCMV infection compared to wild-type mice

increased circulating interleukin-6 level ( J:92260 , J:193137 )

• increased at 12 days after LCMV infection compared to wild-type mice (J:92260)

• in LMCV-infected mice (J:193137)

increased circulating tumor necrosis factor level ( J:92260 , J:193137 )

• increased at 12 days after LCMV infection compared to wild-type mice (J:92260)

• in LMCV-infected mice (J:193137)

increased circulating aspartate transaminase level ( J:193137 )

• in LMCV-infected mice

increased circulating lactate dehydrogenase level ( J:193137 )

• in LMCV-infected mice

abnormal circulating fibrinogen level ( J:92260 )

• 8-10 days after LCMV infection, mutants develop hypofibrinogenemia compared to wild-type controls

decreased body temperature ( J:193137 )

• in LMCV-infected mice

abnormal body temperature homeostasis ( J:92260 )

• while wild-type mice infected with LCMV develop a brief febrile response early after infection, mutants exhibit a prolonged temperature elevation that is still seen at 10 days after infection

integument

ruffled hair ( J:92260 )

• mutants infected with LCMV display ruffled fur 10 days after infection when compared with wild-type controls

liver/biliary system

liver inflammation ( J:92260 )

• by 10-12 days after LCMV infection, livers show prominent periportal infiltrates

cellular

abnormal T cell activation ( J:92260 )

• mutants exhibit an elevation of antigen-specific CD8+ T and CD4+ T cells in the bone marrow, liver, and spleen following LCMV infection compared to wild-type mice

growth/size

weight loss ( J:193137 )

• in LMCV-infected mice

Mouse Models of Human Disease	OMIM ID	Ref(s)
Hemophagocytic Lymphohistiocytosis, Familial, 2; FHL2	603553	J:92260 , J:193137
Multiple Sclerosis, Susceptibility To; MS	126200	J:120427

hm4

Prf1^tm1Sdz/Prf1^tm1Sdz
involves: BALB/c * C57BL/6

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

immune system

impaired natural killer cell mediated cytotoxicity ( J:73948 )

• activated splenic NK cells are unable to kill 4T1 or Renca tumor target cells

hm5

Prf1^tm1Sdz/Prf1^tm1Sdz
NOD.B6-Prf1^tm1Sdz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

abnormal circulating glucose level ( J:43468 )

• after cyclophosphamide treatment, perforin-null NOD mice display temporary hyperglycemia but return to normoglycemia while control NOD mice become hyperglycemic and often die as a result

increased physiological sensitivity to xenobiotic ( J:43468 )

• cyclophosphamide treatment of 8-12 week old NOD control and perforin-heterozygous NOD mice on day 0 and 12 induces diabetes at an incidence of 80-90% after the second treatment between 24 and 30 days, while diabetes occurs in 18% of homozygous NOD mutants between 32 and 38 days

endocrine/exocrine glands

decreased pancreatic beta cell number ( J:43468 )

• diabetic perforin-null mice have a drastically reduced volume density of endocrine islet tissue (beta cells) compared with 7-week old control NOD mice

insulitis ( J:43468 )

• at 8 weeks of age, insulitis is seen to varying degrees in perforin-null and heterozygous mice; by 55 weeks of age, in non-diabetic null mice, severe insulitis develops with a higher frequency than in perforin-expressing NOD controls

periinsulitis ( J:43468 )

• periinsulitis is observed in 8-week old perforin-null and heterozygous mice with little islet cell damage, compared to detection at 5 weeks in control NOD mice

immune system

insulitis ( J:43468 )

periinsulitis ( J:43468 )

• periinsulitis is observed in 8-week old perforin-null and heterozygous mice with little islet cell damage, compared to detection at 5 weeks in control NOD mice

decreased susceptibility to autoimmune diabetes ( J:43468 )

• female perforin-null NOD mice show significantly decrease incidence of diabetes (16%) with a delayed onset between 35 and 41 weeks, while control NOD mice, diabetes occurred between 15 and 30 weeks of age with an incidence of 77%; male control NOD mice show less than 20% incidence of diabetes, while no null NOD mice develop diabetes

Mouse Models of Human Disease		OMIM ID	Ref(s)
Diabetes Mellitus, Insulin-Dependent; IDDM		222100	J:43468

ht6

Prf1^tm1Sdz/Prf1⁺
NOD.B6-Prf1^tm1Sdz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

immune system

insulitis ( J:43468 )

periinsulitis ( J:43468 )

• periinsulitis is observed in 8-week old perforin-null and heterozygous mice with little islet cell damage, compared to detection at 5 weeks in control NOD mice

decreased susceptibility to autoimmune diabetes ( J:43468 )

• female heterozygous NOD mice show a delayed incidence (median: week 27) in development of diabetes (determined by high blood glucose) with an incidence of 67% compared to early onset (median: week 19) with an incidence of 77% in control NOD mice

endocrine/exocrine glands

insulitis ( J:43468 )

periinsulitis ( J:43468 )

• periinsulitis is observed in 8-week old perforin-null and heterozygous mice with little islet cell damage, compared to detection at 5 weeks in control NOD mice

Mouse Models of Human Disease		OMIM ID	Ref(s)
Diabetes Mellitus, Insulin-Dependent; IDDM		222100	J:43468

cx7

Gzma^tm1Simn/Gzma^tm1Simn
Gzmb^tm1Ley/Gzmb^tm1Ley
Prf1^tm1Sdz/Prf1^tm1Sdz
B6.Cg-Gzma^tm1Simn Gzmb^tm1Ley Prf1^tm1Sdz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

increased sensitivity to induced morbidity/mortality ( J:90852 )

• WNV-infected triple homozygotes display prolonged mean survival time (MST) but significantly increased mortality (50%) relative to either wild-type (29%) or Prf1^tm1Sdz (18%) mice

immune system

immune system phenotype ( J:92718 )

N	• triple homozygotes develop a normal contact hypersensitivity (CHS) response (based on increase in ear thickness) to trinitrophenyl (TNP) relative to wild-type mice (J:92718)

increased susceptibility to parasitic infection ( J:81397 )

• decreased clearance and survival after infection with Trypanosoma cruzi

increased susceptibility to viral infection ( J:90852 )

• triple homozygotes display increased susceptibility to West Nile flavivirus (WNV) infection relative to wild-type

• triple mutants show a higher level of infectious virus in brain relative to wild-type or Prf1^tm1Sdz mice at the same time point

cx8

Ifng^tm1Ts/Ifng^tm1Ts
Prf1^tm1Sdz/Prf1^tm1Sdz
C.Cg-Prf1^tm1Sdz Ifng^tm1Ts

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

premature death ( J:77491 )

tumorigenesis

altered tumor morphology ( J:77491 )

• some lymphomas have an unusual histiocytic appearance with a pale eosinophilic cytoplasm

increased lymphoma incidence ( J:77491 )

• incidence is increased and onset is earlier compared to mice homozygous for Prf1^tm1Sdz alone

B cell derived lymphoma ( J:77491 )

decreased tumor latency ( J:77491 )

• incidence is increased and onset is earlier compared to mice homozygous for Prf1^tm1Sdz alone

cx9

Bmgr2^C57BL/6J/?
Prf1^tm1Sdz/Prf1^tm1Sdz
involves: 129S6/SvEvTac * C57BL/6J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

immune system

abnormal response to transplant ( J:116666 )

• increased NK cell-mediated bone marrow graft rejection

cx10

Bmgr3^{129S6/SvEvTac}/Bmgr3^{129S6/SvEvTac}
Prf1^tm1Sdz/Prf1^tm1Sdz
involves: 129S6/SvEvTac * C57BL/6J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

immune system

abnormal response to transplant ( J:116666 )

• increased NK cell-mediated bone marrow graft rejection

cx11

Bmgr4^C57BL/6J/?
Prf1^tm1Sdz/Prf1^tm1Sdz
involves: 129S6/SvEvTac * C57BL/6J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

immune system

abnormal response to transplant ( J:116666 )

• increased NK cell-mediated bone marrow graft rejection

cx12

Bmgr4^C57BL/6J/?
Ebmgr1^{129S6/SvEvTac}/Ebmgr1^{129S6/SvEvTac}
Prf1^tm1Sdz/Prf1^tm1Sdz
involves: 129S6/SvEvTac * C57BL/6J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

immune system

abnormal response to transplant ( J:116666 )

• increased NK cell-mediated bone marrow graft rejection

cx13

Ins2^Akita/Ins2^Akita
Prf1^tm1Sdz/Prf1^tm1Sdz
Rag1^tm1Mom/Rag1^tm1Mom
NOD.Cg-Rag1^tm1Mom Ins2^Akita Prf1^tm1Sdz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

complete postnatal lethality ( J:138005 )

• mice die prior to weaning

cx14

Ins2^Akita/Ins2⁺
Prf1^tm1Sdz/Prf1^tm1Sdz
Rag1^tm1Mom/Rag1^tm1Mom
NOD.Cg-Rag1^tm1Mom Ins2^Akita Prf1^tm1Sdz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:138005 )

• islets exhibit progressively altered morphology

• insulin level is lower compared to Ins2-wild-type mice at 50 days of age and continues to diminish with age

hematopoietic system

increased erythrocyte cell number ( J:138005 )

• erythrocyte/erythocyte lineages (Ter 119+) are increased as compared to NOD controls

absent mature B cells ( J:138005 )

• lacking in mutant animals

absent single-positive T cells ( J:138005 )

• mature T cells are absent in mutant animals

increased granulocyte number ( J:138005 )

• percentage of granulocytes is elevated compared to NOD/Lt

increased macrophage cell number ( J:138005 )

• percentage of granulocytes is elevated

increased monocyte cell number ( J:138005 )

• percentage of granulocytes is elevated

immune system

absent mature B cells ( J:138005 )

• lacking in mutant animals

absent single-positive T cells ( J:138005 )

• mature T cells are absent in mutant animals

increased granulocyte number ( J:138005 )

• percentage of granulocytes is elevated compared to NOD/Lt

increased macrophage cell number ( J:138005 )

• percentage of granulocytes is elevated

increased monocyte cell number ( J:138005 )

• percentage of granulocytes is elevated

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:138005 )

• spontaneously hyperglycemic mice are restored to euglycemia after receiving islet transplants at a dose of 4000 islet equivalents (IEQ) and remain euglycemic for the length of observation; at levels of 2000 and 3000 IEQ, mice display a drop in blood sugar, but eventually return to hyperglycemic status (J:138005)

abnormal glucose homeostasis ( J:138005 )

• glucose regulation is impaired as early as 3 weeks of age in nearly all mice

hyperglycemia ( J:138005 )

• male mice show greater susceptibility to develop hyperglycemia than females

cx15

Rag1^tm1Mom/Rag1^tm1Mom
Prf1^tm1Sdz/Prf1^tm1Sdz
NOD.Cg-Rag1^tm1Mom Prf1^tm1Sdz/Sz

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

premature death ( J:109843 )

• mean lifespan is 262+/-21 days

immune system

increased immature B cell number ( J:109843 )

• IgLkappa- B220+ immature B cells are increased six-fold as compared to NOD controls

decreased mature B cell number ( J:109843 )

• spleens of 8-11 week old mice are deficient in Igkappa+ B220+ T cells

increased NK cell number ( J:109843 )

• numbers of NK cells are increased in comparison to NOD controls

decreased CD4-positive T cell number ( J:109843 )

• spleens of 8-11 week old mice are deficient in CD3+ CD4+ T cells

decreased CD8-positive T cell number ( J:109843 )

• spleens of 8-11 week old mice are deficient in CD3+ CD8+ T cells

increased granulocyte number ( J:109843 )

• numbers of granulocytes are increased in comparison to NOD controls, however, in comparison to NOD-Rag^null numbers are decreased

increased macrophage cell number ( J:109843 )

• numbers of macrophages are increased in comparison to NOD controls

spleen hypoplasia ( J:109843 )

• nucleated spleen cells are reduced 14 fold in 8-11 week old mice as compared to NOD control

abnormal spleen white pulp morphology ( J:109843 )

• spleen lacks lymphoid follicles

abnormal thymus cortex morphology ( J:109843 )

• thymus lacks a clearly defined cortex

thymus hypoplasia ( J:109843 )

• lymphoid cells are severely reduced in thymuses

abnormal lymph node cortex morphology ( J:109843 )

• lymph nodes lack follicles

abnormal level of surface class II molecules ( J:109843 )

• four to five-fold decrease in cells expressing I-A^g7 as compared to NOD control

decreased immunoglobulin level ( J:109843 )

• no serum immunoglobulin is detected in 176-362 day old mice

impaired natural killer cell mediated cytotoxicity ( J:109843 )

• poly I:C stimulated spleen cells exhibit extremely low levels of NK cell cyotoxic activity

abnormal response to transplant ( J:109843 )

• following IP injection of human PMBC, peripheral blood has a fivefold increase in the percentage of human lymphoid cells as compared to NOD-Rag^null controls

• peripheral blood has a 13-fold increase in engraftment of human CD4+ T cells

• spleens have a 9-fold increase in engraftment of human CD45+ cells and a 20-fold increase in human CD4+ cells as compared to control, although there is no significant difference in engraftment of human CD8+ cells

• 6-8 weeks after IP injection, bone marrow exhibits a 12-fold increase in engraftment of human cord blood cells

tumorigenesis

T cell derived lymphoma ( J:109843 )

hematopoietic system

increased immature B cell number ( J:109843 )

• IgLkappa- B220+ immature B cells are increased six-fold as compared to NOD controls

decreased mature B cell number ( J:109843 )

• spleens of 8-11 week old mice are deficient in Igkappa+ B220+ T cells

increased NK cell number ( J:109843 )

• numbers of NK cells are increased in comparison to NOD controls

decreased CD4-positive T cell number ( J:109843 )

• spleens of 8-11 week old mice are deficient in CD3+ CD4+ T cells

decreased CD8-positive T cell number ( J:109843 )

• spleens of 8-11 week old mice are deficient in CD3+ CD8+ T cells

increased granulocyte number ( J:109843 )

• numbers of granulocytes are increased in comparison to NOD controls, however, in comparison to NOD-Rag^null numbers are decreased

increased macrophage cell number ( J:109843 )

• numbers of macrophages are increased in comparison to NOD controls

spleen hypoplasia ( J:109843 )

• nucleated spleen cells are reduced 14 fold in 8-11 week old mice as compared to NOD control

abnormal spleen white pulp morphology ( J:109843 )

• spleen lacks lymphoid follicles

abnormal thymus cortex morphology ( J:109843 )

• thymus lacks a clearly defined cortex

thymus hypoplasia ( J:109843 )

• lymphoid cells are severely reduced in thymuses

cellular

increased immature B cell number ( J:109843 )

• IgLkappa- B220+ immature B cells are increased six-fold as compared to NOD controls

cx16

Prf1^tm1Sdz/Prf1^tm1Sdz
Rag1^tm1Mom/Rag1^tm1Mom
NOD.Cg-Rag1^tm1Mom Prf1^tm1Sdz/SzJ

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

increased circulating glucose level ( J:91764 )

• streptozotocin-treated mice exhibit increased serum glucose levels that can be restored transiently to euglycemia by transplanting islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice

• 70% of streptozotocin-treated mice transplanted with islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice and HLA-A2 negative human peripheral blood mononuclear cells exhibit increased glucose serum levels

• however, all of streptozotocin-treated mice transplanted with islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice and HLA-A2 positive human peripheral blood mononuclear cells exhibit euglycemia

immune system

abnormal response to transplant ( J:91764 )

• streptozotocin-treated mice transplanted with islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice and HLA-A2 negative human peripheral blood mononuclear cells exhibit destruction of engrafted islet cells