Phenotypes Associated with This Genotype

Genotype
MGI:3707399

• Allelic Composition: Prf1^tm1Sdz/Prf1^tm1Sdz
• Genetic Background: C57BL/6-Prf1^tm1Sdz/J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cellular

lymph node necrosis ( J:92260 )

• by 10-12 days after LCMV infection, some lymph nodes exhibit necrotic changes compared to wild-type mice

decreased NK cell degranulation ( J:193137 )

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

mortality/aging

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

• mice die 2 weeks after LCMV infection

increased susceptibility to Riboviria infection induced morbidity/mortality ( J:92260 )

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

• 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

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

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

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

decreased leukocyte cell number ( J:193137 )

• in LCMV-infected mice

decreased neutrophil cell number ( J:193137 )

• lack of neutrophilia in LCMV-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 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

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

decreased 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 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

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

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 LCMV-infected mice (J:193137)

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

• in LCMV-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 LCMV-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 LCMV-infected mice (J:193137)

decreased 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

lymph node necrosis ( J:92260 )

• by 10-12 days after LCMV infection, some lymph nodes exhibit necrotic changes compared to 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 induced morbidity/mortality ( J:193137 )

• mice die 2 weeks after LCMV infection

increased susceptibility to Riboviria infection induced morbidity/mortality ( J:92260 )

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

• 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

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

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

increased susceptibility to Riboviria infection ( J:92260 , J:193137 )

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

• LCMV-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)

• LCMV-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 Picornaviridae infection ( J:120427 )

• inflammation and tissue damage in the brain are greater than in control, resistant mice at 45 and 180 days

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

behavior/neurological

behavior/neurological phenotype ( J:120427 )

N • 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

abnormal behavior ( J:120427 )

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

lethargy ( J:193137 )

• in LMCV-infected mice

hunched posture ( J:92260 , J:193137 )

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

• in LCMV-infected mice (J:193137)

decreased locomotor activity ( J:92260 )

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

hematopoietic system

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

decreased erythrocyte cell number ( J:193137 )

• in LCMV-infected mice

thrombocytopenia ( J:193137 )

• in LMCV-infected mice

decreased leukocyte cell number ( J:193137 )

• in LCMV-infected mice

decreased neutrophil cell number ( J:193137 )

• lack of neutrophilia in LCMV-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)

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 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

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

decreased 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 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

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

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 )

• 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 LCMV-infected mice (J:193137)

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

• in LCMV-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 LCMV-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 LCMV-infected mice (J:193137)

increased circulating aspartate transaminase level ( J:193137 )

• in LCMV-infected mice

increased circulating lactate dehydrogenase level ( J:193137 )

• in LCMV-infected mice

decreased 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 LCMV-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

growth/size/body

weight loss ( J:193137 )

• in LMCV-infected mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
familial hemophagocytic lymphohistiocytosis 2		DOID:0110922	OMIM:603553	J:92260 , J:193137
multiple sclerosis		DOID:2377	OMIM:612594 OMIM:612595 OMIM:612596	J:120427